1
|
Micó-Carnero M, Rojano-Alfonso C, Maroto-Serrat C, Cutrin JC, Casillas-Ramírez A, Peralta C. Relevance of the GH-VEGFB/VEGFA axis in liver grafts from brain-dead donors with alcohol-associated liver disease. Front Cell Dev Biol 2025; 12:1455258. [PMID: 39839674 PMCID: PMC11747040 DOI: 10.3389/fcell.2024.1455258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 12/16/2024] [Indexed: 01/23/2025] Open
Abstract
Introduction Grafts with alcohol-associated liver disease (ALD) subjected to prolonged cold ischaemia from donors after brain death (DBD) are typically unsuitable for transplantation. Here, we investigated the role of growth hormone (GH) in livers with ALD from DBDs and its relationship with vascular endothelial growth factor A (VEGFA) and VEGFB. Methods Livers from rats fed ethanol for 6 weeks and with brain death (BD) were cold stored for 24 h and subjected to ex vivo reperfusion. Hepatic damage and proliferative and inflammatory parameters were analysed after BD, before graft retrieval, and after reperfusion. Survival was monitored using an in vivo transplantation model. Results In DBDs, the administration of GH, which increased the levels in the intestine but not in the liver, induced the generation of both VEGFA and VEGFB in the intestine and protected against hepatic damage caused by BD before retrieving liver grafts from donors. However, VEGFA was the only factor that protected against damage after cold ischemia and reperfusion, which also increased the survival of the recipients. Discussion In conclusion, the signalling pathway and beneficial properties of the GH-VEGFA/VEGFB pathway, in which the intestine-liver axis plays a key role, were disrupted when grafts with ALD from DBDs were retrieved from donors and subjected to cold ischemia and reperfusion.
Collapse
Affiliation(s)
- Marc Micó-Carnero
- Department of Liver, Digestive System and Metabolism, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
- Universitat de Barcelona, Barcelona, Spain
| | - Carlos Rojano-Alfonso
- Department of Liver, Digestive System and Metabolism, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
- Universitat de Barcelona, Barcelona, Spain
| | - Cristina Maroto-Serrat
- Department of Liver, Digestive System and Metabolism, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
- Universitat de Barcelona, Barcelona, Spain
| | - Juan Carlos Cutrin
- Molecular Biotechnology Center II “Guido Tarone”, Department of Molecular Biotechnologies and Science for the Health, University of Torino, Torino, Italy
| | - Araní Casillas-Ramírez
- Hospital Regional de Alta Especialidad de Ciudad Victoria, IMSS-BIENESTAR, Ciudad Victoria, Mexico
- Facultad de Medicina e Ingeniería en Sistemas Computacionales de Matamoros, Universidad Autónoma de Tamaulipas, Matamoros, Mexico
| | - Carmen Peralta
- Department of Liver, Digestive System and Metabolism, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| |
Collapse
|
2
|
Yan T, Shi J. Angiogenesis and EMT regulators in the tumor microenvironment in lung cancer and immunotherapy. Front Immunol 2024; 15:1509195. [PMID: 39737184 PMCID: PMC11682976 DOI: 10.3389/fimmu.2024.1509195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 11/28/2024] [Indexed: 01/01/2025] Open
Abstract
Lung cancer remains the primary cause of cancer-related mortality, with factors such as postoperative tumor recurrence, metastasis, and therapeutic drug resistance exacerbating patient outcomes. Immunotherapy has emerged as a transformative approach, challenging conventional treatment paradigms for lung cancer. Consequently, advancing research in lung cancer immunotherapy is imperative. Recent studies indicate that numerous regulators within the tumor microenvironment (TME) drive tumor angiogenesis and epithelial-mesenchymal transition (EMT); these processes are interdependent, reciprocal, and collectively contribute to tumor progression. Tumor angiogenesis not only supplies adequate oxygen and nutrients for cellular proliferation but also establishes pathways facilitating tumor metastasis and creating hypoxic regions that foster drug resistance. Concurrently, EMT enhances metastatic potential and reinforces drug-resistance genes within tumor cells, creating a reciprocal relationship with angiogenesis. This interplay ultimately results in tumor invasion, metastasis, and therapeutic resistance. This paper reviews key regulators of angiogenesis and EMT, examining their impact on lung cancer immunotherapy and progression, and investigates whether newly identified regulators could influence lung cancer treatment, thus offering valuable insights for developing future therapeutic strategies.
Collapse
Affiliation(s)
- Taotao Yan
- Medical School of Nantong University, Nantong University, Nantong, China
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
- Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, and Research Institution of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Jiahai Shi
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
- Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, and Research Institution of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| |
Collapse
|
3
|
Li Y, Li W, Zhu X, Xu N, Meng Q, Jiang W, Zhang L, Yang M, Xu F, Li Y. VEGFB ameliorates insulin resistance in NAFLD via the PI3K/AKT signal pathway. J Transl Med 2024; 22:976. [PMID: 39468621 PMCID: PMC11520811 DOI: 10.1186/s12967-024-05621-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 08/19/2024] [Indexed: 10/30/2024] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is one of the most universal liver diseases with complicated pathogenesis throughout the world. Insulin resistance is a leading risk factor that contributes to the development of NAFLD. Vascular endothelial growth factor B (VEGFB) was described by researchers as contributing to regulating lipid metabolic disorders. Here, we investigated VEGFB as a main target to regulate insulin resistance and metabolic syndrome. METHODS In this study, bioinformatics, transcriptomics, morphological experiments, and molecular biology were used to explore the role of VEGFB in regulating insulin resistance in NAFLD and its molecular mechanism based on human samples, animal models, and cell models. RNA-seq was performed to analyze the signal pathways associated with VEGFB and NAFLD; Palmitic acid and High-fat diet were used to induce insulin-resistant HepG2 cells model and NAFLD animal model. Intracellular glucolipid contents, glucose uptake, hepatic and serum glucose and lipid levels were examined by Microassay and Elisa. Hematoxylin-eosin staining, Oil Red O staining, and Periodic acid-schiff staining were used to analyze the hepatic steatosis, lipid droplet, and glycogen content in the liver. Western blot and quantitative real-time fluorescent PCR were used to verify the expression levels of the VEGFB and insulin resistance-related signals PI3K/AKT pathway. RESULTS We observed that VEGFB is genetically associated with NAFLD and the PI3K/AKT signal pathway. After VEGFB knockout, glucolipids levels were increased, and glucose uptake ability was decreased in insulin-resistant HepG2 cells. Meanwhile, body weight, blood glucose, blood lipids, and hepatic glucose of NAFLD mice were increased, and hepatic glycogen, glucose tolerance, and insulin sensitivity were decreased. Moreover, VEGFB overexpression reduced glucolipids and insulin resistance levels in HepG2 cells. Specifically, VEGFB/VEGFR1 activates the PI3K/AKT signals by activating p-IRS1Ser307 expression, inhibiting p-FOXO1pS256 and p-GSK3Ser9 expressions to reduce gluconeogenesis and glycogen synthesis in the liver. Moreover, VEGFB could also enhance the expression level of GLUT2 to accelerate glucose transport and reduce blood glucose levels, maintaining glucose homeostasis. CONCLUSIONS Our studies suggest that VEGFB could present a novel strategy for treating NAFLD as a positive factor.
Collapse
Affiliation(s)
- Yuqi Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai, Shandong Province, China
| | - Wenhao Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai, Shandong Province, China
| | - Xiaonan Zhu
- Department of Intensive Care Medicine, The Second School of Clinical Medical, Binzhou Medical University, Yantai, Shandong, China
| | - Nuo Xu
- Department of Intensive Care Medicine, The Second School of Clinical Medical, Binzhou Medical University, Yantai, Shandong, China
| | - Qinyu Meng
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai, Shandong Province, China
| | - Wenguo Jiang
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, School of Pharmacy, Binzhou Medical University, Yantai, China
| | - Lei Zhang
- Department of Infectious Diseases, The Second School clinical Medicine, YanTai Affiliated Hospital of Bin Zhou Medical University, Yantai, China
| | - Meizi Yang
- Department of Pharmacology, School of Basic Medicine of Binzhou Medical University, Yantai, Chian, China
| | - Fang Xu
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai, Shandong Province, China.
| | - Yana Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai, Shandong Province, China.
| |
Collapse
|
4
|
Kurmanova A, Ashirbekov Y, Kurmanova G, Mamedaliyeva N, Anartayeva G, Moshkalova G, Salimbayeva D, Tulesheva A, Zhankina Z. Altered Expressions of IL-15, IFNG, and HPRT1 Genes in the Thin Endometria of Patients with Reproductive Disorders: A Prospective Comparative Study. J Clin Med 2024; 13:6184. [PMID: 39458137 PMCID: PMC11508821 DOI: 10.3390/jcm13206184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 09/23/2024] [Accepted: 10/04/2024] [Indexed: 10/28/2024] Open
Abstract
Reproductive disorders are common events in modern reproductive medicine, occurring both in spontaneous and assisted pregnancies. Studies on the molecular mechanisms of implantation disorders in thin endometria, including the study of gene transcriptional activities, have shed light on the identification of the potential biological markers of endometrial receptivity. Background/Objectives: The goal of this study was to reveal the significantly dysregulated selected gene expressions between RIF and RPL patients with thin endometria. Methods: Endometrial samples were collected from RIF patients (n = 20) and RPL patients (n = 19) during the implantation window days (LH + 7-LH + 10) of their natural menstrual cycles. Ten genes were chosen as the target genes regarding their possible relations with the implantation process. The total RNA was purified and reverse-transcribed, and gene expressions were quantified by RT-PCR. Results: The expressions of the IL-15, INFG, and HPRT1 genes were significantly decreased in the RIF patients with thin endometria compared to the RPL patients (log2 fold change = 0.92, p = 0.023 for IL-15; log2 fold change = 1.24, p = 0.046 for INFG; and log2 fold change = 0.579, p = 0.046 for HPRT1). There were no significant differences in the expressions of the CXCL8, CXCL1, MMP10, C4BPA, TNC, VEGFB, and HAND2 genes between the groups. Conclusions: Decreased expressions of the IL-15, INFG, and HPRT1 genes were found in patients with RIF with thin endometria compared to the endometria of women with RPL. This has practical significance for clinicians for the differentiated prescription of immunomodulatory therapy in patients undergoing ART programs.
Collapse
Affiliation(s)
- Almagul Kurmanova
- Faculty of Medicine and Healthcare, Al Farabi Kazakh National University, 71, Al-Farabi Avenue, 050040 Almaty, Kazakhstan
| | - Yeldar Ashirbekov
- Laboratory of Structural and Functional Genomics, M. Aitkhozhin Institute of Molecular Biology and Biochemistry, 86, Dosmukhamedov Street, 050012 Almaty, Kazakhstan
| | - Gaukhar Kurmanova
- Faculty of Medicine and Healthcare, Al Farabi Kazakh National University, 71, Al-Farabi Avenue, 050040 Almaty, Kazakhstan
| | - Nagima Mamedaliyeva
- Faculty of Medicine and Healthcare, Al Farabi Kazakh National University, 71, Al-Farabi Avenue, 050040 Almaty, Kazakhstan
| | - Gaini Anartayeva
- Faculty of Medicine and Healthcare, Al Farabi Kazakh National University, 71, Al-Farabi Avenue, 050040 Almaty, Kazakhstan
| | - Gaukhar Moshkalova
- Faculty of Medicine and Healthcare, Al Farabi Kazakh National University, 71, Al-Farabi Avenue, 050040 Almaty, Kazakhstan
| | - Damilya Salimbayeva
- Department of Science and Strategy, Scientific Center of Obstetrics, Gynecology and Perinatology, 125, Dostyk Ave., 050010 Almaty, Kazakhstan
| | - Aidana Tulesheva
- Faculty of Medicine and Healthcare, Al Farabi Kazakh National University, 71, Al-Farabi Avenue, 050040 Almaty, Kazakhstan
| | - Zhamilya Zhankina
- Faculty of Natural Sciences, Friedrich Alexander University Erlangen Nürnberg, Schlossplatz 4, 91054 Erlangen, Germany
| |
Collapse
|
5
|
Kurmanova G, Ashirbekov Y, Kurmanova A, Mamedaliyeva N, Moshkalova G, Anartayeva G, Salimbayeva D, Tulesheva A. Altered Expression of C4BPA and CXCL1 Genes in the Endometrium of Patients with Recurrent Implantation Failure after In Vitro Fertilization and Thin Endometrium. Diagnostics (Basel) 2024; 14:1967. [PMID: 39272751 PMCID: PMC11394423 DOI: 10.3390/diagnostics14171967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 08/30/2024] [Accepted: 09/04/2024] [Indexed: 09/15/2024] Open
Abstract
Currently, recurrent implantation failure (RIF) after in vitro fertilization is a problem that is commonly faced by reproductive specialists. The phenomenon of a thin endometrium in RIF patients is not yet completely understood or sufficiently treated. This study aimed to reveal the dysregulated expression of selected genes between RIF patients with a thin endometrium and fertile women. Endometrial samples were collected in the implantation window (21-24 days of the natural menstrual cycle) from RIF patients (n = 20) and fertile women (n = 14). Ten genes were chosen as target genes regarding their possible relations with the implantation process. The endometrial gene expression levels showed differences in RIF samples compared to fertile samples. Significant downregulation was observed for the CXCL1 (p = 0.005) and C4BPA (p = 0.03) genes. There was no statistically significant difference between the RIF group and the fertile group in the expression of eight genes: CXCL8, HPRT1, MMP10, INFG, VEGFB, HAND2, IL-15, and TNC (p > 0.05). The use of a combination of two markers (C4BPA + CXCL1) allows for the good discrimination of RIF patients from fertile women (AUC 0.806).
Collapse
Affiliation(s)
- Gaukhar Kurmanova
- Medicine and Healthcare Faculty, Al Farabi Kazakh National University, 71 Al-Farabi Avenue, Almaty 050040, Kazakhstan
| | - Yeldar Ashirbekov
- M. Aitkhozhin Institute of Molecular Biology and Biochemistry, 86 Dosmukhamedov Street, Almaty 050012, Kazakhstan
| | - Almagul Kurmanova
- Medicine and Healthcare Faculty, Al Farabi Kazakh National University, 71 Al-Farabi Avenue, Almaty 050040, Kazakhstan
| | - Nagima Mamedaliyeva
- Medicine and Healthcare Faculty, Al Farabi Kazakh National University, 71 Al-Farabi Avenue, Almaty 050040, Kazakhstan
| | - Gaukhar Moshkalova
- Medicine and Healthcare Faculty, Al Farabi Kazakh National University, 71 Al-Farabi Avenue, Almaty 050040, Kazakhstan
| | - Gaini Anartayeva
- Medicine and Healthcare Faculty, Al Farabi Kazakh National University, 71 Al-Farabi Avenue, Almaty 050040, Kazakhstan
| | - Damilya Salimbayeva
- Scientific Center of Obstetrics, Gynecology and Perinatology, 125 Dostyk Ave., Almaty 050010, Kazakhstan
| | - Aidana Tulesheva
- Medicine and Healthcare Faculty, Al Farabi Kazakh National University, 71 Al-Farabi Avenue, Almaty 050040, Kazakhstan
| |
Collapse
|
6
|
Su N, Zheng J, Zhang G, Guan J, Gao X, Cheng Z, Xu C, Xie D, Li Y. Molecular characterization of vascular endothelial growth factor b from spotted sea bass (Lateolabrax maculatus) and its potential roles in decreasing lipid deposition. Int J Biol Macromol 2024; 267:131507. [PMID: 38604419 DOI: 10.1016/j.ijbiomac.2024.131507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 03/15/2024] [Accepted: 04/08/2024] [Indexed: 04/13/2024]
Abstract
Vascular endothelial growth factor B (VEGFB), a member of the VEGF family, exhibits limited angiogenic activity in mammals but plays an unexpected role in targeting lipids to peripheral tissues. However, its role in lipid metabolism in fish is unknown. In this study, the vegfb gene was cloned and characterized from spotted sea bass (Lateolabrax maculatus). It encodes 254 amino acids and possesses the typical characteristics of the Vegfb family, demonstrating high homology with those from other vertebrate species. The vegfb gene exhibits the highest expression levels in the liver, followed by the gills, intestine, and adipose tissues in spotted sea bass. In vivo, high-lipid diets decreased vegfb expression and increased lipid deposition in liver of fish. In vitro, palmitic acid + oleic acid treatment or vegfb knockdown significantly increased TG and TC contents, promoting lipid droplet deposition in hepatocytes. Vegfb overexpression has the opposite effects, inhibiting lipid deposition and downregulating fatty acid transport and adipogenesis genes. In contrast, the vegfb knockdown significantly upregulated the expression levels of c/ebpα, plin2, and dgat1 (P < 0.05). These results demonstrate that Vegfb may play an important role in reducing lipid deposition by regulating fatty acid transport and adipogenesis in the hepatocytes of spotted sea bass.
Collapse
Affiliation(s)
- Ningning Su
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Jun Zheng
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Guanrong Zhang
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Junfeng Guan
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Xin Gao
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Zhiyi Cheng
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Chao Xu
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Dizhi Xie
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Yuanyou Li
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China.
| |
Collapse
|
7
|
Lang L, Liang S, Zhang F, Fu Y, Wang J, Deng K, Wang L, Gao P, Zhu C, Shu G, Wu R, Jiang Q, Wang S. Knockdown of the VEGFB/VEGFR1 signaling suppresses pubertal mammary gland development of mice via the inhibition of PI3K/Akt pathway. Int J Biol Macromol 2024; 264:130782. [PMID: 38471613 DOI: 10.1016/j.ijbiomac.2024.130782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 03/05/2024] [Accepted: 03/08/2024] [Indexed: 03/14/2024]
Abstract
Vascular endothelial growth factor B (VEGFB) has been well demonstrated to play a crucial role in regulating vascular function by binding to the VEGF receptors (VEGFRs). However, the specific role of VEGFB and VEGFRs in pubertal mammary gland development remains unclear. In this study, we observed that blocking the VEGF receptors with Axitinib suppressed the pubertal mammary gland development. Meanwhile, the proliferation of mammary epithelial cells (HC11) was repressed by blocking the VEGF receptors with Axitinib. Additionally, knockdown of VEGFR1 rather than VEGFR2 and NRP1 elicited the inhibition of HC11 proliferation, suggesting the essential role of VEGFR1 during this process. Furthermore, Axitinib or VEGFR1 knockdown led to the inhibition of the PI3K/Akt pathway. However, the inhibition of HC11 proliferation induced by Axitinib and or VEGFR1 knockdown was eliminated by the Akt activator SC79, indicating the involvement of the PI3K/Akt pathway. Finally, the knockdown of VEGFB and VEGFR1 suppressed the pubertal development of mice mammary gland with the inhibition of the PI3K/Akt pathway. In summary, the results showed that knockdown of the VEGFB/VEGFR1 signaling suppresses pubertal mammary gland development of mice via the inhibition of the PI3K/Akt pathway, which provides a new target for the regulation of pubertal mammary gland development.
Collapse
Affiliation(s)
- Limin Lang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, PR China
| | - Shuyi Liang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, PR China
| | - Fenglin Zhang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, PR China
| | - Yiming Fu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, PR China
| | - Junfeng Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, PR China
| | - Kaixin Deng
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, PR China
| | - Lina Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, PR China
| | - Ping Gao
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, PR China
| | - Canjun Zhu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, PR China
| | - Gang Shu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, PR China
| | - Ruifan Wu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, PR China
| | - Qingyan Jiang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, PR China
| | - Songbo Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, PR China; Yunfu Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Research Institute of Wens Foodstuff Group Co., Ltd., Xinxing 527400, PR China.
| |
Collapse
|
8
|
Ceci C, Lacal PM, Barbaccia ML, Mercuri NB, Graziani G, Ledonne A. The VEGFs/VEGFRs system in Alzheimer's and Parkinson's diseases: Pathophysiological roles and therapeutic implications. Pharmacol Res 2024; 201:107101. [PMID: 38336311 DOI: 10.1016/j.phrs.2024.107101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 01/25/2024] [Accepted: 02/05/2024] [Indexed: 02/12/2024]
Abstract
The vascular endothelial growth factors (VEGFs) and their cognate receptors (VEGFRs), besides their well-known involvement in physiological angiogenesis/lymphangiogenesis and in diseases associated to pathological vessel formation, play multifaceted functions in the central nervous system (CNS). In addition to shaping brain development, by controlling cerebral vasculogenesis and regulating neurogenesis as well as astrocyte differentiation, the VEGFs/VEGFRs axis exerts essential functions in the adult brain both in physiological and pathological contexts. In this article, after describing the physiological VEGFs/VEGFRs functions in the CNS, we focus on the VEGFs/VEGFRs involvement in neurodegenerative diseases by reviewing the current literature on the rather complex VEGFs/VEGFRs contribution to the pathogenic mechanisms of Alzheimer's (AD) and Parkinson's (PD) diseases. Thereafter, based on the outcome of VEGFs/VEGFRs targeting in animal models of AD and PD, we discuss the factual relevance of pharmacological VEGFs/VEGFRs modulation as a novel and potential disease-modifying approach for these neurodegenerative pathologies. Specific VEGFRs targeting, aimed at selective VEGFR-1 inhibition, while preserving VEGFR-2 signal transduction, appears as a promising strategy to hit the molecular mechanisms underlying AD pathology. Moreover, therapeutic VEGFs-based approaches can be proposed for PD treatment, with the aim of fine-tuning their brain levels to amplify neurotrophic/neuroprotective effects while limiting an excessive impact on vascular permeability.
Collapse
Affiliation(s)
- Claudia Ceci
- Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | | | - Maria Luisa Barbaccia
- Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Nicola Biagio Mercuri
- Neurology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; IRCCS Santa Lucia Foundation, Department of Experimental Neuroscience, Rome, Italy; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
| | - Grazia Graziani
- Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
| | - Ada Ledonne
- Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; IRCCS Santa Lucia Foundation, Department of Experimental Neuroscience, Rome, Italy; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
| |
Collapse
|
9
|
Li YQ, Zhang LY, Zhao YC, Xu F, Hu ZY, Wu QH, Li WH, Li YN. Vascular endothelial growth factor B improves impaired glucose tolerance through insulin-mediated inhibition of glucagon secretion. World J Diabetes 2023; 14:1643-1658. [DOI: 10.4239/wjd.v14.i11.1643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 07/11/2023] [Accepted: 09/06/2023] [Indexed: 11/14/2023] Open
Abstract
BACKGROUND Impaired glucose tolerance (IGT) is a homeostatic state between euglycemia and hyperglycemia and is considered an early high-risk state of diabetes. When IGT occurs, insulin sensitivity decreases, causing a reduction in insulin secretion and an increase in glucagon secretion. Recently, vascular endothelial growth factor B (VEGFB) has been demonstrated to play a positive role in improving glucose metabolism and insulin sensitivity. Therefore, we constructed a mouse model of IGT through high-fat diet feeding and speculated that VEGFB can regulate hyperglycemia in IGT by influencing insulin-mediated glucagon secretion, thus contributing to the prevention and cure of prediabetes.
AIM To explore the potential molecular mechanism and regulatory effects of VEGFB on insulin-mediated glucagon in mice with IGT.
METHODS We conducted in vivo experiments through systematic VEGFB knockout and pancreatic-specific VEGFB overexpression. Insulin and glucagon secretions were detected via enzyme-linked immunosorbent assay, and the protein expression of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) was determined using western blot. Further, mRNA expression of forkhead box protein O1, phosphoenolpyruvate carboxykinase, and glucose-6 phosphatase was detected via quantitative polymerase chain reaction, and the correlation between the expression of proteins was analyzed via bioinformatics.
RESULTS In mice with IGT and VEGFB knockout, glucagon secretion increased, and the protein expression of PI3K/AKT decreased dramatically. Further, in mice with VEGFB overexpression, glucagon levels declined, with the activation of the PI3K/AKT signaling pathway.
CONCLUSION VEGFB/vascular endothelial growth factor receptor 1 can promote insulin-mediated glucagon secretion by activating the PI3K/AKT signaling pathway to regulate glucose metabolism disorders in mice with IGT.
Collapse
Affiliation(s)
- Yu-Qi Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Lu-Yang Zhang
- Department of Rheumatology and Immunology, Yantaishan Hospital, Yantai 264000, Shandong Province, China
| | - Yu-Chi Zhao
- Department of Surgery, Yantaishan Hospital, Yantai 264000, Shandong Province, China
| | - Fang Xu
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Zhi-Yong Hu
- School of Public Health and Management, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Qi-Hao Wu
- The First School of Clinical Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Wen-Hao Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Ya-Nuo Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| |
Collapse
|
10
|
Li YQ, Xin L, Zhao YC, Li SQ, Li YN. Role of vascular endothelial growth factor B in nonalcoholic fatty liver disease and its potential value. World J Hepatol 2023; 15:786-796. [PMID: 37397934 PMCID: PMC10308292 DOI: 10.4254/wjh.v15.i6.786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 04/27/2023] [Accepted: 05/09/2023] [Indexed: 06/25/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) refers to fatty liver disease caused by liver injury factors other than alcohol. The disease is characterized by diffuse fat infiltration, including simple steatosis (no inflammatory fat deposition), nonalcoholic fatty hepatitis, liver fibrosis, and so on, which may cause liver cirrhosis, liver failure, and even liver cancer in the later stage of disease progression. At present, the pathogenesis of NAFLD is still being studied. The "two-hit" theory, represented by lipid metabolism disorder and inflammatory reactions, is gradually enriched by the "multiple-hit" theory, which includes multiple factors, such as insulin resistance and adipocyte dysfunction. In recent years, vascular endothelial growth factor B (VEGFB) has been reported to have the potential to regulate lipid metabolism and is expected to become a novel target for ameliorating metabolic diseases, such as obesity and type 2 diabetes. This review summarizes the regulatory role of VEGFB in the onset and development of NAFLD and illustrates its underlying molecular mechanism. In conclusion, the signaling pathway mediated by VEGFB in the liver may provide an innovative approach to the diagnosis and treatment of NAFLD.
Collapse
Affiliation(s)
- Yu-Qi Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Lei Xin
- Department of Gastrointestinal Surgery, Yantaishan Hospital, Yantai 264000, Shandong Province, China
| | - Yu-Chi Zhao
- Department of Surgery, Yantaishan Hospital, Yantai 264000, Shandong Province, China
| | - Shang-Qi Li
- The First School of Clinical Medicine, Binzhou Medical University, Yantai 264000, Shandong, China, Yantai 264000, Shandong Province, China
| | - Ya-Nuo Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| |
Collapse
|
11
|
Li X, Zhou J, Wang X, Li C, Ma Z, Wan Q, Peng F. New advances in the research of clinical treatment and novel anticancer agents in tumor angiogenesis. Biomed Pharmacother 2023; 163:114806. [PMID: 37163782 DOI: 10.1016/j.biopha.2023.114806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 04/24/2023] [Accepted: 04/30/2023] [Indexed: 05/12/2023] Open
Abstract
In 1971, Folkman proposed that tumors could be limited to very small sizes by blocking angiogenesis. Angiogenesis is the generation of new blood vessels from pre-existing vessels, considered to be one of the important processes in tumor growth and metastasis. Angiogenesis is a complex process regulated by various factors and involves many secreted factors and signaling pathways. Angiogenesis is important in the transport of oxygen and nutrients to the tumor during tumor development. Therefore, inhibition of angiogenesis has become an important strategy in the clinical management of many solid tumors. Combination therapies of angiogenesis inhibitors with radiotherapy and chemotherapy are often used in clinical practice. In this article, we will review common targets against angiogenesis, the most common and up-to-date anti-angiogenic drugs and clinical treatments in recent years, including active ingredients from chemical and herbal medicines.
Collapse
Affiliation(s)
- Xin Li
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Jianbo Zhou
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Xue Wang
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Chunxi Li
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Zifan Ma
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Qiaoling Wan
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Fu Peng
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
| |
Collapse
|
12
|
Signaling pathways and targeted therapies in lung squamous cell carcinoma: mechanisms and clinical trials. Signal Transduct Target Ther 2022; 7:353. [PMID: 36198685 PMCID: PMC9535022 DOI: 10.1038/s41392-022-01200-x] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 09/03/2022] [Accepted: 09/18/2022] [Indexed: 11/08/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related death across the world. Unlike lung adenocarcinoma, patients with lung squamous cell carcinoma (LSCC) have not benefitted from targeted therapies. Although immunotherapy has significantly improved cancer patients' outcomes, the relatively low response rate and severe adverse events hinder the clinical application of this promising treatment in LSCC. Therefore, it is of vital importance to have a better understanding of the mechanisms underlying the pathogenesis of LSCC as well as the inner connection among different signaling pathways, which will surely provide opportunities for more effective therapeutic interventions for LSCC. In this review, new insights were given about classical signaling pathways which have been proved in other cancer types but not in LSCC, including PI3K signaling pathway, VEGF/VEGFR signaling, and CDK4/6 pathway. Other signaling pathways which may have therapeutic potentials in LSCC were also discussed, including the FGFR1 pathway, EGFR pathway, and KEAP1/NRF2 pathway. Next, chromosome 3q, which harbors two key squamous differentiation markers SOX2 and TP63 is discussed as well as its related potential therapeutic targets. We also provided some progress of LSCC in epigenetic therapies and immune checkpoints blockade (ICB) therapies. Subsequently, we outlined some combination strategies of ICB therapies and other targeted therapies. Finally, prospects and challenges were given related to the exploration and application of novel therapeutic strategies for LSCC.
Collapse
|
13
|
Inflammation- and Metastasis-Related Proteins Expression Changes in Early Stages in Tumor and Non-Tumor Adjacent Tissues of Colorectal Cancer Samples. Cancers (Basel) 2022; 14:cancers14184487. [PMID: 36139645 PMCID: PMC9497293 DOI: 10.3390/cancers14184487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 09/05/2022] [Accepted: 09/14/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Non-tumor adjacent tissue plays a key role in colorectal cancer development, as well as chronic inflammation, but their role has not yet been dilucidated. In addition, inflammation is a process which is related to epithelial-mesenchymal transition and metastasis, but their changes across the different colorectal cancer stages are not fully studied. Understanding how these processes participate in all colorectal cancer phases can be key to a better understanding of the disease. Abstract Chronic inflammation can induce malignant cell transformation, having an important role in all colorectal cancer (CRC) phases. Non-tumor adjacent tissue plays an important role in tumor progression, but its implication in CRC has not yet been fully elucidated. The aim was to analyze the expression of inflammatory, epithelial-mesenchymal transition (EMT), and metastasis-related proteins in both tumor and non-tumor adjacent tissues from CRC patients by western blot. Tumor tissue presented an increase in metastasis and EMT-related proteins compared to non-tumor adjacent tissue, especially in stage II. Tumor tissue stage II also presented an increase in inflammatory-related proteins compared to other stages, which was also seen in non-tumor adjacent tissue stage II. Additionally, the relapse-free survival study of Vimentin and VEGF-B expression levels in stage II patients showed that the higher the expression levels of each protein, the lower 10-year relapse-free survival. These could suggest that some metastasis-related signalling pathways may be activated in stage II in tumor tissue, accompanied by an increase in inflammation. Furthermore, non-tumor adjacent tissue presented an increase of the inflammatory status that could be the basis for future tumor progression. In conclusion, these proteins could be useful as biomarkers of diagnosis for CRC at early stages.
Collapse
|
14
|
Sarkar J, Luo Y, Zhou Q, Ivakhnitskaia E, Lara D, Katz E, Sun MG, Guaiquil V, Rosenblatt M. VEGF receptor heterodimers and homodimers are differentially expressed in neuronal and endothelial cell types. PLoS One 2022; 17:e0269818. [PMID: 35862373 PMCID: PMC9302817 DOI: 10.1371/journal.pone.0269818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 05/29/2022] [Indexed: 11/27/2022] Open
Abstract
PURPOSE We have previously reported that VEGF-B is more potent than VEGF-A in mediating corneal nerve growth in vitro and in vivo, and this stimulation of nerve growth appears to be different from stimulation of angiogenesis by these same ligands, at least in part due to differences in VEGF receptor activation. VEGF signaling may be modulated by a number of factors including receptor number or the formation of receptor hetero- vs. homodimers. In endothelial cells, VEGF receptor heterodimer (VEGR1/R2) activation after ligand binding and subsequent phosphorylation alters the activation of downstream signaling cascades. However, our understanding of these processes in neuronal cell types remains unclear. The purpose of this study was to identify the presence and distribution of VEGF Receptor-Ligand interactions in neuronal cells as compared to endothelial cells. METHODS PC12 (rat neuronal cell line), MAEC (mouse aortic endothelial cell line), MVEC (mouse venous endothelial cell line) and HUVEC (human umbilical venous endothelial cell line; control group) were used. Cells were acutely stimulated either with VEGF-A (50 ng/μL) or VEGF-B (50 ng/μL) or "vehicle" (PBS; control group). We also isolated mouse trigeminal ganglion cells from thy1-YFP neurofluorescent mice. After treatment, cells were used as follows: (i) One group was fixed in 4% paraformaldehyde and processed for VEGFR1 and VEGFR2 immunostaining and visualized using confocal fluorescence microscopy and Total Internal Reflection (TIRF) microscopy; (ii) the second group was harvested in cell lysis buffer (containing anti-protease / anti-phosphatase cocktail), lysed and processed for immunoprecipitation (IP; Thermo Fisher IP kit) and immunoblotting (IB; LI-COR® Systems). Immunoprecipitated proteins were probed either with anti-VEGFR1 or anti-VEGFR2 IgG antibodies to evaluate VEGFR1-R2-heterodimerization; (iii) a third group of cells was also processed for Duolink Proximity Ligation Assay (PLA; Sigma) to assess the presence and distribution of VEGF-receptor homo- and heterodimers in neuronal and endothelial cells. RESULTS TIRF and fluorescence confocal microscopy revealed the presence of VEGFR1 co-localized with VEGFR2 in endothelial and PC12 neuronal cells. Cell lysates immunoprecipitated with anti-VEGFR1 further validated the existence of VEGFR1-R2 heterodimers in PC12 neuronal cells. Neuronal cells showed higher levels of VEGFR1-R2 heterodimers as compared to endothelial cells whereas endothelial cells showed higher VEGFR2-R2 homodimers compared to neuronal cells as demonstrated by Duolink PLA. Levels of VEGFR1-R1 homodimers were very low in neuronal and endothelial cells. CONCLUSIONS Differences in VEGF Receptor homo- and heterodimer distribution may explain the differential role of VEGF ligands in neuronal versus endothelial cell types. This may in turn influence VEGF activity and regulation of neuronal cell homeostasis.
Collapse
Affiliation(s)
- Joy Sarkar
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, College of Medicine, Chicago, Illinois, United States of America
| | - Yuncin Luo
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, College of Medicine, Chicago, Illinois, United States of America
| | - Qiang Zhou
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, College of Medicine, Chicago, Illinois, United States of America
| | - Evguenia Ivakhnitskaia
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, College of Medicine, Chicago, Illinois, United States of America
| | - Daniel Lara
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, College of Medicine, Chicago, Illinois, United States of America
| | - Eitan Katz
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, College of Medicine, Chicago, Illinois, United States of America
| | - Michael G. Sun
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, College of Medicine, Chicago, Illinois, United States of America
| | - Victor Guaiquil
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, College of Medicine, Chicago, Illinois, United States of America
| | - Mark Rosenblatt
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, College of Medicine, Chicago, Illinois, United States of America
| |
Collapse
|
15
|
Ling M, Lai X, Quan L, Li F, Lang L, Fu Y, Feng S, Yi X, Zhu C, Gao P, Zhu X, Wang L, Shu G, Jiang Q, Wang S. Knockdown of VEGFB/VEGFR1 Signaling Promotes White Adipose Tissue Browning and Skeletal Muscle Development. Int J Mol Sci 2022; 23:ijms23147524. [PMID: 35886871 PMCID: PMC9315609 DOI: 10.3390/ijms23147524] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 07/04/2022] [Accepted: 07/06/2022] [Indexed: 02/01/2023] Open
Abstract
It has been demonstrated that vascular endothelial growth factor B (VEGFB) and vascular endothelial growth factor receptor 1 (VEGFR1) play a vital role in regulating vascular biological function. However, the role of VEGFB and VEGFR1 in regulating fat deposition and skeletal muscle growth remains unclear. Therefore, this study was conducted to investigate the effects of VEGFB and VEGFR1 on fat deposition and skeletal muscle growth in mice. Our results showed that knockdown of VEGFB decreased body weight and iWAT index, stimulated the browning of mice iWAT with increased expression of UCP1, decreased the diameters of adipocytes, and elevated energy expenditure. In contrast, knockdown of VEGFB increased gastrocnemius (GAS) muscle index with increased proliferation of GAS muscle by expression of PCNA and Cyclin D1. Meanwhile, knockdown of endothelial VEGFR1 induced the browning of iWAT with increased expression of UCP1 and decreased diameters of adipocytes. By contrast, knockdown of endothelial VEGFR1 inhibited GAS muscle differentiation with decreased expression of MyoD. In conclusion, these results suggested that the loss of VEGFB/VEGFR1 signaling is associated with enhanced browning of inguinal white adipose tissue and skeletal muscle development. These results provided new insights into the regulation of skeletal muscle growth and regeneration, as well as fat deposition, suggesting the potential application of VEGFB/VEGFR1 as an intervention for the restriction of muscle diseases and obesity and related metabolic disorders.
Collapse
Affiliation(s)
- Mingfa Ling
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Xumin Lai
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Lulu Quan
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Fan Li
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Limin Lang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Yiming Fu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Shengchun Feng
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Xin Yi
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Canjun Zhu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Ping Gao
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Xiaotong Zhu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Lina Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Gang Shu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Qingyan Jiang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Songbo Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
- Correspondence: ; Tel.: +86-135-7051-8681
| |
Collapse
|
16
|
Gomes DA, Joubert AM, Visagie MH. In Vitro Effects of Papaverine on Cell Migration and Vascular Endothelial Growth Factor in Cancer Cell Lines. Int J Mol Sci 2022; 23:4654. [PMID: 35563045 PMCID: PMC9104338 DOI: 10.3390/ijms23094654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 04/21/2022] [Accepted: 04/21/2022] [Indexed: 02/04/2023] Open
Abstract
Papaverine (PPV) is a benzylisoquinoline alkaloid isolated from Papaver somniferum that exerts antiproliferative activity. However, several questions remain regarding the biochemical pathways affected by PPV in tumourigenic cells. In this study, the influence of PPV on cell migration (light microscopy), expression of vascular endothelial growth factor (VEGF) B, VEGF R1, VEGF R2, and phosphorylated focal adhesion kinase (pFAK) were investigated using spectrophotometry in MDA-MB-231-, A549- and DU145 cell lines. The migration assay revealed that, after 48 h, PPV (100 µM) reduced cell migration to 81%, 91%, and 71% in MDA-MB-231-, A549-, and DU145 cells, respectively. VEGF B expression was reduced to 0.79-, 0.71-, and 0.73-fold after 48 h of exposure to PPV in MDA-MB-231-, A549- and DU145 cells, while PPV exposure of 48 h increased VEGF R1 expression in MDA-MB-231- and DU145 cells to 1.38 and 1.46. A fold decrease in VEGF R1 expression was observed in A549 cells to 0.90 after exposure to 150 µM. No statistically significant effects were observed on VEGF R2- and FAK expression after exposure to PPV. This study contributes to the understanding of the effects of a phytomedicinal alkaloid compound in cancer cells and may provide novel approaches to the application of non-addictive alkaloids.
Collapse
Affiliation(s)
| | | | - Michelle Helen Visagie
- Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Gezina, Pretoria 0031, South Africa; (D.A.G.); (A.M.J.)
| |
Collapse
|
17
|
Jia JD, Jiang WG, Luo X, Li RR, Zhao YC, Tian G, Li YN. Vascular endothelial growth factor B inhibits insulin secretion in MIN6 cells and reduces Ca 2+ and cyclic adenosine monophosphate levels through PI3K/AKT pathway. World J Diabetes 2021; 12:480-498. [PMID: 33889292 PMCID: PMC8040075 DOI: 10.4239/wjd.v12.i4.480] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/25/2021] [Accepted: 03/08/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Type 2 diabetes (T2D) is characterized by insufficient insulin secretion caused by defective pancreatic β-cell function or insulin resistance, resulting in an increase in blood glucose. However, the mechanism involved in this lack of insulin secretion is unclear. The level of vascular endothelial growth factor B (VEGF-B) is significantly increased in T2D patients. The inactivation of VEGF-B could restore insulin sensitivity in db/db mice by reducing fatty acid accumulation. It is speculated that VEGF-B is related to pancreatic β-cell dysfunction and is an important factor affecting β-cell secretion of insulin. As an in vitro model of normal pancreatic β-cells, the MIN6 cell line can be used to analyze the mechanism of insulin secretion and related biological effects.
AIM To study the role of VEGF-B in the insulin secretion signaling pathway in MIN6 cells and explore the effect of VEGF-B on blood glucose regulation.
METHODS The MIN6 mouse pancreatic islet β-cell line was used as the model system. By administering exogenous VEGF-B protein or knocking down VEGF-B expression in MIN6 cells, we examined the effects of VEGF-B on insulin secretion, Ca2+ and cyclic adenosine monophosphate (cAMP) levels, and the insulin secretion signaling pathway.
RESULTS Exogenous VEGF-B inhibited the secretion of insulin and simultaneously reduced the levels of Ca2+ and cAMP in MIN6 cells. Exogenous VEGF-B also reduced the expression of phospholipase C gamma 1 (PLCγ1), phosphatidylinositol 3-kinase (PI3K), serine/threonine kinase (AKT), and other proteins in the insulin secretion pathway. Upon knockdown of VEGF-B, MIN6 cells exhibited increased insulin secretion and Ca2+ and cAMP levels and upregulated expression of PLCγ1, PI3K, AKT, and other proteins.
CONCLUSION VEGF-B can regulate insulin secretion by modulating the levels of Ca2+ and cAMP. VEGF-B involvement in insulin secretion is related to the expression of PLCγ1, PI3K, AKT, and other signaling proteins. These results provide theoretical support and an experimental basis for the study of VEGF-B in the pathogenesis of T2D.
Collapse
Affiliation(s)
- Jing-Dan Jia
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264003, Shandong Province, China
| | - Wen-Guo Jiang
- Department of Pharmacy, Binzhou Medical University, Yantai 264003, Shandong Province, China
| | - Xu Luo
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264003, Shandong Province, China
| | - Rong-Rong Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264003, Shandong Province, China
| | - Yu-Chi Zhao
- Department of Surgery, Yantaishan Hospital, Yantai 264001, Shandong Province, China
| | - Geng Tian
- Department of Pharmacy, Binzhou Medical University, Yantai 264003, Shandong Province, China
| | - Ya-Na Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264003, Shandong Province, China
| |
Collapse
|
18
|
Llorián-Salvador M, Barabas P, Byrne EM, Lechner J, Augustine J, Curtis TM, Chen M, Xu H. VEGF-B Is an Autocrine Gliotrophic Factor for Müller Cells under Pathologic Conditions. Invest Ophthalmol Vis Sci 2021; 61:35. [PMID: 32945843 PMCID: PMC7509798 DOI: 10.1167/iovs.61.11.35] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Purpose Müller glia are important in retinal health and disease and are a major source of retinal VEGF-A. Of the different VEGF family members, the role of VEGF-A in retinal health and disease has been studied extensively. The potential contribution of other VEGF family members to retinal pathophysiology, however, remains poorly defined. This study aimed to understand the role of VEGF-B in Müller cell pathophysiology. Methods The expression of different VEGFs and their receptors in human MIO-M1 and mouse QMMuC-1 Müller cell lines and primary murine Müller cells was examined by RT-PCR, ELISA, and Western blot. The effect of recombinant VEGF-B or VEGF-B neutralization on Müller cell viability and survival under normal, hypoxic, and oxidative (4-hydroxynonenal [4-HNE]) conditions was evaluated by Alamar Blue, Yo-Pro uptake, and immunocytochemistry. The expression of glial fibrillary acidic protein, aquaporin-4, inward rectifying K+ channel subtype 4.1, glutamine synthetase, and transient receptor potential vanilloid 4 under different treatment conditions was examined by RT-PCR, immunocytochemistry, and Western blot. Transient receptor potential vanilloid 4 channel activity was assessed using a Fura-2–based calcium assay. Results VEGF-B was expressed in Müller cells at the highest levels compared with other members of the VEGF family. VEGF-B neutralization did not affect Müller cell viability or functionality under normal conditions, but enhanced hypoxia– or 4-HNE–induced Müller cell death and decreased inward rectifying K+ channel subtype 4.1 and aquaporin-4 expression. Recombinant VEGF-B restored Müller cell glutamine synthetase expression under hypoxic conditions and protected Müller cells from 4-HNE–induced damage by normalizing transient receptor potential vanilloid 4 channel expression and activity. Conclusions Autocrine production of VEGF-B protects Müller cells under pathologic conditions.
Collapse
Affiliation(s)
- María Llorián-Salvador
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, BT9 7BL. Belfast, United Kingdom
| | - Peter Barabas
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, BT9 7BL. Belfast, United Kingdom
| | - Eimear M Byrne
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, BT9 7BL. Belfast, United Kingdom
| | - Judith Lechner
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, BT9 7BL. Belfast, United Kingdom
| | - Josy Augustine
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, BT9 7BL. Belfast, United Kingdom
| | - Timothy M Curtis
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, BT9 7BL. Belfast, United Kingdom
| | - Mei Chen
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, BT9 7BL. Belfast, United Kingdom
| | - Heping Xu
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, BT9 7BL. Belfast, United Kingdom
| |
Collapse
|
19
|
Ureña-Guerrero ME, Castañeda-Cabral JL, Rivera-Cervantes MC, Macias-Velez RJ, Jarero-Basulto JJ, Gudiño-Cabrera G, Beas-Zárate C. Neuroprotective and Neurorestorative Effects of Epo and VEGF: Perspectives for New Therapeutic Approaches to Neurological Diseases. Curr Pharm Des 2020; 26:1263-1276. [PMID: 31942853 DOI: 10.2174/1381612826666200114104342] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 11/27/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Erythropoietin (Epo) and vascular endothelial growth factor (VEGF) are two vasoactive molecules with essential trophic effects for brain development. The expression and secretion of both molecules increase in response to neuronal damage and they exert protective and restorative effects, which may also be accompanied by adverse side effects. OBJECTIVE We review the most relevant evidence on the neuroprotective and neurorestorative effects of Epo and VEGF in three of the most frequent neurological disorders, namely, stroke, epilepsy and Alzheimer's disease, to develop new therapeutic approaches. METHODS Several original scientific manuscripts and reviews that have discussed the evidence in critical way, considering both the beneficial and adverse effects of Epo and VEGF in the selected neurological disorders, were analysed. In addition, throughout this review, we propose several considerations to take into account in the design of therapeutic approaches based on Epo and VEGF signalling. RESULTS Although the three selected disorders are triggered by different mechanisms, they evolve through similar processes: excitotoxicity, oxidative stress, neuroinflammation, neuronal death, glial reactivity and vascular remodelling. Epo and VEGF exert neuroprotective and neurorestorative effects by acting on these processes due to their pleiotropism. In general, the evidence shows that both Epo and VEGF reduce neuronal death but that at the vascular level, their effects are contradictory. CONCLUSION Because the Epo and VEGF signalling pathways are connected in several ways, we conclude that more experimental studies, primarily studies designed to thoroughly assess the functional interactions between Epo and VEGF in the brain under both physiological and pathophysiological conditions, are needed.
Collapse
Affiliation(s)
- Mónica E Ureña-Guerrero
- Departamento de Biologia Celular y Molecular, Centro Universitario de Ciencias Biologicas y Agropecuarias (CUCBA), Universidad de Guadalajara, Zapopan, Jalisco, Mexico
| | - José L Castañeda-Cabral
- Departamento de Biologia Celular y Molecular, Centro Universitario de Ciencias Biologicas y Agropecuarias (CUCBA), Universidad de Guadalajara, Zapopan, Jalisco, Mexico.,Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados (CINVESTAV sede Sur), IPN, Ciudad de México, México
| | - Martha C Rivera-Cervantes
- Departamento de Biologia Celular y Molecular, Centro Universitario de Ciencias Biologicas y Agropecuarias (CUCBA), Universidad de Guadalajara, Zapopan, Jalisco, Mexico
| | - Rafael J Macias-Velez
- Departamento de Biologia Celular y Molecular, Centro Universitario de Ciencias Biologicas y Agropecuarias (CUCBA), Universidad de Guadalajara, Zapopan, Jalisco, Mexico
| | - José J Jarero-Basulto
- Departamento de Biologia Celular y Molecular, Centro Universitario de Ciencias Biologicas y Agropecuarias (CUCBA), Universidad de Guadalajara, Zapopan, Jalisco, Mexico
| | - Graciela Gudiño-Cabrera
- Departamento de Biologia Celular y Molecular, Centro Universitario de Ciencias Biologicas y Agropecuarias (CUCBA), Universidad de Guadalajara, Zapopan, Jalisco, Mexico
| | - Carlos Beas-Zárate
- Departamento de Biologia Celular y Molecular, Centro Universitario de Ciencias Biologicas y Agropecuarias (CUCBA), Universidad de Guadalajara, Zapopan, Jalisco, Mexico
| |
Collapse
|
20
|
Ye X, Kong W, Zafar MI, Zeng J, Yang R, Chen LL. Plasma vascular endothelial growth factor B is elevated in non-alcoholic fatty liver disease patients and associated with blood pressure and renal dysfunction. EXCLI JOURNAL 2020; 19:1186-1195. [PMID: 33408593 PMCID: PMC7783472 DOI: 10.17179/excli2020-2647] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 08/17/2020] [Indexed: 01/02/2023]
Abstract
Vascular endothelial growth factor B (VEGF-B) is a critical metabolic regulator in insulin resistance, and lipid distribution. We intended to ascertain the relationship between circulating VEGF-B and non-alcoholic fatty liver disease (NAFLD) in the general public. We recruited a total of 194 general participants for a routine physical health examination; of these, 84 participants were identified with NAFLD and 110 without NAFLD based on ultrasonographic findings. Homeostasis model assessment of insulin resistance (HOMA-IR), body mass index (BMI), HbA1c, liver function, kidney function, plasma VEGF-B levels and indexes of metabolic syndrome (blood pressure, fasting plasma glucose, fasting lipids) were evaluated. Plasma VEGF-B values were significantly higher in individuals with NAFLD compared to those without NAFLD (P = 0.022), and analysis of covariance confirmed this result. VEGF-B showed a positive correlation with γ-glutamyl transpeptidase (γ-GT) and HOMA-IR in univariate analysis (q = 0.242; P = 0.001; q =0.174; P = 0.019, respectively). Multiple linear regression analysis showed that γ-GT and ALT were independently correlated with VEGF-B even after adjusted for gender and age (q = 0.286; P = 0.01; q =0.237; P = 0.033, respectively). Moreover, plasma VEGF-B showed a powerful correlation with blood pressure and renal dysfunction. Plasma VEGF-B might be a new clinical variable related to NAFLD and could be a proper biomarker for the early detection of hypertension and renal dysfunction. However, further studies with large cohorts' size are warranted to validate our findings.
Collapse
Affiliation(s)
- Xiaofeng Ye
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.,Hubei provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan 430022, China
| | - Wen Kong
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.,Hubei provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan 430022, China
| | - Mohammad Ishraq Zafar
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Junchao Zeng
- Healthcare Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Rui Yang
- Healthcare Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Lu-Lu Chen
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.,Hubei provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan 430022, China
| |
Collapse
|
21
|
Dmytriyeva O, de Diego Ajenjo A, Lundø K, Hertz H, Rasmussen KK, Christiansen AT, Klingelhofer J, Nielsen AL, Hoeber J, Kozlova E, Woldbye DPD, Pankratova S. Neurotrophic Effects of Vascular Endothelial Growth Factor B and Novel Mimetic Peptides on Neurons from the Central Nervous System. ACS Chem Neurosci 2020; 11:1270-1282. [PMID: 32283014 DOI: 10.1021/acschemneuro.9b00685] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Vascular endothelial growth factor B (VEGFB) is a pleiotropic trophic factor, which in contrast to the closely related VEGFA is known to have a limited effect on angiogenesis. VEGFB improves survival in various tissues including the nervous system, where the effect was observed mainly for peripheral neurons. The neurotrophic effect of VEGFB on central nervous system neurons has been less investigated. Here we demonstrated that VEGFB promotes neurite outgrowth from primary cerebellar granule, hippocampal, and retinal neurons in vitro. VEGFB protected hippocampal and retinal neurons from both oxidative stress and glutamate-induced neuronal death. The VEGF receptor 1 (VEGFR1) is required for VEGFB-induced neurotrophic and neuroprotective effects. Using a structure-based approach, we designed short peptides, termed Vefin1-7, mimicking the binding interface of VEGFB to VEGFR1. Vefins were analyzed for their secondary structure and binding to VEGF receptors and compared with previously described peptides derived from VEGFA, another ligand of VEGFR1. We show that Vefins have neurotrophic and neuroprotective effects on primary hippocampal, cerebellar granule, and retinal neurons in vitro with potencies comparable to VEGFB. Similar to VEGFB, Vefins were not mitogenic for MCF-7 cancer cells. Furthermore, one of the peptides, Vefin7, even dose-dependently inhibited the proliferation of MCF-7 cells in vitro. Unraveling the neurotrophic and neuroprotective potentials of VEGFB, the only nonangiogenic factor of the VEGF family, is promising for the development of neuroprotective peptide-based therapies.
Collapse
Affiliation(s)
- Oksana Dmytriyeva
- Laboratory of Neural Plasticity, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
- Laboratory for Molecular Pharmacology, Department of Biomedical Science and Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Amaia de Diego Ajenjo
- Laboratory of Neural Plasticity, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Kathrine Lundø
- Laboratory of Neural Plasticity, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Henrik Hertz
- Laboratory of Neuropsychiatry, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Kim K. Rasmussen
- Laboratory of Neural Plasticity, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Anders T. Christiansen
- Laboratory of Neural Plasticity, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Jorg Klingelhofer
- Laboratory of Neural Plasticity, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Alexander L. Nielsen
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark
| | - Jan Hoeber
- Department of Neuroscience, Uppsala University, Uppsala 75124, Sweden
| | - Elena Kozlova
- Department of Neuroscience, Uppsala University, Uppsala 75124, Sweden
| | - David P. D. Woldbye
- Laboratory of Neural Plasticity, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Stanislava Pankratova
- Laboratory of Neural Plasticity, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
- Research Laboratory for Stereology and Neuroscience, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Copenhagen 2200, Denmark
| |
Collapse
|
22
|
Zhang X, Wu J, Wu C, Bian AL, Geng S, Dai RP. Comparison of aqueous humor levels of PlGF and VEGF in proliferative diabetic retinopathy before and after intravitreal conbercept injection. Diabetes Res Clin Pract 2020; 162:108083. [PMID: 32057965 DOI: 10.1016/j.diabres.2020.108083] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Revised: 02/05/2020] [Accepted: 02/10/2020] [Indexed: 01/02/2023]
Abstract
AIMS The aim of this paper is to observe the change of aqueous humor levels of placenta growth factor (PlGF) and vascular endothelial growth factor (VEGF) in proliferative diabetic retinopathy (PDR) patients before and one week after intravitreal conbercept injection. METHODS A prospective case series study was conducted in 24 active PDR patients (24 eyes). All the patients had received 0.5 mg of intravitreal conbercept followed by vitrectomy one week later. The aqueous humor was collected before conbercept injection and at the beginning of vitrectomy. RESULTS Before conbercept injection, the aqueous humor median levels of VEGF-A, VEGF-B and PlGF were457.0pg/mL(IQRfrom392.9to860.6pg/mL), 43.6pg/mL(IQRfrom33.6to81.6pg/mL), 37.5pg/mL(IQRfrom25.0to53.6pg/mL), respectively. One week after conbercept injection, the aqueous humor levels of VEGF-A, VEGF-B and PiGF decreased significantly. The aqueous humor VEGF-A levels in PDR patients with fibrovascular membranes were lower than those without them. There was positive correlation between aqueous humor VEGF-B and PiGF levels (P = 0.007). No significant correlation was found between VEGF-A and PiGF levels. No ocular and systemic adverse events were observed. CONCLUSIONS The aqueous humor levels of PlGF was correlated with VEGF-B, and levels of VEGF-A, VEGF-B, and PlGF decreased after intravitreal conbercept injection in active PDR patients.
Collapse
Affiliation(s)
- Xiao Zhang
- Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Jie Wu
- Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Chan Wu
- Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Ai-Ling Bian
- Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Shuang Geng
- Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Rong-Ping Dai
- Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
| |
Collapse
|
23
|
Zhao W, Cao L, Ying H, Zhang W, Li D, Zhu X, Xue W, Wu S, Cao M, Fu C, Qi H, Hao Y, Tang YC, Qin J, Zhong TP, Lin X, Yu L, Li X, Li L, Wu D, Pan W. Endothelial CDS2 deficiency causes VEGFA-mediated vascular regression and tumor inhibition. Cell Res 2019; 29:895-910. [PMID: 31501519 PMCID: PMC6889172 DOI: 10.1038/s41422-019-0229-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 08/23/2019] [Indexed: 01/06/2023] Open
Abstract
The response of endothelial cells to signaling stimulation is critical for vascular morphogenesis, homeostasis and function. Vascular endothelial growth factor-a (VEGFA) has been commonly recognized as a pro-angiogenic factor in vertebrate developmental, physiological and pathological conditions for decades. Here we report a novel finding that genetic ablation of CDP-diacylglycerol synthetase-2 (CDS2), a metabolic enzyme that controls phosphoinositide recycling, switches the output of VEGFA signaling from promoting angiogenesis to unexpectedly inducing vessel regression. Live imaging analysis uncovered the presence of reverse migration of the angiogenic endothelium in cds2 mutant zebrafish upon VEGFA stimulation, and endothelium regression also occurred in postnatal retina and implanted tumor models in mice. In tumor models, CDS2 deficiency enhanced the level of tumor-secreted VEGFA, which in-turn trapped tumors into a VEGFA-induced vessel regression situation, leading to suppression of tumor growth. Mechanistically, VEGFA stimulation reduced phosphatidylinositol (4,5)-bisphosphate (PIP2) availability in the absence of CDS2-controlled-phosphoinositide metabolism, subsequently causing phosphatidylinositol (3,4,5)-triphosphate (PIP3) deficiency and FOXO1 activation to trigger regression of CDS2-null endothelium. Thus, our data indicate that the effect of VEGFA on vasculature is context-dependent and can be converted from angiogenesis to vascular regression.
Collapse
Affiliation(s)
- Wencao Zhao
- Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), Shanghai, China
| | - Le Cao
- Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), Shanghai, China
| | - Hanru Ying
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China
| | - Wenjuan Zhang
- Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), Shanghai, China
| | - Dantong Li
- Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), Shanghai, China
| | - Xiaolong Zhu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Molecular Medicine, East China Normal University School of Life Sciences, Shanghai, China
| | - Wenzhi Xue
- Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), Shanghai, China
| | - Shuang Wu
- Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), Shanghai, China
| | - Mengye Cao
- Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), Shanghai, China
| | - Cong Fu
- Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), Shanghai, China
| | - Haonan Qi
- Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), Shanghai, China
| | - Yimei Hao
- Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), Shanghai, China
| | - Yun-Chi Tang
- Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), Shanghai, China
| | - Jun Qin
- Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), Shanghai, China
| | - Tao P Zhong
- Shanghai Key Laboratory of Regulatory Biology, Institute of Molecular Medicine, East China Normal University School of Life Sciences, Shanghai, China
| | - Xiaoxi Lin
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China.,Innovative Research Team of High-level Local University in Shanghai, Shanghai, China
| | - Luyang Yu
- Institute of Genetics, College of Life Sciences, Zhejiang University, Hangzhou, China
| | - Xuri Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Lin Li
- State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, CAS, Shanghai, China
| | - Dianqing Wu
- Department of Pharmacology, Vascular Biology and Therapeutic Program, School of Medicine, Yale University, New Haven, CT, USA
| | - Weijun Pan
- Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), Shanghai, China. .,Innovative Research Team of High-level Local University in Shanghai, Shanghai, China.
| |
Collapse
|
24
|
Li LJ, Ma J, Li SB, Chen X, Zhang J. Vascular endothelial growth factor B inhibits lipid accumulation in C2C12 myotubes incubated with fatty acids. Growth Factors 2019; 37:76-84. [PMID: 31215273 DOI: 10.1080/08977194.2019.1626851] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
To investigate (1) the effect of vascular endothelial growth factor B (VEGFB) on lipid accumulation and the alteration of fatty acids and fatty acid-related enzymes in C2C12 myotubes incubated with fatty acids and (2) the regulatory effect of VEGFB on skeletal muscle lipid metabolism. Mouse C2C12 myotubes were incubated with oleic acid (OA) and palmitic acid (PA), and differentiated mature C2C12 myotubes were treated with VEGFB. Oil-red O staining, BODIPY staining and cell triglycerides (TG) content were examined. Total RNA was isolated, and real-time PCR analysis was performed. Treatment with 100 μM OA and 50 μM PA induced lipid droplet accumulation and increased TG content (p < .01), and 100 ng/mL VEGFB reduced lipid droplet accumulation and decreased TG content (p < .01). Treatment with 100 ng/mL VEGFB significantly induced the mRNA expression of fatty acid transport protein 1 (FATP1) (p < .01) and FATP4 (p < .01). Treatment with 100 ng/mL VEGFB significantly induced the mRNA expression of adipose TG lipase and hormone-sensitive lipase (p < .01) as well as carnitine palmitoyltransferase I (p < .01), peroxisome proliferator-activated receptor-γ coactivator-1α (p < .01), acyl-coa dehydrogenase very long chain (p < .05), acyl-coa synthetase long-chain family member 1 (p < .01), peroxisomal acyl-coenzyme A oxidase 1 (p < .05), and mitochondrial uncoupling protein 3 (p < .01). VEGFB enhanced FATP1and FATP4 expression, promoted C2C12 myotube fatty acid oxidation and TG decomposition, and inhibited C2C12 myotube fatty acid re-esterification, thus inhibiting lipid accumulation in C2C12 myotubes incubated with fatty acids.
Collapse
Affiliation(s)
- Ling-Jie Li
- a College of P.E. and Sports, Beijing Normal University , Beijing , China
| | - Jin Ma
- a College of P.E. and Sports, Beijing Normal University , Beijing , China
| | - Song-Bo Li
- b China Academy of Sport and Health Science, Beijing Sport University , Beijing , China
| | - Xuefei Chen
- a College of P.E. and Sports, Beijing Normal University , Beijing , China
| | - Jing Zhang
- a College of P.E. and Sports, Beijing Normal University , Beijing , China
| |
Collapse
|
25
|
Chen R, Lee C, Lin X, Zhao C, Li X. Novel function of VEGF-B as an antioxidant and therapeutic implications. Pharmacol Res 2019; 143:33-39. [PMID: 30851357 DOI: 10.1016/j.phrs.2019.03.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Revised: 03/01/2019] [Accepted: 03/01/2019] [Indexed: 12/14/2022]
Abstract
Oxidative stress, due to insufficiency of antioxidants or over-production of oxidants, can lead to severe cell and tissue damage. Oxidative stress occurs constantly and has been shown to be involved in innumerable diseases, such as degenerative, cardiovascular, neurological, and metabolic disorders, cancer, and aging, thus highlighting the vital need of antioxidant defense mechanisms. Vascular endothelial growth factor B (VEGF-B) was discovered a long time ago, and is abundantly expressed in most types of cells and tissues. VEGF-B remained functionally mysterious for many years and later on has been shown to be minimally angiogenic. Recently, VEGF-B is reported to be a potent antioxidant by boosting the expression of key antioxidant enzymes. Thus, one major role of VEGF-B lies in safeguarding tissues and cells from oxidative stress-induced damage. VEGF-B may therefore have promising therapeutic utilities in treating oxidative stress-related diseases. In this review, we discuss the current knowledge on the newly discovered antioxidant function of VEGF-B and the related molecular mechanisms, particularly, in relationship to some oxidative stress-related diseases, such as retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy, glaucoma, amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease.
Collapse
Affiliation(s)
- Rongyuan Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Chunsik Lee
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Xianchai Lin
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Chen Zhao
- Eye Institute, Eye and ENT Hospital, Shanghai Medical College, Fudan University, China; Key Laboratory of Myopia of State Health Ministry (Fudan University) and Shanghai Key Laboratory of Visual Impairment and Restoration, 200023, Shanghai, China.
| | - Xuri Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
| |
Collapse
|
26
|
Potential effect on molecular pathways in different targeted genes in the VEGF family in retina - From the genomic point of view. Exp Eye Res 2018; 176:78-87. [PMID: 29944851 DOI: 10.1016/j.exer.2018.06.024] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Revised: 06/03/2018] [Accepted: 06/22/2018] [Indexed: 01/13/2023]
Abstract
This study's goal is to determine similarities and differences in the molecular pathways or potential functions of the various targeted regions or genes of the Vegf family-VegfA, VegfB, VegfC, and Pgf-using the BXD genetic reference panel. Data from whole genome expression profiles of retinas from the well-characterized mouse recombinant inbred (RI) strain population derived from C57BL/6J X DBA/2J (BXD) were analyzed. Multiple analytical tools and statistical strategies were used to investigate the expression level. The expression Quantitative Trait Loci (QTLs) of these probes were mapped and compared. Our data showed that VegfA2 has the highest expression levels among all probes of Vegf genes. The expression levels of Vegf family genes are not significantly correlated. In the overall comparison, expression levels of VegfA1 and VegfA2 are positively correlated (R = 0.540). The expression levels of VegfB and VegfC are weakly correlated (R = 0.360). VegfC is also weakly correlated with the expression levels of Pgf (R = 0.324). The interaction of VegfB- and VegfA2-associated 50a2 genes was very weak (R50 ab = 0.3129). The interaction of top VegfB-associated 50b genes with VegfA2 has a reciprocal negative impact (R50ba = -0.42758). The VegfC-associated top 50c genes are strongly correlated with VegfB (R50 cb = 0.8159), while they are negatively correlated with VegfA2 (R50ca = -0.1450). Expression quantitative trait loci (eQTL) analysis suggested that the regulatory mechanisms for the expression levels of these genes in the Vegf family are different from each other. The expression level of VegfA associates with a group of genes that are not associated with other genes in the Vegf family.
Collapse
|
27
|
Ding Z, Cao J, Shen Y, Zou Y, Yang X, Zhou W, Guo Q, Huang C. Resveratrol Promotes Nerve Regeneration via Activation of p300 Acetyltransferase-Mediated VEGF Signaling in a Rat Model of Sciatic Nerve Crush Injury. Front Neurosci 2018; 12:341. [PMID: 29875625 PMCID: PMC5974253 DOI: 10.3389/fnins.2018.00341] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 05/02/2018] [Indexed: 12/25/2022] Open
Abstract
Peripheral nerve injuries are generally associated with incomplete restoration of motor function. The slow rate of nerve regeneration after injury may account for this. Although many benefits of resveratrol have been shown in the nervous system, it is not clear whether resveratrol could promote fast nerve regeneration and motor repair after peripheral nerve injury. This study showed that the motor deficits caused by sciatic nerve crush injury were alleviated by daily systematic resveratrol treatment within 10 days. Resveratrol increased the number of axons in the distal part of the injured nerve, indicating enhanced nerve regeneration. In the affected ventral spinal cord, resveratrol enhanced the expression of several vascular endothelial growth factor family proteins (VEGFs) and increased the phosphorylation of p300 through Akt signaling, indicating activation of p300 acetyltransferase. Inactivation of p300 acetyltransferase reversed the resveratrol-induced expression of VEGFs and motor repair in rats that had undergone sciatic nerve crush injury. The above results indicated that daily systematic resveratrol treatment promoted nerve regeneration and led to rapid motor repair. Resveratrol activated p300 acetyltransferase-mediated VEGF signaling in the affected ventral spinal cord, which may have thus contributed to the acceleration of nerve regeneration and motor repair.
Collapse
Affiliation(s)
- Zhuofeng Ding
- Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, China
| | - Jiawei Cao
- Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, China
| | - Yu Shen
- Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, China
| | - Yu Zou
- Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, China
| | - Xin Yang
- Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, China
| | - Wen Zhou
- Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, China
| | - Qulian Guo
- Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, China
| | - Changsheng Huang
- Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, China
| |
Collapse
|
28
|
Varricchi G, Loffredo S, Galdiero MR, Marone G, Cristinziano L, Granata F, Marone G. Innate effector cells in angiogenesis and lymphangiogenesis. Curr Opin Immunol 2018; 53:152-160. [PMID: 29778674 DOI: 10.1016/j.coi.2018.05.002] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 05/02/2018] [Accepted: 05/03/2018] [Indexed: 12/12/2022]
Abstract
Angiogenesis and lymphangiogenesis are distinct and complex processes requiring a finely tuned balance between stimulatory and inhibitory signals. During adulthood, angiogenesis and lymphangiogenesis are activated at sites of tumor growth, tissue injury and remodeling, and chronic inflammation. Vascular endothelial growth factors (VEGFs), angiopoietin (ANGPTs) and a multitude of additional signaling molecules play distinct roles in the modulation of angiogenesis/lymphangiogenesis. VEGFs and ANGPTs activate specific tyrosine kinase receptor (e.g., VEGFR1, VEGFR-2, VEGFR-3 and TIE2 respectively), expressed on blood endothelial cells (angiogenesis) and lymphatic endothelial cells (lymphangiogenesis). Although tumor cells produce VEGFs and other proangiogenic mediators, tissue resident (e.g., macrophages, mast cells) and circulating immune cells (e.g., basophils, neutrophils, monocytes, eosinophils) are an important source of angiogenic/lymphangiogenic mediators in inflammation and in tumor microenvironment and at site of chronic inflammation. Certain immune cells can also release anti-angiogenic factors. Mast cells, basophils, neutrophils and presumably other immune cells are not only a source of angiogenic/lymphangiogenic molecules, but also their target. Cells of the immune system need consideration as major players and possible targets for therapeutic manipulation of angiogenesis/lymphangiogenesis in chronic inflammatory disorders and tumors.
Collapse
Affiliation(s)
- Gilda Varricchi
- Department of Traslational Medicine, University of Naples Federico II, Naples, Italy; Center for Basic and Clinical Immunology Research (CISI), Naples, Italy; World Allergy Organization (WAO), Center of Excellence, Naples, Italy.
| | - Stefania Loffredo
- Department of Traslational Medicine, University of Naples Federico II, Naples, Italy; Center for Basic and Clinical Immunology Research (CISI), Naples, Italy; World Allergy Organization (WAO), Center of Excellence, Naples, Italy
| | - Maria Rosaria Galdiero
- Department of Traslational Medicine, University of Naples Federico II, Naples, Italy; Center for Basic and Clinical Immunology Research (CISI), Naples, Italy; World Allergy Organization (WAO), Center of Excellence, Naples, Italy
| | - Giancarlo Marone
- Department of Public Health, Section of Hygiene, University of Naples Federico II, Naples, Italy; Monaldi Hospital Pharmacy, Naples, Italy
| | - Leonardo Cristinziano
- Department of Traslational Medicine, University of Naples Federico II, Naples, Italy; Center for Basic and Clinical Immunology Research (CISI), Naples, Italy
| | - Francescopaolo Granata
- Department of Traslational Medicine, University of Naples Federico II, Naples, Italy; Center for Basic and Clinical Immunology Research (CISI), Naples, Italy; World Allergy Organization (WAO), Center of Excellence, Naples, Italy
| | - Gianni Marone
- Department of Traslational Medicine, University of Naples Federico II, Naples, Italy; Center for Basic and Clinical Immunology Research (CISI), Naples, Italy; World Allergy Organization (WAO), Center of Excellence, Naples, Italy; Institute of Experimental Endocrinology and Oncology "Gaetano Salvatore", National Research Council, Naples, Italy.
| |
Collapse
|
29
|
Rothhammer V, Borucki DM, Tjon EC, Takenaka MC, Chao CC, Ardura-Fabregat A, de Lima KA, Gutiérrez-Vázquez C, Hewson P, Staszewski O, Blain M, Healy L, Neziraj T, Borio M, Wheeler M, Dragin LL, Laplaud DA, Antel J, Alvarez JI, Prinz M, Quintana FJ. Microglial control of astrocytes in response to microbial metabolites. Nature 2018; 557:724-728. [PMID: 29769726 DOI: 10.1038/s41586-018-0119-x] [Citation(s) in RCA: 726] [Impact Index Per Article: 103.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 04/11/2018] [Indexed: 12/14/2022]
Abstract
Microglia and astrocytes modulate inflammation and neurodegeneration in the central nervous system (CNS)1-3. Microglia modulate pro-inflammatory and neurotoxic activities in astrocytes, but the mechanisms involved are not completely understood4,5. Here we report that TGFα and VEGF-B produced by microglia regulate the pathogenic activities of astrocytes in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Microglia-derived TGFα acts via the ErbB1 receptor in astrocytes to limit their pathogenic activities and EAE development. Conversely, microglial VEGF-B triggers FLT-1 signalling in astrocytes and worsens EAE. VEGF-B and TGFα also participate in the microglial control of human astrocytes. Furthermore, expression of TGFα and VEGF-B in CD14+ cells correlates with the multiple sclerosis lesion stage. Finally, metabolites of dietary tryptophan produced by the commensal flora control microglial activation and TGFα and VEGF-B production, modulating the transcriptional program of astrocytes and CNS inflammation through a mechanism mediated by the aryl hydrocarbon receptor. In summary, we identified positive and negative regulators that mediate the microglial control of astrocytes. Moreover, these findings define a pathway through which microbial metabolites limit pathogenic activities of microglia and astrocytes, and suppress CNS inflammation. This pathway may guide new therapies for multiple sclerosis and other neurological disorders.
Collapse
Affiliation(s)
- Veit Rothhammer
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Davis M Borucki
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Emily C Tjon
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Maisa C Takenaka
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Chun-Cheih Chao
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Kalil Alves de Lima
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Cristina Gutiérrez-Vázquez
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Patrick Hewson
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ori Staszewski
- Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany
| | - Manon Blain
- Neuroimmunology Unit, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
| | - Luke Healy
- Neuroimmunology Unit, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
| | - Tradite Neziraj
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Matilde Borio
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Michael Wheeler
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Loic Lionel Dragin
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | | | - Jack Antel
- Neuroimmunology Unit, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
| | - Jorge Ivan Alvarez
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Marco Prinz
- Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany.,BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany
| | - Francisco J Quintana
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. .,Broad Institute of MIT and Harvard, Cambridge, MA, USA.
| |
Collapse
|
30
|
Mesquita J, Castro-de-Sousa JP, Vaz-Pereira S, Neves A, Passarinha LA, Tomaz CT. Evaluation of the growth factors VEGF-a and VEGF-B in the vitreous and serum of patients with macular and retinal vascular diseases. Growth Factors 2018; 36:48-57. [PMID: 29969324 DOI: 10.1080/08977194.2018.1477140] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
VEGF-A and VEGF-B are proangiogenic and key regulating factors for blood vessel growth. This study aims to compare VEGF-A and VEGF-B levels in the serum and vitreous of patients with neovascular pathology versus non-neovascular pathology. Our findings showed vitreous VEGF-A and VEGF-B levels increased in patients with neovascular disease, with higher levels of VEGF-A compared to VEGF-B (p ≤ .05). In the diabetic retinopathy (DR) group, higher vitreous VEGF-A or VEGF-B were found in proliferative diabetic retinopathy (PDR) than in non-PDR. The strong correlation between VEGF-A and VEGF-B demonstrates a simultaneous pathological increase of cytokines (p < .001), suggesting besides VEGF-A, VEGF-B is another contributor to ocular pathologies involving angiogenesis. There was no correlation between vitreous and serum VEGF-A or VEGF-B; however, a correlation between vitreous (VEGF-A or VEGF-B) and macular volume (p < .05) in DR patients was found. Targeting VEGF-A and VEGF-B in macular and retinal vascular diseases, involving neovascularization, may improve treatment outcomes.
Collapse
Affiliation(s)
- Joana Mesquita
- a CICS-UBI-Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique , Covilhã , Portugal
| | - João Paulo Castro-de-Sousa
- b Faculty of Medical Sciences , Universidade da Beira Interior , Covilhã , Portugal
- c Department of Ophthalmology , Centro Hospitalar de Leiria, R. das Olhalvas , Leiria , Portugal
| | - Sara Vaz-Pereira
- d Department of Ophthalmology , Hospital de Santa Maria, Av. Professor Egas Moniz , Lisbon , Portugal
- e Department of Ophthalmology, Faculty of Medicine , Universidade de Lisboa, Av. Professor Egas Moniz , Lisbon , Portugal
| | - Arminda Neves
- c Department of Ophthalmology , Centro Hospitalar de Leiria, R. das Olhalvas , Leiria , Portugal
| | - Luís A Passarinha
- a CICS-UBI-Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique , Covilhã , Portugal
- b Faculty of Medical Sciences , Universidade da Beira Interior , Covilhã , Portugal
| | - Cândida T Tomaz
- a CICS-UBI-Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique , Covilhã , Portugal
| |
Collapse
|
31
|
Lim S, Hosaka K, Nakamura M, Cao Y. Co-option of pre-existing vascular beds in adipose tissue controls tumor growth rates and angiogenesis. Oncotarget 2018; 7:38282-38291. [PMID: 27203675 PMCID: PMC5122389 DOI: 10.18632/oncotarget.9436] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 04/27/2016] [Indexed: 12/15/2022] Open
Abstract
Many types of cancer develop in close association with highly vascularized adipose tissues. However, the role of adipose pre-existing vascular beds on tumor growth and angiogenesis is unknown. Here we report that pre-existing microvascular density in tissues where tumors originate is a crucial determinant for tumor growth and neovascularization. In three independent tumor types including breast cancer, melanoma, and fibrosarcoma, inoculation of tumor cells in the subcutaneous tissue, white adipose tissue (WAT), and brown adipose tissue (BAT) resulted in markedly differential tumor growth rates and angiogenesis, which were in concordance with the degree of pre-existing vascularization in these tissues. Relative to subcutaneous tumors, WAT and BAT tumors grew at accelerated rates along with improved neovascularization, blood perfusion, and decreased hypoxia. Tumor cells implanted in adipose tissues contained leaky microvessel with poor perivascular cell coverage. Thus, adipose vasculature predetermines the tumor microenvironment that eventually supports tumor growth.
Collapse
Affiliation(s)
- Sharon Lim
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden
| | - Kayoko Hosaka
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden
| | - Masaki Nakamura
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden
| | - Yihai Cao
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.,Department of Medical and Health Sciences, Linköping University, 581 83 Linköping, Sweden.,Affiliated WuXi No 2 Hospital of Nanjing Medical University, 214 002 Wuxi, China.,Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, LE3 9QP Leicester, UK
| |
Collapse
|
32
|
Mesquita J, Castro-de-Sousa JP, Vaz-Pereira S, Neves A, Passarinha LA, Tomaz CT. Vascular endothelial growth factors and placenta growth factor in retinal vasculopathies: Current research and future perspectives. Cytokine Growth Factor Rev 2017; 39:102-115. [PMID: 29248329 DOI: 10.1016/j.cytogfr.2017.11.005] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2017] [Revised: 11/27/2017] [Accepted: 11/30/2017] [Indexed: 12/23/2022]
Abstract
Vision loss due to disease or degeneration of the eye (retina, choroid, retinal veins, or macula) is a leading cause of blindness worldwide. In most cases, vision-threatening ocular diseases are accompanied by abnormal changes in the vasculature of the eye, especially the retina, and these conditions are collectively referred to as retinal vasculopathies. Impaired blood supply or hypoxia stimulates angiogenesis in the vascular and non-vascular sections of the eye, which results in neovascularization, leading to conditions such as diabetic retinopathy or age-related macular degeneration. Studies show that vascular endothelial growth factors: VEGF-A, VEGF-B, and placental growth factor (PlGF) are elevated in these diseases, and hence, these factors could be used as markers for disease prognosis and therapy. In this review, we discuss the function of these growth factors in normal development and disease, with focus on ocular disorders and emphasize the importance of accurately determining their levels in the vitreous and serum of patients for correct diagnosis and therapy.
Collapse
Affiliation(s)
- Joana Mesquita
- CICS-UBI-Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6201-506 Covilhã, Portugal.
| | - João Paulo Castro-de-Sousa
- Faculty of Medical Sciences, Universidade da Beira Interior, Covilhã, Portugal; Department of Ophthalmology, Centro Hospitalar de Leiria, R. das Olhalvas, 2410-197 Leiria, Portugal.
| | - Sara Vaz-Pereira
- Department of Ophthalmology, Hospital de Santa Maria, Av. Professor Egas Moniz, 1649-035 Lisbon, Portugal; Department of Ophthalmology, Faculty of Medicine, Universidade de Lisboa, Av. Professor Egas Moniz, 1649-035 Lisbon, Portugal.
| | - Arminda Neves
- Department of Ophthalmology, Centro Hospitalar de Leiria, R. das Olhalvas, 2410-197 Leiria, Portugal.
| | - Luís A Passarinha
- CICS-UBI-Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6201-506 Covilhã, Portugal; Faculty of Medical Sciences, Universidade da Beira Interior, Covilhã, Portugal.
| | - Cândida T Tomaz
- CICS-UBI-Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6201-506 Covilhã, Portugal.
| |
Collapse
|
33
|
Gomes M, Archer F, Girard N, Gineys B, Dolmazon C, Bobet Erny A, Mornex JF, Leroux C. Blocked expression of key genes of the angiogenic pathway in JSRV-induced pulmonary adenocarcinomas. Vet Res 2017; 48:76. [PMID: 29137669 PMCID: PMC5686813 DOI: 10.1186/s13567-017-0480-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Accepted: 09/20/2017] [Indexed: 02/06/2023] Open
Abstract
JSRV (Jaagsiekte Sheep Retrovirus) is a retrovirus inducing a transmissible lung adenocarcinoma in sheep and goats with predominantly lepidic and papillary lesions. This naturally occurring lung cancer in large animals shares many features with human pneumonic-type lung adenocarcinomas with predominant lepidic growth. The metastatic spread is rare in both human and animal cancers. This unique feature prompted us to decipher the angiogenesis pathway in these cancers. We focused on the levels of mRNA and proteins of genes implicated in the extension of JSRV-induced lung adenocarcinomas by studying their expression in lung cancers (n = 10) and normal lungs (n = 10) and in primary epithelial alveolar type II cells derived from cancers (n = 10) or normal lungs (n = 6). In parallel, we evaluated the levels of expression of key genes in lung tissues collected from lepidic (n = 13) or papillary (n = 5) human adenocarcinomas and, when available, adjacent normal lungs (n = 11). We measured the expression of the same key genes implicated in angiogenesis, lymphangiogenesis and degradation of the extracellular matrix. In ovine adenocarcinomas, VEGFR2 and VEGFD mRNA were downregulated in cancers; MMP9, TIMP1 and FGFR2 mRNA were overexpressed as compared to normal lungs. Importantly, VEGFA and VEGFR2 proteins were not expressed in JSRV-induced cancers. In human lepidic adenocarcinomas, VEGFA and VEGFR2 mRNA were weakly expressed and no VEGFR2 protein was detectable. Downregulation of key angiogenic players may contribute to the control of extra thoracic invasion of cancer cells in human and ovine pneumonic-type adenocarcinoma with predominant lepidic growth.
Collapse
Affiliation(s)
- Maryline Gomes
- IVPC UMR754, INRA, Univ Lyon, Université Claude Bernard Lyon 1, EPHE, Lyon, France
| | - Fabienne Archer
- IVPC UMR754, INRA, Univ Lyon, Université Claude Bernard Lyon 1, EPHE, Lyon, France
| | - Nicolas Girard
- IVPC UMR754, INRA, Univ Lyon, Université Claude Bernard Lyon 1, EPHE, Lyon, France.,Department of Respiratory Diseases, Hospices Civils de Lyon, Louis Pradel Hospital, Lyon, France
| | - Barbara Gineys
- IVPC UMR754, INRA, Univ Lyon, Université Claude Bernard Lyon 1, EPHE, Lyon, France
| | - Christine Dolmazon
- IVPC UMR754, INRA, Univ Lyon, Université Claude Bernard Lyon 1, EPHE, Lyon, France
| | - Alexandra Bobet Erny
- IVPC UMR754, INRA, Univ Lyon, Université Claude Bernard Lyon 1, EPHE, Lyon, France
| | - Jean-François Mornex
- IVPC UMR754, INRA, Univ Lyon, Université Claude Bernard Lyon 1, EPHE, Lyon, France.,Department of Respiratory Diseases, Hospices Civils de Lyon, Louis Pradel Hospital, Lyon, France
| | - Caroline Leroux
- IVPC UMR754, INRA, Univ Lyon, Université Claude Bernard Lyon 1, EPHE, Lyon, France.
| |
Collapse
|
34
|
Abstract
Angiogenesis plays an important role in controlling tissue development and maintaining normal tissue function. Dysregulated angiogenesis is implicated in the pathogenesis of a variety of diseases, particularly diabetes, cancers, and neurodegenerative disorders. As the major regulator of angiogenesis, the vascular endothelial growth factor (VEGF) family is composed of a group of crucial members including VEGF-B. While the physiological roles of VEGF-B remain debatable, increasing evidence suggests that this protein is able to protect certain type of cells from apoptosis under pathological conditions. More importantly, recent studies reveal that VEGF-B is involved in lipid transport and energy metabolism, implicating this protein in obesity, diabetes and related metabolic complications. This article summarizes the current knowledge and understanding of VEGF-B in physiology and pathology, and shed light on the therapeutic potential of this crucial protein.
Collapse
Affiliation(s)
- Hongyu Zhu
- a State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University , Nanjing , China
| | - Mingming Gao
- b Department of Pharmaceutical and Biomedical Sciences , University of Georgia , Athens , GA , USA
| | - Xiangdong Gao
- a State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University , Nanjing , China
| | - Yue Tong
- a State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University , Nanjing , China
| |
Collapse
|
35
|
The role of vascular endothelial growth factor-B in metabolic homoeostasis: current evidence. Biosci Rep 2017; 37:BSR20171089. [PMID: 28798193 PMCID: PMC5577206 DOI: 10.1042/bsr20171089] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Revised: 08/09/2017] [Accepted: 08/10/2017] [Indexed: 02/07/2023] Open
Abstract
It has been shown that adipose tissue and skeletal muscles in lean individuals respond to meal-induced hyperinsulinemia by increase in perfusion, the effect not observed in patients with metabolic syndrome. In conditions of hyperglycaemia and hypertriglyceridemia, this insufficient vascularization leads to the liberation of reactive oxygen species (ROS), and disruption of nitric oxide (NO) synthesis and endothelial signalling responsible for the uptake of circulating fatty acids (FAs), whose accumulation in skeletal muscles and adipose tissue is widely associated with the impairment of insulin signalling. While the angiogenic role of VEGF-A and its increased circulating concentrations in obesity have been widely confirmed, the data related to the metabolic role of VEGF-B are diverse. However, recent discoveries indicate that this growth factor may be a promising therapeutic agent in patients with metabolic syndrome. Preclinical studies agree over two crucial metabolic effects of VEGF-B: (i) regulation of FAs uptake and (ii) regulation of tissue perfusion via activation of VEGF-A/vascular endothelial growth factor receptor (VEGFR) 2 (VEGFR2) pathway. While in some preclinical high-fat diet studies, VEGF-B overexpression reverted glucose intolerance and stimulated fat burning, in others it further promoted accumulation of lipids and lipotoxicity. Data from clinical studies point out the changes in circulating or tissue expression levels of VEGF-B in obese compared with lean patients. Potentially beneficial effects of VEGF-B, achieved through enhanced blood flow (increased availability of insulin and glucose uptake in target organs) and decreased FAs uptake (prevention of lipotoxicity and improved insulin signalling), and its safety for clinical use, remain to be clarified through future translational research.
Collapse
|
36
|
Mesquita J, Castro de Sousa JP, Vaz-Pereira S, Neves A, Tavares-Ratado P, M Santos F, A Passarinha L, T Tomaz C. VEGF-B Levels in the Vitreous of Diabetic and Non-Diabetic Patients with Ocular Diseases and Its Correlation with Structural Parameters. Med Sci (Basel) 2017; 5:medsci5030017. [PMID: 29099033 PMCID: PMC5635802 DOI: 10.3390/medsci5030017] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 07/29/2017] [Accepted: 08/08/2017] [Indexed: 12/20/2022] Open
Abstract
Vascular endothelial growth factor B (VEGF-B) is one of the enigmatic members of the VEGF family. The knowledge gap about VEGF-B expression and how its levels are altered in diabetic eyes were the focus of this investigation that was addressed by comparing and correlating vitreous VEGF-B between diabetic and non-diabetic patients. VEGF-B levels were measured by enzyme-linked immunosorbent assay in vitreous samples (n = 33) from diabetic (n = 25) and non-diabetic (n = 8) patients. Results were compared between groups. Optical coherence tomography from diabetic patients was evaluated for central retinal thickness (CRT) and macular volume (MV). Mean vitreous VEGF-B concentration was higher in diabetic (18.82 ± 1.44 pg/mL) vs. non-diabetic patients (17.90 ± 0.32 pg/mL) (p = 0.006), and in proliferative diabetic retinopathy (PDR) (19.03 ± 1.52 pg/mL) vs. non-PDR (NPDR) patients (18.18 ±0.96 pg/mL) (p = 0.025). In diabetic retinopathy (DR) patients, correlation between VEGF-B and CRT (μm) was positive and moderate: rs = 0.441 (p ≤ 0.05) and the correlation between VEGF-B and MV (mm3) was positive and robust: rs = 0.716 (p ≤ 0.01). VEGF-B levels are overexpressed in vitreous of diabetic patients, and the levels are higher in developed stages of DR. Correlation results show that CRT and MV increase with increased levels of VEGF-B. Targeting VEGF-B inhibition may have therapeutic beneficial implications.
Collapse
Affiliation(s)
- Joana Mesquita
- CICS-UBI-Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, 6201-506 Covilhã, Portugal.
| | - João Paulo Castro de Sousa
- Faculty of Medical Sciences, Universidade da Beira Interior, 6201-506 Covilhã, Portugal.
- Department of Ophthalmology, Centro Hospitalar de Leiria, 2410-197 Leiria, Portugal.
| | - Sara Vaz-Pereira
- Department of Ophthalmology, Hospital de Santa Maria, 1649 - 035 Lisbon, Portugal.
- Department of Ophthalmology, Faculty of Medicine, Universidade de Lisboa, 1649 - 035 Lisbon, Portugal.
| | - Arminda Neves
- Department of Ophthalmology, Centro Hospitalar de Leiria, 2410-197 Leiria, Portugal.
| | - Paulo Tavares-Ratado
- Faculty of Medical Sciences, Universidade da Beira Interior, 6201-506 Covilhã, Portugal.
| | - Fátima M Santos
- CICS-UBI-Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, 6201-506 Covilhã, Portugal.
| | - Luís A Passarinha
- CICS-UBI-Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, 6201-506 Covilhã, Portugal.
- Faculty of Medical Sciences, Universidade da Beira Interior, 6201-506 Covilhã, Portugal.
| | - Cândida T Tomaz
- CICS-UBI-Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, 6201-506 Covilhã, Portugal.
| |
Collapse
|
37
|
Castañeda-Cabral JL, Beas-Zarate C, Gudiño-Cabrera G, Ureña-Guerrero ME. Glutamate Neonatal Excitotoxicity Modifies VEGF-A, VEGF-B, VEGFR-1 and VEGFR-2 Protein Expression Profiles During Postnatal Development of the Cerebral Cortex and Hippocampus of Male Rats. J Mol Neurosci 2017; 63:17-27. [PMID: 28755050 DOI: 10.1007/s12031-017-0952-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 07/18/2017] [Indexed: 12/20/2022]
Abstract
Vascular endothelial growth factor (VEGF) exerts both neuroprotective and proinflammatory effects in the brain, depending on the VEGF (A-E) and VEGF receptor (VEGFR1-3) types involved. Neonatal monosodium glutamate (MSG) treatment triggers an excitotoxic degenerative process associated with several neuropathological conditions, and VEGF messenger RNA (mRNA) expression is increased at postnatal day (PD) 14 in rat hippocampus (Hp) following the treatment. The aim of this work was to establish the changes in immunoreactivity to VEGF-A, VEGF-B, VEGFR-1 and VEGFR-2 proteins induced by neonatal MSG treatment (4 g/kg, subcutaneous, at PD1, 3, 5 and 7) in the cerebral motor cortex (CMC) and Hp. Samples collected from PD2 to PD60 from control and MSG-treated male Wistar rats were assessed by western blotting for each protein. Considering that immunoreactivity measured by western blotting is related to the protein expression level, we found that each protein in each cerebral region has a specific expression profile throughout the studied ages, and all profiles were differentially modified by MSG. Specifically, neonatal MSG treatment significantly increased the immunoreactivity to the following: (1) VEGF-A at PD8-PD10 in the CMC and at PD6-PD8 in the Hp; (2) VEGF-B at PD2, PD6 and PD10 in the CMC and at PD8-PD9 in the Hp; and (3) VEGFR-2 at PD6-PD8 in the CMC and at PD21-PD60 in the Hp. Also, MSG significantly reduced the immunoreactivity to the following: (1) VEGF-B at PD8-PD9 and PD45-PD60 in the CMC; and (2) VEGFR-1 at PD4-PD6 and PD14-PD21 in the CMC and at PD4, PD9-PD10 and PD60 in the Hp. Our results indicate that VEGF-mediated signalling is involved in the excitotoxic process triggered by neonatal MSG treatment and should be further characterized.
Collapse
Affiliation(s)
- Jose Luis Castañeda-Cabral
- Departamento de Biología Celular y Molecular, Centro Universitario de Ciencias Biológicas y Agropecuarias (CUCBA), Universidad de Guadalajara, Zapopan, Jalisco, Mexico
| | - Carlos Beas-Zarate
- Departamento de Biología Celular y Molecular, Centro Universitario de Ciencias Biológicas y Agropecuarias (CUCBA), Universidad de Guadalajara, Zapopan, Jalisco, Mexico. .,Laboratorio de Regeneración y Desarrollo Neural, Departamento de Biología Celular y Molecular, CUCBA, Universidad de Guadalajara, Km 15.5 Carretera a Nogales, Camino Ing. Ramón Padilla Sánchez Km 2, 45221, Zapopan, Jalisco, Mexico.
| | - Graciela Gudiño-Cabrera
- Departamento de Biología Celular y Molecular, Centro Universitario de Ciencias Biológicas y Agropecuarias (CUCBA), Universidad de Guadalajara, Zapopan, Jalisco, Mexico
| | - Monica E Ureña-Guerrero
- Departamento de Biología Celular y Molecular, Centro Universitario de Ciencias Biológicas y Agropecuarias (CUCBA), Universidad de Guadalajara, Zapopan, Jalisco, Mexico. .,Laboratorio de Biología de la Neurotransmisión, Edificio de Posgrado, Departamento de Biología Celular y Molecular, CUCBA, Universidad de Guadalajara, Km 15.5 Carretera a Nogales, Camino Ing. Ramón Padilla Sánchez Km 2, 45221, Zapopan, Jalisco, Mexico.
| |
Collapse
|
38
|
Lal N, Chiu APL, Wang F, Zhang D, Jia J, Wan A, Vlodavsky I, Hussein B, Rodrigues B. Loss of VEGFB and its signaling in the diabetic heart is associated with increased cell death signaling. Am J Physiol Heart Circ Physiol 2017; 312:H1163-H1175. [DOI: 10.1152/ajpheart.00659.2016] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Revised: 02/08/2017] [Accepted: 02/23/2017] [Indexed: 11/22/2022]
Abstract
Vascular endothelial growth factor B (VEGFB) is highly expressed in metabolically active tissues, such as the heart and skeletal muscle, suggesting a function in maintaining oxidative metabolic and contractile function in these tissues. Multiple models of heart failure have indicated a significant drop in VEGFB. However, whether there is a role for decreased VEGFB in diabetic cardiomyopathy is currently unknown. Of the VEGFB located in cardiomyocytes, there is a substantial and readily releasable pool localized on the cell surface. The immediate response to high glucose and the secretion of endothelial heparanase is the release of this surface-bound VEGFB, which triggers signaling pathways and gene expression to influence endothelial cell (autocrine action) and cardiomyocyte (paracrine effects) survival. Under conditions of hyperglycemia, when VEGFB production is impaired, a robust increase in vascular endothelial growth factor receptor (VEGFR)-1 expression ensues as a possible mechanism to enhance or maintain VEGFB signaling. However, even with an increase in VEGFR1 after diabetes, cardiomyocytes are unable to respond to VEGFB. In addition to the loss of VEGFB production and signaling, evaluation of latent heparanase, the protein responsible for VEGFB release, also showed a significant decline in expression in whole hearts from animals with chronic or acute diabetes. Defects in these numerous VEGFB pathways were associated with an increased cell death signature in our models of diabetes. Through this bidirectional interaction between endothelial cells (which secrete heparanase) and cardiomyocytes (which release VEGFB), this growth factor could provide the diabetic heart protection against cell death and may be a critical tool to delay or prevent cardiomyopathy. NEW & NOTEWORTHY We discovered a bidirectional interaction between endothelial cells (which secrete heparanase) and cardiomyocytes [which release vascular endothelial growth factor B (VEGFB)]. VEGFB promoted cell survival through ERK and cell death gene expression. Loss of VEGFB and its downstream signaling is an early event following hyperglycemia, is sustained with disease progression, and could explain diabetic cardiomyopathy.
Collapse
Affiliation(s)
- Nathaniel Lal
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada; and
| | - Amy Pei-Ling Chiu
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada; and
| | - Fulong Wang
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada; and
| | - Dahai Zhang
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada; and
| | - Jocelyn Jia
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada; and
| | | | - Israel Vlodavsky
- Rappaport Faculty of Medicine, Cancer and Vascular Biology Research Center, Technion, Haifa, Israel
| | - Bahira Hussein
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada; and
| | - Brian Rodrigues
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada; and
| |
Collapse
|
39
|
Kinoshita S, Noda K, Saito W, Kanda A, Ishida S. Vitreous levels of vascular endothelial growth factor-B in proliferative diabetic retinopathy. Acta Ophthalmol 2016; 94:e521-3. [PMID: 26826065 DOI: 10.1111/aos.12969] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Satoshi Kinoshita
- Laboratory of Ocular Cell Biology and Visual Science; Hokkaido University Graduate School of Medicine; Sapporo Japan
- Department of Ophthalmology; Hokkaido University Graduate School of Medicine; Sapporo Japan
| | - Kousuke Noda
- Laboratory of Ocular Cell Biology and Visual Science; Hokkaido University Graduate School of Medicine; Sapporo Japan
- Department of Ophthalmology; Hokkaido University Graduate School of Medicine; Sapporo Japan
| | - Wataru Saito
- Department of Ophthalmology; Hokkaido University Graduate School of Medicine; Sapporo Japan
| | - Atsuhiro Kanda
- Laboratory of Ocular Cell Biology and Visual Science; Hokkaido University Graduate School of Medicine; Sapporo Japan
- Department of Ophthalmology; Hokkaido University Graduate School of Medicine; Sapporo Japan
| | - Susumu Ishida
- Laboratory of Ocular Cell Biology and Visual Science; Hokkaido University Graduate School of Medicine; Sapporo Japan
- Department of Ophthalmology; Hokkaido University Graduate School of Medicine; Sapporo Japan
| |
Collapse
|
40
|
Wan A, Rodrigues B. Endothelial cell-cardiomyocyte crosstalk in diabetic cardiomyopathy. Cardiovasc Res 2016; 111:172-83. [PMID: 27288009 DOI: 10.1093/cvr/cvw159] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 05/21/2016] [Indexed: 12/19/2022] Open
Abstract
The incidence of diabetes is increasing globally, with cardiovascular disease accounting for a substantial number of diabetes-related deaths. Although atherosclerotic vascular disease is a primary reason for this cardiovascular dysfunction, heart failure in patients with diabetes might also be an outcome of an intrinsic heart muscle malfunction, labelled diabetic cardiomyopathy. Changes in cardiomyocyte metabolism, which encompasses a shift to exclusive fatty acid utilization, are considered a leading stimulus for this cardiomyopathy. In addition to cardiomyocytes, endothelial cells (ECs) make up a significant proportion of the heart, with the majority of ATP generation in these cells provided by glucose. In this review, we will discuss the metabolic machinery that drives energy metabolism in the cardiomyocyte and EC, its breakdown following diabetes, and the research direction necessary to assist in devising novel therapeutic strategies to prevent or delay diabetic heart disease.
Collapse
Affiliation(s)
- Andrea Wan
- Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3
| | - Brian Rodrigues
- Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3
| |
Collapse
|
41
|
Expression, purification and characterization of a vascular endothelial growth factor fusion protein. Biotechnol Lett 2016; 38:1115-20. [DOI: 10.1007/s10529-016-2081-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2016] [Accepted: 03/07/2016] [Indexed: 01/03/2023]
|
42
|
Chen S, Zhou M, Wang W, Wu H, Yu X, Huang W, Gao X, Wang J, Li X, Du S, Ding X, Zhang X. Levels of angiogenesis-related vascular endothelial growth factor family in neovascular glaucoma eyes. Acta Ophthalmol 2015; 93:e556-60. [PMID: 25783445 DOI: 10.1111/aos.12624] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Accepted: 10/31/2014] [Indexed: 12/25/2022]
Abstract
PURPOSE This study aimed to evaluate the angiogenesis-related factors of the vascular endothelial growth factor (VEGF) family in the aqueous humour of patients with neovascular glaucoma (NVG). METHODS This study involved 22 eyes of 22 patients with advanced NVG requiring antiglaucomatous surgery and 20 control subjects with cataracts. The NVG eyes received an intravitreal injection of ranibizumab (IVR) treatment before antiglaucomatous surgery. Aqueous humour and blood were collected at the time of IVR and cataract surgery. Protein concentration of VEGF-A, VEGF-B and placenta growth factor (PlGF) in aqueous humour and plasma was determined by ELISA tests. RESULTS The mean concentration (standard deviation) of VEGF-A and PlGF in the aqueous humour of patients with NVG were 3037 (2387) pg/ml and 1078 (712) pg/ml, respectively; both were significantly higher than the control group (both p < 0.001). However, levels of VEGF-A and PlGF in the serum of NVG and control subjects remained low. High concentrations of VEGF-A were closely correlated with high levels of PlGF in patients with NVG (r = 0.593, p = 0.004). Concentrations of VEGF-B in aqueous humour and serum remained unchanged (p > 0.05). CONCLUSION There were high concentrations of angiogenesis factors of the VEGF family, with the exception of VEGF-B, in the aqueous humour of patients with NVG, and there was a positive correlation between VEGF-A and PlGF. High PlGF levels in patients with NVG may provide another potential target for treatment of NVG.
Collapse
Affiliation(s)
- Shida Chen
- Zhongshan Ophthalmic Center; State Key Laboratory of Ophthalmology; Sun Yat-Sen University; Guangzhou China
| | - Minwen Zhou
- Zhongshan Ophthalmic Center; State Key Laboratory of Ophthalmology; Sun Yat-Sen University; Guangzhou China
- Department of Ophthalmology; Shanghai First People's Hospital; School of Medicine; Shanghai JiaoTong University; Shanghai China
- Shanghai Key Laboratory of Fundus Disease; Shanghai China
| | - Wei Wang
- Zhongshan Ophthalmic Center; State Key Laboratory of Ophthalmology; Sun Yat-Sen University; Guangzhou China
| | - Huimin Wu
- Zhongshan Ophthalmic Center; State Key Laboratory of Ophthalmology; Sun Yat-Sen University; Guangzhou China
| | - Xiling Yu
- Zhongshan Ophthalmic Center; State Key Laboratory of Ophthalmology; Sun Yat-Sen University; Guangzhou China
| | - Wenbin Huang
- Zhongshan Ophthalmic Center; State Key Laboratory of Ophthalmology; Sun Yat-Sen University; Guangzhou China
| | - Xinbo Gao
- Zhongshan Ophthalmic Center; State Key Laboratory of Ophthalmology; Sun Yat-Sen University; Guangzhou China
| | - Jiawei Wang
- Zhongshan Ophthalmic Center; State Key Laboratory of Ophthalmology; Sun Yat-Sen University; Guangzhou China
| | - Xingyi Li
- Zhongshan Ophthalmic Center; State Key Laboratory of Ophthalmology; Sun Yat-Sen University; Guangzhou China
| | - Shaolin Du
- Zhongshan Ophthalmic Center; State Key Laboratory of Ophthalmology; Sun Yat-Sen University; Guangzhou China
| | - Xiaoyan Ding
- Zhongshan Ophthalmic Center; State Key Laboratory of Ophthalmology; Sun Yat-Sen University; Guangzhou China
| | - Xiulan Zhang
- Zhongshan Ophthalmic Center; State Key Laboratory of Ophthalmology; Sun Yat-Sen University; Guangzhou China
| |
Collapse
|
43
|
Sultan SA, Liu W, Peng Y, Roberts W, Whitelaw D, Graham AM. The Role of Maternal Gestational Diabetes in Inducing Fetal Endothelial Dysfunction. J Cell Physiol 2015; 230:2695-705. [PMID: 25808705 DOI: 10.1002/jcp.24993] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Accepted: 03/19/2015] [Indexed: 12/27/2022]
Abstract
Gestational diabetes mellitus (GDM) is known to be associated with fetal endothelial dysfunction, however, the mechanisms are not fully understood. This study examines the effect of maternal diabetes on fetal endothelial function and gene expression under physiological glucose conditions (5 mM). Human umbilical vein endothelial cell (HUVEC) isolated from diabetic mothers (d.HUVEC) grew more slowly than HUVEC isolated from healthy mothers (c.HUVEC) and had delayed doubling time despite increased levels of total vascular endothelial growth factor (VEGF) expression and protein production as determined by real-time PCR and ELISA respectively. Using western blot, the levels of antiproliferative VEGF165b isoform were increased in d.HUVEC relative to c.HUVEC. Successful VEGF165b knockdown by small interfering RNA (siRNA) resulted in increased proliferation of d.HUVEC measured by MTT, compared with negative siRNA control, to similar levels measured in c.HUVEC. In addition, d.HUVEC generated excess levels of ROS as revealed by 2',7' Dichlorodihydrofluorescein Diacetate (DCFH-DA) and Nitrotetrazolium blue (NBT). Using microarray, 102 genes were differentially overexpressed between d.HUVEC versus c.HUVEC (>1.5-fold change; P < 0.05). Functional clustering analysis of these differentially expressed genes revealed participation in inflammatory responses (including adhesion) which may be related to pathological outcomes. Of these genes, ICAM-1 was validated as upregulated, confirming microarray results. Additional confirmatory immunofluorescence staining revealed increased protein expression of ICAM-1 compared with c.HUVEC which was reduced by vitamin C treatment (100 μM). Thus, maternal diabetes induces persistent alterations in fetal endothelial function and gene expression following glucose normalization and antioxidant treatment could help reverse endothelium dysfunction.
Collapse
Affiliation(s)
- Samar A Sultan
- Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Wanting Liu
- School of Computing, Informatics and Media, University of Bradford, Bradford, UK
| | - Yonghong Peng
- School of Computing, Informatics and Media, University of Bradford, Bradford, UK
| | - W Roberts
- School of Medical Sciences, University of Bradford, Bradford, UK
| | - Donald Whitelaw
- Department of Diabetes and Endocrinology, Bradford Royal Infirmary, Bradford, UK
| | - Anne M Graham
- School of Medical Sciences, University of Bradford, Bradford, UK
| |
Collapse
|
44
|
Woolf EC, Curley KL, Liu Q, Turner GH, Charlton JA, Preul MC, Scheck AC. The Ketogenic Diet Alters the Hypoxic Response and Affects Expression of Proteins Associated with Angiogenesis, Invasive Potential and Vascular Permeability in a Mouse Glioma Model. PLoS One 2015; 10:e0130357. [PMID: 26083629 PMCID: PMC4470583 DOI: 10.1371/journal.pone.0130357] [Citation(s) in RCA: 81] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Accepted: 05/18/2015] [Indexed: 01/09/2023] Open
Abstract
Background The successful treatment of malignant gliomas remains a challenge despite the current standard of care, which consists of surgery, radiation and temozolomide. Advances in the survival of brain cancer patients require the design of new therapeutic approaches that take advantage of common phenotypes such as the altered metabolism found in cancer cells. It has therefore been postulated that the high-fat, low-carbohydrate, adequate protein ketogenic diet (KD) may be useful in the treatment of brain tumors. We have demonstrated that the KD enhances survival and potentiates standard therapy in a mouse model of malignant glioma, yet the mechanisms are not fully understood. Methods To explore the effects of the KD on various aspects of tumor growth and progression, we used the immunocompetent, syngeneic GL261-Luc2 mouse model of malignant glioma. Results Tumors from animals maintained on KD showed reduced expression of the hypoxia marker carbonic anhydrase 9, hypoxia inducible factor 1-alpha, and decreased activation of nuclear factor kappa B. Additionally, tumors from animals maintained on KD had reduced tumor microvasculature and decreased expression of vascular endothelial growth factor receptor 2, matrix metalloproteinase-2 and vimentin. Peritumoral edema was significantly reduced in animals fed the KD and protein analyses showed altered expression of zona occludens-1 and aquaporin-4. Conclusions The KD directly or indirectly alters the expression of several proteins involved in malignant progression and may be a useful tool for the treatment of gliomas.
Collapse
MESH Headings
- Animals
- Aquaporin 4/genetics
- Aquaporin 4/metabolism
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Brain Neoplasms/blood supply
- Brain Neoplasms/diet therapy
- Brain Neoplasms/metabolism
- Brain Neoplasms/pathology
- Carbonic Anhydrase IX
- Carbonic Anhydrases/genetics
- Carbonic Anhydrases/metabolism
- Cell Membrane Permeability
- Diet, Ketogenic
- Disease Models, Animal
- Female
- Glioma/blood supply
- Glioma/diet therapy
- Glioma/metabolism
- Glioma/pathology
- Hypoxia/diet therapy
- Hypoxia/metabolism
- Hypoxia/pathology
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Immunoenzyme Techniques
- Matrix Metalloproteinase 2/genetics
- Matrix Metalloproteinase 2/metabolism
- Mice
- Mice, Inbred C57BL
- NF-kappa B/genetics
- NF-kappa B/metabolism
- Neoplasm Invasiveness
- Neovascularization, Pathologic/diet therapy
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- RNA, Messenger/genetics
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/metabolism
- Zonula Occludens-1 Protein/genetics
- Zonula Occludens-1 Protein/metabolism
Collapse
Affiliation(s)
- Eric C. Woolf
- Neuro-Oncology Research, Barrow Brain Tumor Research Center, Barrow Neurological Institute dba St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America
- School of Life Sciences, Arizona State University, Tempe, Arizona, 85281, United States of America
| | - Kara L. Curley
- Neuro-Oncology Research, Barrow Brain Tumor Research Center, Barrow Neurological Institute dba St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America
| | - Qingwei Liu
- BNI-ASU Center for Preclinical Imaging, Barrow Neurological Institute dba St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America
| | - Gregory H. Turner
- BNI-ASU Center for Preclinical Imaging, Barrow Neurological Institute dba St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America
| | - Julie A. Charlton
- Neuro-Oncology Research, Barrow Brain Tumor Research Center, Barrow Neurological Institute dba St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America
| | - Mark C. Preul
- Neurosurgery Research, Barrow Neurological Institute dba St. Joseph's Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America
| | - Adrienne C. Scheck
- Neuro-Oncology Research, Barrow Brain Tumor Research Center, Barrow Neurological Institute dba St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America
- School of Life Sciences, Arizona State University, Tempe, Arizona, 85281, United States of America
- Neurosurgery Research, Barrow Neurological Institute dba St. Joseph's Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America
- * E-mail:
| |
Collapse
|
45
|
Deissler HL, Lang GK, Lang GE. Binding of VEGF-A is sufficient to abrogate the disturbing effects of VEGF-B together with VEGF-A on retinal endothelial cells. Graefes Arch Clin Exp Ophthalmol 2015; 253:885-94. [PMID: 25663437 PMCID: PMC4445774 DOI: 10.1007/s00417-015-2944-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Revised: 01/14/2015] [Accepted: 01/19/2015] [Indexed: 02/07/2023] Open
Abstract
Purpose Inhibition of vascular endothelial growth factor (VEGF) is a promising strategy to treat retinal complications of diabetes. In contrast to VEGF-A binding ranibizumab, aflibercept also binds to other members of the VEGF family including VEGF-B, but potential effects of this factor on permeability and angiogenic processes are unclear. Therefore, we studied how VEGF-B variants as single agents or together with VEGF-A165 might affect proliferation, migration, or barrier function of retinal endothelial cells (REC). Also investigated was the normalization of REC properties with both VEGF-inhibitors to explore if additional targeting of VEGF-B is relevant. Methods Stimulation of proliferation or migration of immortalized bovine REC (iBREC) and disturbance of their barrier by exposure to VEGF-B variants (as single factors or together with VEGF-A165) was determined with or without VEGF-binding proteins being added. Permeability of iBREC was assessed by measuring their transendothelial resistance (TER) and expression of the tight junction protein claudin-1. Results VEGF-B167 and VEGF-B186 enhanced proliferation of iBREC but these isoforms did not affect cell migration. Interestingly, ranibizumab completely blocked both migration and proliferation induced by VEGF-A plus VEGF-B. Both VEGF-B variants did also not affect barrier function or claudin-1 expression in a normal or high-glucose environment. Accordingly, binding VEGF-A was enough to normalize a reduced TER and reinstate claudin-1 lost during treatment with this factor in combination with VEGF-B. Conclusions Important properties and functions of REC seem not to be affected by any VEGF-B variant and targeting the key factor VEGF-A is sufficient to normalize growth factor-disturbed cells of this type. Electronic supplementary material The online version of this article (doi:10.1007/s00417-015-2944-z) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Heidrun L Deissler
- Department of Ophthalmology, University of Ulm, Prittwitzstrasse 43, 89075, Ulm, Germany,
| | | | | |
Collapse
|
46
|
VEGF-B selectively regenerates injured peripheral neurons and restores sensory and trophic functions. Proc Natl Acad Sci U S A 2014; 111:17272-7. [PMID: 25404333 DOI: 10.1073/pnas.1407227111] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
VEGF-B primarily provides neuroprotection and improves survival in CNS-derived neurons. However, its actions on the peripheral nervous system have been less characterized. We examined whether VEGF-B mediates peripheral nerve repair. We found that VEGF-B induced extensive neurite growth and branching in trigeminal ganglia neurons in a manner that required selective activation of transmembrane receptors and was distinct from VEGF-A-induced neuronal growth. VEGF-B-induced neurite elongation required PI3K and Notch signaling. In vivo, VEGF-B is required for normal nerve regeneration: mice lacking VEGF-B showed impaired nerve repair with concomitant impaired trophic function. VEGF-B treatment increased nerve regeneration, sensation recovery, and trophic functions of injured corneal peripheral nerves in VEGF-B-deficient and wild-type animals, without affecting uninjured nerves. These selective effects of VEGF-B on injured nerves and its lack of angiogenic activity makes VEGF-B a suitable therapeutic target to treat nerve injury.
Collapse
|
47
|
Pronto-Laborinho AC, Pinto S, de Carvalho M. Roles of vascular endothelial growth factor in amyotrophic lateral sclerosis. BIOMED RESEARCH INTERNATIONAL 2014; 2014:947513. [PMID: 24987705 PMCID: PMC4022172 DOI: 10.1155/2014/947513] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Accepted: 03/24/2014] [Indexed: 12/11/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal devastating neurodegenerative disorder, involving progressive degeneration of motor neurons in spinal cord, brainstem, and motor cortex. Riluzole is the only drug approved in ALS but it only confers a modest improvement in survival. In spite of a high number of clinical trials no other drug has proved effectiveness. Recent studies support that vascular endothelial growth factor (VEGF), originally described as a key angiogenic factor, also plays a key role in the nervous system, including neurogenesis, neuronal survival, neuronal migration, and axon guidance. VEGF has been used in exploratory clinical studies with promising results in ALS and other neurological disorders. Although VEGF is a very promising compound, translating the basic science breakthroughs into clinical practice is the major challenge ahead. VEGF-B, presenting a single safety profile, protects motor neurons from degeneration in ALS animal models and, therefore, it will be particularly interesting to test its effects in ALS patients. In the present paper the authors make a brief description of the molecular properties of VEGF and its receptors and review its different features and therapeutic potential in the nervous system/neurodegenerative disease, particularly in ALS.
Collapse
Affiliation(s)
- Ana Catarina Pronto-Laborinho
- Institute of Physiology, Faculty of Medicine, University of Lisbon, Avenida Professor Egas Moniz, 1649-028 Lisbon, Portugal
- Instituto de Medicina Molecular (IMM), Translational Clinical Physiology Unit, Avenida Professor Egas Moniz, 1649-028 Lisbon, Portugal
| | - Susana Pinto
- Institute of Physiology, Faculty of Medicine, University of Lisbon, Avenida Professor Egas Moniz, 1649-028 Lisbon, Portugal
- Instituto de Medicina Molecular (IMM), Translational Clinical Physiology Unit, Avenida Professor Egas Moniz, 1649-028 Lisbon, Portugal
| | - Mamede de Carvalho
- Institute of Physiology, Faculty of Medicine, University of Lisbon, Avenida Professor Egas Moniz, 1649-028 Lisbon, Portugal
- Instituto de Medicina Molecular (IMM), Translational Clinical Physiology Unit, Avenida Professor Egas Moniz, 1649-028 Lisbon, Portugal
- Department of Neurosciences, Hospital Santa Maria, Centro Hospitalar Lisboa Norte, Avenida Professor Egas Moniz, 1649-028 Lisbon, Portugal
| |
Collapse
|
48
|
Hagberg C, Mehlem A, Falkevall A, Muhl L, Eriksson U. Endothelial fatty acid transport: role of vascular endothelial growth factor B. Physiology (Bethesda) 2014; 28:125-34. [PMID: 23455771 DOI: 10.1152/physiol.00042.2012] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Dietary lipids present in the circulation have to be transported through the vascular endothelium to be utilized by tissue cells, a vital mechanism that is still poorly understood. Vascular endothelial growth factor B (VEGF-B) regulates this process by controlling the expression of endothelial fatty acid transporter proteins (FATPs). Here, we summarize research on the role of the vascular endothelium in nutrient transport, with emphasis on VEGF-B signaling.
Collapse
|
49
|
Zhang GH, Qin R, Zhang SH, Zhu H. Effects of vascular endothelial growth factor B on proliferation and migration in EA.Hy926 cells. Mol Biol Rep 2013; 41:779-85. [DOI: 10.1007/s11033-013-2917-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2012] [Accepted: 12/18/2013] [Indexed: 01/05/2023]
|
50
|
van Lookeren Campagne M, LeCouter J, Yaspan BL, Ye W. Mechanisms of age-related macular degeneration and therapeutic opportunities. J Pathol 2013; 232:151-64. [DOI: 10.1002/path.4266] [Citation(s) in RCA: 222] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Revised: 09/09/2013] [Accepted: 09/11/2013] [Indexed: 12/27/2022]
Affiliation(s)
| | - Jennifer LeCouter
- Molecular Biology Department; Genentech; South San Francisco CA 94080 USA
| | - Brian L Yaspan
- ITGR Human Genetics Department; Genentech; South San Francisco CA 94080 USA
| | - Weilan Ye
- Molecular Biology Department; Genentech; South San Francisco CA 94080 USA
| |
Collapse
|