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Alves-Silva T, Húngaro TG, Freitas-Lima LC, de Melo Arthur G, Arruda AC, Santos RB, Oyama LM, Mori MA, Bader M, Araujo RC. Kinin B1 receptor controls maternal adiponectin levels and influences offspring weight gain. iScience 2023; 26:108409. [PMID: 38058311 PMCID: PMC10696114 DOI: 10.1016/j.isci.2023.108409] [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: 03/09/2023] [Revised: 06/16/2023] [Accepted: 11/03/2023] [Indexed: 12/08/2023] Open
Abstract
Given the importance of the kinin B1 receptor in insulin and leptin hormonal regulation, which in turn is crucial in maternal adaptations to ensure nutrient supply to the fetus, we investigated the role of this receptor in maternal metabolism and fetoplacental development. Wild-type and kinin B1 receptor-deficient (B1KO) female mice were mated with male mice of the opposite genotype. Consequently, the entire litter was heterozygous for kinin B1 receptor, ensuring that there would be no influence of offspring genotype on the maternal phenotype. Maternal kinin B1 receptor blockade reduces adiponectin secretion by adipose tissue ex vivo, consistent with lower adiponectin levels in pregnant B1KO mice. Furthermore, fasting insulinemia also increased, which was associated with placental insulin resistance, reduced placental glycogen accumulation, and heavier offspring. Therefore, we propose the combination of chronic hyperinsulinemia and reduced adiponectin secretion in B1KO female mice create a maternal obesogenic environment that results in heavier pups.
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Affiliation(s)
- Thaís Alves-Silva
- Laboratory of Genetics and Exercise Metabolism, Molecular Biology Program, Biophysics Department, Federal University of São Paulo (UNIFESP), São Paulo 04039-032, Brazil
- Max-Delbrück Center for Molecular Medicine (MDC), Campus Berlin-Buch, 13125 Berlin, Germany
| | - Talita G.R. Húngaro
- Laboratory of Genetics and Exercise Metabolism, Nephrology Program, Biophysics Department, Federal University of São Paulo (UNIFESP), São Paulo 04039-032, Brazil
| | - Leandro C. Freitas-Lima
- Laboratory of Genetics and Exercise Metabolism, Molecular Biology Program, Biophysics Department, Federal University of São Paulo (UNIFESP), São Paulo 04039-032, Brazil
| | - Gabriel de Melo Arthur
- Laboratory of Genetics and Exercise Metabolism, Molecular Biology Program, Biophysics Department, Federal University of São Paulo (UNIFESP), São Paulo 04039-032, Brazil
| | - Adriano C. Arruda
- Laboratory of Genetics and Exercise Metabolism, Nephrology Program, Biophysics Department, Federal University of São Paulo (UNIFESP), São Paulo 04039-032, Brazil
| | - Raisa B. Santos
- Laboratory of Genetics and Exercise Metabolism, Nephrology Program, Biophysics Department, Federal University of São Paulo (UNIFESP), São Paulo 04039-032, Brazil
| | - Lila M. Oyama
- Laboratory of Nutrition and Endocrine Physiology, Physiology Department, Federal University of São Paulo (UNIFESP), São Paulo 04023-901, Brazil
| | - Marcelo A.S. Mori
- Laboratory of Aging Biology, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), São Paulo 13083-862, Brazil
| | - Michael Bader
- Max-Delbrück Center for Molecular Medicine (MDC), Campus Berlin-Buch, 13125 Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- Institute for Biology, University of Lübeck, Lübeck, Germany
- Charité University Medicine Berlin, Berlin, Germany
| | - Ronaldo C. Araujo
- Laboratory of Genetics and Exercise Metabolism, Molecular Biology Program, Biophysics Department, Federal University of São Paulo (UNIFESP), São Paulo 04039-032, Brazil
- Laboratory of Genetics and Exercise Metabolism, Nephrology Program, Biophysics Department, Federal University of São Paulo (UNIFESP), São Paulo 04039-032, Brazil
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Visniauskas B, Perry JC, Gomes GN, Nogueira-Pedro A, Paredes-Gamero EJ, Tufik S, Chagas JR. Intermittent hypoxia changes the interaction of the kinin-VEGF system and impairs myocardial angiogenesis in the hypertrophic heart. Physiol Rep 2021; 9:e14863. [PMID: 33991464 PMCID: PMC8123545 DOI: 10.14814/phy2.14863] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 03/29/2021] [Accepted: 04/13/2021] [Indexed: 12/12/2022] Open
Abstract
Intermittent hypoxia (IH) is a feature of obstructive sleep apnea (OSA), a condition highly associated with hypertension-related cardiovascular diseases. Repeated episodes of IH contribute to imbalance of angiogenic growth factors in the hypertrophic heart, which is key in the progression of cardiovascular complications. In particular, the interaction between vascular endothelial growth factor (VEGF) and the kallikrein-kinin system (KKS) is essential for promoting angiogenesis. However, researchers have yet to investigate experimental models of IH that reproduce OSA, myocardial angiogenesis, and expression of KKS components. We examined temporal changes in cardiac angiogenesis in a mouse IH model. Adult male C57BI/6 J mice were implanted with Matrigel plugs and subjected to IH for 1-5 weeks with subsequent weekly histological evaluation of vascularization. Expression of VEGF and KKS components was also evaluated. After 3 weeks, in vivo myocardial angiogenesis and capillary density were decreased, accompanied by a late increase of VEGF and its type 2 receptor. Furthermore, IH increased left ventricular myocardium expression of the B2 bradykinin receptor, while reducing mRNA levels of B1 receptor. These results suggest that in IH, an unexpected response of the VEGF and KKS systems could explain the reduced capillary density and impaired angiogenesis in the hypoxic heart, with potential implications in hypertrophic heart malfunction.
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Affiliation(s)
- Bruna Visniauskas
- Departamento de Psicobiologia, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Juliana C Perry
- Departamento de Psicobiologia, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Guiomar N Gomes
- Departmento de Fisiologia, Universidade Federal de São Paulo, São Paulo, Brazil
| | | | | | - Sergio Tufik
- Departamento de Psicobiologia, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Jair R Chagas
- Departamento de Psicobiologia, Universidade Federal de São Paulo, São Paulo, Brazil.,Departamento de Biofísica, Universidade Federal de São Paulo, São Paulo, Brazil
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Wang Q, Zhang X, Wang K, Zhu L, Qiu B, Chen X, Lin X, Nie Y. An In Vitro Model of Diabetic Retinal Vascular Endothelial Dysfunction and Neuroretinal Degeneration. J Diabetes Res 2021; 2021:9765119. [PMID: 34805414 PMCID: PMC8598328 DOI: 10.1155/2021/9765119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 10/09/2021] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Diabetic retinopathy (DR) is a leading cause of blindness in working-age populations. Proper in vitro DR models are crucial for exploring pathophysiology and identifying novel therapeutic targets. This study establishes a rational in vitro diabetic retinal neuronal-endothelial dysfunction model and a comprehensive downstream validation system. METHODS Human retinal vascular endothelial cells (HRMECs) and retinal ganglion cells (RGCs) were treated with different glucose concentrations with mannitol as matched osmotic controls. Cell proliferation and viability were evaluated by the Cell Counting Kit-8. Cell migration was measured using a transwell migration assay. Cell sprouting was assessed by a tube formation assay. The VEGF expression was assessed by ELISA. RGCs were labeled by neurons and RGC markers TUJ1 and BRN3A for quantitative and morphological analysis. Apoptosis was detected using PI/Hoechst staining and TUNEL assay and quantified by ImageJ. RESULTS Cell proliferation and migration in HRMECs were significantly higher in the 25 mM glucose-treated group (p < 0.001) but lower in the 50 mM and 100 mM groups (p < 0.001). The permeability and the apoptotic index in HRMECs were statistically higher in the 25 mM, 50 mM, and 100 mM groups (p < 0.05). The tube formation assay found that all the parameters were significantly higher in the 25 mM and 50 mM groups (p < 0.001) concomitant with the elevated VEGFA expression in HRMECs (p = 0.016). Cell viability was significantly lower in the 50 mM, 100 mM, and 150 mM groups in RGCs (p 50mM = 0.013, p 100mM = 0.019, and p 150mM = 0.002). Apoptosis was significantly elevated, but the proportion of RGCs with neurite extension was significantly lower in the 50 mM, 100 mM, and 150 mM groups (p 50mM < 0.001, p 100mM < 0.001, and p 150mM < 0.001). CONCLUSIONS We have optimized glucose concentrations to model diabetic retinal endothelial (25-50 mM) or neuronal (50-100 mM) dysfunction in vitro, which have a wide range of downstream applications.
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Affiliation(s)
- Qiyun Wang
- Beijing Institute of Ophthalmology, Tongren Eye Center, Beijing Tongren Hospital, Capital Medical Univeristy, Beijing, China
- Beijing Retinal and Choroidal Vascular Diseases Study Group, China
| | - Xinyuan Zhang
- Beijing Institute of Ophthalmology, Tongren Eye Center, Beijing Tongren Hospital, Capital Medical Univeristy, Beijing, China
- Beijing Retinal and Choroidal Vascular Diseases Study Group, China
| | - Kaiyue Wang
- Beijing Institute of Ophthalmology, Tongren Eye Center, Beijing Tongren Hospital, Capital Medical Univeristy, Beijing, China
| | - Ling Zhu
- Save Sight Institute, Department of Ophthalmology, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Bingjie Qiu
- Beijing Institute of Ophthalmology, Tongren Eye Center, Beijing Tongren Hospital, Capital Medical Univeristy, Beijing, China
- Beijing Retinal and Choroidal Vascular Diseases Study Group, China
| | - Xiaosi Chen
- Beijing Institute of Ophthalmology, Tongren Eye Center, Beijing Tongren Hospital, Capital Medical Univeristy, Beijing, China
- Beijing Retinal and Choroidal Vascular Diseases Study Group, China
| | - Xiao Lin
- Beijing Institute of Ophthalmology, Tongren Eye Center, Beijing Tongren Hospital, Capital Medical Univeristy, Beijing, China
| | - Yao Nie
- Beijing Institute of Ophthalmology, Tongren Eye Center, Beijing Tongren Hospital, Capital Medical Univeristy, Beijing, China
- Beijing Retinal and Choroidal Vascular Diseases Study Group, China
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Wang J, Ji E, Lin C, Wang L, Dai L, Gao W. Effects of bradykinin on the survival of multiterritory perforator flaps in rats. World J Surg Oncol 2019; 17:44. [PMID: 30813916 PMCID: PMC6394035 DOI: 10.1186/s12957-019-1570-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Accepted: 01/27/2019] [Indexed: 02/08/2023] Open
Abstract
Background Bradykinin, a vasoactive peptide, has many biological functions. For example, it accelerates angiogenesis. Thus, we studied the effects of bradykinin on the survival of perforator flaps. Methods Averagely, 50 male Sprague–Dawley rats were divided into control and bradykinin groups and underwent procedures to the multiterritory perforator flap. Areas of flap survival were tested 7 days later. Flap perfusion was evaluated by laser Doppler imaging. We assessed the extent of autophagy by determining LC3-II/I, Beclin 1, and p62. Flap angiogenesis was assessed by immunohistochemistry and H&E staining. We measured the level of vascular endothelial growth factor (VEGF) protein using western blot. We assessed oxidative stress by measuring the activity of superoxide dismutase (SOD) and malondialdehyde (MDA) levels. The apoptotic index was also evaluated by western blot, and we determined nitric oxide (NO) production using an NO assay kit. Results The bradykinin group exhibited significantly larger areas of flap survival, higher blood supply, and more neovascularization. The bradykinin group also had higher SOD activity, higher VEGF expression and NO content, and reduced MDA compared to the control group. Rats treated with bradykinin also had lower levels of apoptosis and autophagy relative to the control group. Conclusion Our results suggest that bradykinin promotes the survival of multiterritory perforator flaps by increasing angiogenesis, promoting the release of NO, suppressing apoptosis, reducing oxidative stress, and inhibiting autophagy.
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Affiliation(s)
- Jieke Wang
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, The Second Clinical Medical College of Wenzhou Medical University, Wenzhou Medical University, No. 109, Xue Yuan Road (West), Lucheng District, Wenzhou, 325000, China
| | - Encheng Ji
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, The Second Clinical Medical College of Wenzhou Medical University, Wenzhou Medical University, No. 109, Xue Yuan Road (West), Lucheng District, Wenzhou, 325000, China
| | - Chen Lin
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, The Second Clinical Medical College of Wenzhou Medical University, Wenzhou Medical University, No. 109, Xue Yuan Road (West), Lucheng District, Wenzhou, 325000, China
| | - Long Wang
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, The Second Clinical Medical College of Wenzhou Medical University, Wenzhou Medical University, No. 109, Xue Yuan Road (West), Lucheng District, Wenzhou, 325000, China
| | - Li Dai
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, The Second Clinical Medical College of Wenzhou Medical University, Wenzhou Medical University, No. 109, Xue Yuan Road (West), Lucheng District, Wenzhou, 325000, China
| | - Weiyang Gao
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, The Second Clinical Medical College of Wenzhou Medical University, Wenzhou Medical University, No. 109, Xue Yuan Road (West), Lucheng District, Wenzhou, 325000, China.
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Chao J, Li P, Chao L. Kallistatin suppresses cancer development by multi-factorial actions. Crit Rev Oncol Hematol 2017; 113:71-78. [PMID: 28427524 PMCID: PMC5441310 DOI: 10.1016/j.critrevonc.2017.03.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 02/17/2017] [Accepted: 03/11/2017] [Indexed: 01/07/2023] Open
Abstract
Kallistatin was first identified in human plasma as a tissue kallikrein-binding protein and a serine proteinase inhibitor. Kallistatin via its two structural elements regulates differential signaling cascades, and thus a wide spectrum of biological functions. Kallistatin's active site is essential for: inhibiting tissue kallikrein's activity; stimulating endothelial nitric oxide synthase and sirtuin 1 expression and activation; and modulating the synthesis of the microRNAs, miR-34a, miR-21 and miR-203. Kallistatin's heparin-binding site is crucial for antagonizing the signaling pathways of vascular endothelial growth factor, tumor necrosis factor-α, Wnt, transforming growth factor-β and epidermal growth factor. Circulating kallistatin levels are markedly reduced in patients with prostate and colon cancer. Kallistatin administration attenuates angiogenesis, inflammation, tumor growth and invasion in animal models and cultured cells. Therefore, tumor progression may be substantially suppressed by kallistatin's pleiotropic activities. In this review, we will discuss the role and mechanisms of kallistatin in the regulation of cancer development.
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Affiliation(s)
- Julie Chao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.
| | - Pengfei Li
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Lee Chao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
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Intracellular signaling pathways involved in the release of IL-4 and VEGF from human keratinocytes by activation of kinin B1 receptor: functional relevance to angiogenesis. Arch Dermatol Res 2015; 307:803-17. [PMID: 26338700 DOI: 10.1007/s00403-015-1595-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Revised: 08/04/2015] [Accepted: 08/20/2015] [Indexed: 12/11/2022]
Abstract
The injured skin produces a number of mediators that directly or indirectly modulate cell chemotaxis, migration, proliferation, and angiogenesis. Components of the kinin pathway including the kinin B1 receptor (B1R) have been found to occur in the human skin, but information about its role on keratinocyte biology is still scarce. Our aim was to determine whether stimulation of B1R causes the secretion of IL-4 and/or VEGF from human keratinocytes and to evaluate the role of the B1R agonist Lys-des[Arg(9)]bradykinin and IL-4 on various stages of angiogenesis, such as cell migration, proliferation, and release of metalloproteases. By using ELISA and Western blotting, we showed that HaCaT keratinocytes stimulated with the B1R agonist release IL-4 and VEGF. Stimulation of B1R also caused transient c-JunN-terminal kinase phosphorylation and JunB nuclear translocation, transcription factor that regulates IL-4 expression. The 3D-angiogenesis assay, performed on spheroids of EA.hy923 endothelial cells embedded in a collagen matrix, showed that their cumulative sprout area increased significantly following stimulation with either IL-4 or B1R agonist. Furthermore, these ligands produced significant endothelial cell migration and release of metalloproteases 2 and 9, but did not increase endothelial cell proliferation as measured by 5-bromo-2'-deoxyuridine incorporation. Our results provide experimental evidence that establishes IL-4 and B1R agonist as important angiogenic factors of relevance for skin repair.
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Roh YJ, Jee D, Rho CR, Cho WK, Kang S. Anti-angiogenic effect of ALS-L1023, an extract of Melissa officinalis L., on experimental choroidal neovascularization in mice. Clin Exp Ophthalmol 2015. [PMID: 26221970 DOI: 10.1111/ceo.12583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND The effect of ALS-L1023, an extract of Melissa officinalis L. (Labiatae; lemon balm) leaves, on experimental choroidal neovascularization (CNV) in mice was evaluated. METHODS C57BL/6 mice were given either vehicle or ALS-L1023 daily via oral gavage for 3 weeks (days 0-21). CNV was induced by rupturing Bruch's membrane using laser photocoagulation (day 7). Two weeks after laser injury (day 21), the CNV lesions were evaluated by an examination of choroidal flat mounts using fluorescein-labelled dextran, immunofluorescence staining with isolectin B4 and fluorescence angiography. The effects of ALS-L1023 on endothelial cell tube formation and the expression of phosphorylated extracellular signal-regulated kinase 1/2 were evaluated using human umbilical vein endothelial cells. RESULTS The extent of CNV was reduced by ALS-L1023. Mice treated with 100 and 200 mg/kg/day of the material exhibited 44.3 and 68.1% reductions in the extent of CNV lesions, respectively, compared to the vehicle group (P < 0.001). The size of the isolectin B4-labelled area was also significantly decreased in the ALS-L1023-treated groups (P < 0.001). On fluorescein angiography, ALS-L1023-treated mice exhibited significantly less leakage of fluorescent material than did vehicle-treated mice. ALS-L1023 decreased vascular endothelial growth factor-induced human umbilical vein endothelial cell tube formation in a dose-dependent manner. The expression of phosphorylated extracellular signal-regulated kinase 1/2 was suppressed by ALS-L1023. CONCLUSIONS The laser-induced CNV in mice can be inhibited by ALS-L1023. Therefore, it may have therapeutic potential for the treatment of diseases involving CNV.
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Affiliation(s)
- Young-Jung Roh
- Department of Ophthalmology and Visual Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Donghyun Jee
- Department of Ophthalmology and Visual Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Chang-Rae Rho
- Department of Ophthalmology and Visual Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Clinical Research Institute, College of Medicine , Daejeon St. Mary's Hospital, The Catholic University of Korea, Daejeon, Republic of Korea
| | - Won-Kyung Cho
- Department of Ophthalmology and Visual Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Clinical Research Institute, College of Medicine , Daejeon St. Mary's Hospital, The Catholic University of Korea, Daejeon, Republic of Korea
| | - Seungbum Kang
- Department of Ophthalmology and Visual Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Clinical Research Institute, College of Medicine , Daejeon St. Mary's Hospital, The Catholic University of Korea, Daejeon, Republic of Korea
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Huang D, Wang FB, Guo M, Li S, Yan ML, Yu T, Wei M, Li JB. Effect of combined treatment with rosuvastatin and protein kinase Cβ2 inhibitor on angiogenesis following myocardial infarction in diabetic rats. Int J Mol Med 2014; 35:829-38. [PMID: 25524396 DOI: 10.3892/ijmm.2014.2043] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2014] [Accepted: 12/12/2014] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to investigate the effects of combined treatment with rosuvastatin and LY333531, a selective protein kinase C (PKC)β2 inhibitor, on angiogenesis under hyperglycemic conditions. Human umbilical vein endothelial cells (HUVECs) cultured in medium containing a normal or high concentration of glucose (33.3 mmol/l) were treated with rosuvastatin (0.1 µmol/l) alone or in combination with LY333531 (10 nmol/l). HUVEC migration and tube formation were assessed. Furthermore, rats with streptozotocin-induced diabetes were randomly divided into groups and treated with either rosuvastatin alone (5 mg/kg/day) or in combination with LY333531 (10 mg/kg/day) for 4 weeks following the induction of myocardial infarction (MI). Echocardiographic patterns, the extent of myocardial fibrosis, capillary density in myocardial tissue, the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS), as well as the expression levels of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-α (HIF‑1α) were assessed. The results from the in vitro experiment revealed that the tube-forming and migration ability of the HUVECs exposed to high-glucose medium was significantly improved in the group treated with the combination of rosuvastatin and LY333531. In vivo, the combination of rosuvastatin and LY333531 significantly improved left ventricular function, reduced the extent of myocardial fibrosis and increased myocardial capillary density compared to treatment with rosuvastatin alone. In addition, the expression levels of VEGF, and Akt and eNOS phosphorylation were significantly higher in the group exposed to the combination treatment than in the group treated with rosuvastatin alone. The results of the present study indicate that, compared to treatment with rosuvastatin alone, combined treatment with rosuvastatin and LY333531 promotes a greater level of angiogenesis in diabetic rats with MI. This effect is likely mediated through the upregulation of the VEGF‑dependent Akt/eNOS signaling pathway.
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Affiliation(s)
- Dong Huang
- Division of Cardiology, The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai Jiaotong University School of Medicine, State Key Discipline Division, Shanghai 200233, P.R. China
| | - Fa-Bin Wang
- Division of Cardiology, Tengzhou Central People's Hospital, Tengzhou, Shandong 277500, P.R. China
| | - Ming Guo
- Division of Cardiology, Tengzhou Central People's Hospital, Tengzhou, Shandong 277500, P.R. China
| | - Shuai Li
- Division of Cardiology, The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai Jiaotong University School of Medicine, State Key Discipline Division, Shanghai 200233, P.R. China
| | - Mei-Ling Yan
- Division of Cardiology, The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai Jiaotong University School of Medicine, State Key Discipline Division, Shanghai 200233, P.R. China
| | - Tao Yu
- Division of Cardiology, The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai Jiaotong University School of Medicine, State Key Discipline Division, Shanghai 200233, P.R. China
| | - Meng Wei
- Division of Cardiology, The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai Jiaotong University School of Medicine, State Key Discipline Division, Shanghai 200233, P.R. China
| | - Jing-Bo Li
- Division of Cardiology, The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai Jiaotong University School of Medicine, State Key Discipline Division, Shanghai 200233, P.R. China
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Chao J, Bledsoe G, Chao L. Kallikrein-kinin in stem cell therapy. World J Stem Cells 2014; 6:448-457. [PMID: 25258666 PMCID: PMC4172673 DOI: 10.4252/wjsc.v6.i4.448] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 08/27/2014] [Accepted: 09/01/2014] [Indexed: 02/06/2023] Open
Abstract
The tissue kallikrein-kinin system exerts a wide spectrum of biological activities in the cardiovascular, renal and central nervous systems. Tissue kallikrein-kinin modulates the proliferation, viability, mobility and functional activity of certain stem cell populations, namely mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), mononuclear cell subsets and neural stem cells. Stimulation of these stem cells by tissue kallikrein-kinin may lead to protection against renal, cardiovascular and neural damage by inhibiting apoptosis, inflammation, fibrosis and oxidative stress and promoting neovascularization. Moreover, MSCs and EPCs genetically modified with tissue kallikrein are resistant to hypoxia- and oxidative stress-induced apoptosis, and offer enhanced protective actions in animal models of heart and kidney injury and hindlimb ischemia. In addition, activation of the plasma kallikrein-kinin system promotes EPC recruitment to the inflamed synovium of arthritic rats. Conversely, cleaved high molecular weight kininogen, a product of plasma kallikrein, reduces the viability and vasculogenic activity of EPCs. Therefore, kallikrein-kinin provides a new approach in enhancing the efficacy of stem cell therapy for human diseases.
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Koyama Y, Hayashi M, Nagae R, Tokuyama S, Konishi T. Endothelin-1 increases the expression of VEGF-R1/Flt-1 receptors in rat cultured astrocytes through ETB receptors. J Neurochem 2014; 130:759-69. [PMID: 24862165 DOI: 10.1111/jnc.12770] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Revised: 05/22/2014] [Accepted: 05/23/2014] [Indexed: 01/04/2023]
Abstract
Expressions of vascular endothelial growth factor (VEGF) receptors in astrocytes are increased in damaged brains. To clarify the regulatory mechanisms of VEGF receptors, the effects of endothelin-1 (ET-1) were examined in rat cultured astrocytes. Expressions of VEGF-R1 and -R2 receptor mRNA were at similar levels, whereas the mRNA expressions of VEGF-R3 and Tie-2, a receptor for angiopoietins, were lower. Placenta growth factor, a selective agonist of the VEGF-R1 receptor, induced phosphorylation of focal adhesion kinase (FAK) and extracellular signal regulated kinase 1/2 (ERK1/2). Phosphorylations of FAK and ERK 1/2 were also stimulated by VEGF-E, a selective VEGF-R2 agonist. Increased phosphorylations of FAK and ERK1/2 by VEGF165 were reduced by selective antagonists for VEGF-R1 and -R2. Treatment with ET-1 increased VEGF-R1 mRNA and protein levels. The effects of ET-1 on VEGF-R1 mRNA were mimicked by Ala(1,3,11,15) -ET-1, a selective agonist for ETB receptors, and inhibited by BQ788, an ETB antagonist. ET-1 did not affect the mRNA levels of VEGF-R2, -R3, and Tie-2. Pre-treatment with ET-1 potentiated the effects of placenta growth factor on phosphorylations of FAK and ERK1/2. These findings suggest that ET-1 induces up-regulation of VEGF-R1 receptors in astrocytes, and potentiates VEGF signals in damaged nerve tissues. To clarify the regulatory mechanisms of vascular endothelial growth factor (VEGF) receptors, the effects of endothelin-1 (ET-1) were examined in rat cultured astrocytes. Effects of selective VEGF-R1 and R2 agonist showed that these receptors were linked to focal adhesion kinase (FAK) and extracellular signal regulated kinase 1/2 (ERK1/2). Treatment with ET-1 increased expression of VEGF-R1, which was mediated by ETB receptors. Pre-treatment with ET-1 potentiated the VEGF-R1-mediated activations of FAK and ERK1/2. These findings suggest that ET-1 induces up-regulation of VEGF-R1 receptors in astrocytes.
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Affiliation(s)
- Yutaka Koyama
- Laboratory of Pharmacology, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan
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McDaniel JS, Pilia M, Ward CL, Pollot BE, Rathbone CR. Characterization and multilineage potential of cells derived from isolated microvascular fragments. J Surg Res 2014; 192:214-22. [PMID: 24969547 DOI: 10.1016/j.jss.2014.05.047] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Revised: 05/13/2014] [Accepted: 05/16/2014] [Indexed: 12/31/2022]
Abstract
BACKGROUND A number of therapies are being developed that use microvessels isolated from adipose tissue (microvascular fragments [MVFs]) to improve tissue perfusion and implant survival. Because it has been demonstrated that stem cells are associated with microvessels, the purpose of these studies was to gain further insight into the stem cells associated with MVFs to better understand their therapeutic potential. MATERIALS AND METHODS Cells derived from MVF explants were compared with adipose-derived stem cells (ASCs) based on the expression of cell surface proteins for mesenchymal stem cells and their capacity for angiogenic, neurogenic, adipogenic, and osteogenic differentiation. RESULTS The expression of cell surface proteins for mesenchymal stem cell markers was similar between MVF-derived cells and ASCs; however, the increase in markers consistent with endothelial cells and pericytes was accompanied by an improved ability to form capillary-like networks when cultured on matrigel. MVF-derived cells had increased neuregulin, leptin, and osteopontin expression compared with ASCs when exposed to neurogenic, adipogenic, and osteogenic induction media, respectively. CONCLUSIONS The stem cell functionality of cells derived from MVFs is retained after their isolation. This helps to explain the ability of MVFs to improve tissue perfusion and has implications for the use of MVFs as a means to deliver stem cells within their niche.
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Affiliation(s)
- Jennifer S McDaniel
- Extremity Trauma and Regenerative Medicine Task Area, United States Army Institute of Surgical Research, Fort Sam Houston, Texas
| | - Marcello Pilia
- Extremity Trauma and Regenerative Medicine Task Area, United States Army Institute of Surgical Research, Fort Sam Houston, Texas
| | - Catherine L Ward
- Extremity Trauma and Regenerative Medicine Task Area, United States Army Institute of Surgical Research, Fort Sam Houston, Texas
| | - Beth E Pollot
- Extremity Trauma and Regenerative Medicine Task Area, United States Army Institute of Surgical Research, Fort Sam Houston, Texas; Department of Biomedical Engineering, The University of Texas at San Antonio, San Antonio, Texas
| | - Christopher R Rathbone
- Extremity Trauma and Regenerative Medicine Task Area, United States Army Institute of Surgical Research, Fort Sam Houston, Texas.
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12
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Kränkel N, Madeddu P. Helping the circulatory system heal itself: manipulating kinin signaling to promote neovascularization. Expert Rev Cardiovasc Ther 2014; 7:215-9. [DOI: 10.1586/14779072.7.3.215] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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13
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Chao J, Bledsoe G, Chao L. Tissue kallikrein-kinin therapy in hypertension and organ damage. PROGRESS IN DRUG RESEARCH. FORTSCHRITTE DER ARZNEIMITTELFORSCHUNG. PROGRES DES RECHERCHES PHARMACEUTIQUES 2014; 69:37-57. [PMID: 25130039 DOI: 10.1007/978-3-319-06683-7_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Tissue kallikrein is a serine proteinase that cleaves low molecular weight kininogen to produce kinin peptides, which in turn activate kinin receptors to trigger multiple biological functions. In addition to its kinin-releasing activity, tissue kallikrein directly interacts with the kinin B2 receptor, protease-activated receptor-1, and gamma-epithelial Na channel. The tissue kallikrein-kinin system (KKS) elicits a wide spectrum of biological activities, including reducing hypertension, cardiac and renal damage, restenosis, ischemic stroke, and skin wound injury. Both loss-of-function and gain-of-function studies have shown that the KKS plays an important endogenous role in the protection against health pathologies. Tissue kallikrein/kinin treatment attenuates cardiovascular, renal, and brain injury by inhibiting oxidative stress, apoptosis, inflammation, hypertrophy, and fibrosis and promoting angiogenesis and neurogenesis. Approaches that augment tissue kallikrein-kinin activity might provide an effective strategy for the treatment of hypertension and associated organ damage.
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Girolami JP, Blaes N, Bouby N, Alhenc-Gelas F. Genetic manipulation and genetic variation of the kallikrein-kinin system: impact on cardiovascular and renal diseases. PROGRESS IN DRUG RESEARCH. FORTSCHRITTE DER ARZNEIMITTELFORSCHUNG. PROGRES DES RECHERCHES PHARMACEUTIQUES 2014; 69:145-196. [PMID: 25130042 DOI: 10.1007/978-3-319-06683-7_6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Genetic manipulation of the kallikrein-kinin system (KKS) in mice, with either gain or loss of function, and study of human genetic variability in KKS components which has been well documented at the phenotypic and genomic level, have allowed recognizing the physiological role of KKS in health and in disease. This role has been especially documented in the cardiovascular system and the kidney. Kinins are produced at slow rate in most organs in resting condition and/or inactivated quickly. Yet the KKS is involved in arterial function and in renal tubular function. In several pathological situations, kinin production increases, kinin receptor synthesis is upregulated, and kinins play an important role, whether beneficial or detrimental, in disease outcome. In the setting of ischemic, diabetic or hemodynamic aggression, kinin release by tissue kallikrein protects against organ damage, through B2 and/or B1 bradykinin receptor activation, depending on organ and disease. This has been well documented for the ischemic or diabetic heart, kidney and skeletal muscle, where KKS activity reduces oxidative stress, limits necrosis or fibrosis and promotes angiogenesis. On the other hand, in some pathological situations where plasma prekallikrein is inappropriately activated, excess kinin release in local or systemic circulation is detrimental, through oedema or hypotension. Putative therapeutic application of these clinical and experimental findings through current pharmacological development is discussed in the chapter.
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15
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Hypoxia induces permeability and giant cell responses of Andes virus-infected pulmonary endothelial cells by activating the mTOR-S6K signaling pathway. J Virol 2013; 87:12999-3008. [PMID: 24067973 DOI: 10.1128/jvi.02103-13] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Andes virus (ANDV) is a South American hantavirus that causes a highly lethal hantavirus pulmonary syndrome (HPS) characterized by hypoxia, thrombocytopenia, and vascular leakage leading to acute pulmonary edema. ANDV infects human pulmonary microvascular and lymphatic endothelial cells (MECs and LECs, respectively) and nonlytically enhances the permeability of interendothelial cell adherence junctions in response to vascular endothelial growth factor (VEGF). Recent findings also indicate that ANDV causes the formation of giant endothelial cells. Here, we demonstrate that hypoxic conditions alone enhance permeability and giant cell responses of ANDV-infected MECs and LECs through activation of the mTOR signaling pathway. In contrast to infection of cells with nonpathogenic Tula virus (TULV), we observed that exposure of ANDV-infected MECs and LECs to hypoxic conditions resulted in a 3- to 6-fold increase in monolayer permeability and the formation of giant cells 3× to 5× normal size. ANDV infection in combination with hypoxic conditions resulted in the enhancement of hypoxia-inducible factor 1α (HIF1α)-directed VEGF A, angiopoietin 4, and EGLN3 transcriptional responses. Constitutive mTOR signaling induces the formation of giant cells via phosphorylation of S6K, and mTOR regulates hypoxia and VEGF A-induced cellular responses. We found that S6K was hyperphosphorylated in ANDV-infected, hypoxia-treated MECs and LECs and that rapamycin treatment for 1 h inhibited mTOR signaling responses and blocked permeability and giant cell formation in ANDV-infected monolayers. These findings indicate that ANDV infection and hypoxic conditions enhance mTOR signaling responses, resulting in enhanced endothelial cell permeability and suggest a role for rapamycin in therapeutically stabilizing the endothelium of microvascular and lymphatic vessels during ANDV infection.
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16
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WANG FABIN, HUANG DONG, ZHU WEI, LI SHUAI, YAN MEILING, WEI MENG, LI JINGBO. Selective inhibition of PKCβ2 preserves cardiac function after myocardial infarction and is associated with improved angiogenesis of ischemic myocardium in diabetic rats. Int J Mol Med 2013; 32:1037-46. [DOI: 10.3892/ijmm.2013.1477] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 08/21/2013] [Indexed: 11/05/2022] Open
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17
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Whalley ET, Figueroa CD, Gera L, Bhoola KD. Discovery and therapeutic potential of kinin receptor antagonists. Expert Opin Drug Discov 2012; 7:1129-48. [DOI: 10.1517/17460441.2012.729038] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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18
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Effects of simulated microgravity on human umbilical vein endothelial cell angiogenesis and role of the PI3K-Akt-eNOS signal pathway. PLoS One 2012; 7:e40365. [PMID: 22808143 PMCID: PMC3396652 DOI: 10.1371/journal.pone.0040365] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2012] [Accepted: 06/07/2012] [Indexed: 01/20/2023] Open
Abstract
Endothelial cells are very sensitive to microgravity and the morphological and functional changes in endothelial cells are believed to be at the basis of weightlessness-induced cardiovascular deconditioning. It has been shown that the proliferation, migration, and morphological differentiation of endothelial cells play critical roles in angiogenesis. However, the influence of microgravity on the ability of endothelial cells to foster angiogenesis remains to be explored in detail. In the present study, we used a clinostat to simulate microgravity, and we observed tube formation, migration, and expression of endothelial nitric oxide synthase (eNOS) in human umbilical vein endothelial cells (HUVEC-C). Specific inhibitors of eNOS and phosphoinositide 3-kinase (PI3K) were added to the culture medium and gravity-induced changes in the pathways that mediate angiogenesis were investigated. After 24 h of exposure to simulated microgravity, HUVEC-C tube formation and migration were significantly promoted.This was reversed by co-incubation with the specific inhibitor of N-nitro-L-arginine methyl ester hydrochloride (eNOS). Immunofluorescence assay, RT-PCR, and Western blot analysis demonstrated that eNOS expression in the HUVEC-C was significantly elevated after simulated microgravity exhibition. Ultrastructure observation via transmission electron microscope showed the number of caveolae organelles in the membrane of HUVEC-C to be significantly reduced. This was correlated with enhanced eNOS activity. Western blot analysis then showed that phosphorylation of eNOS and serine/threonine kinase (Akt) were both up-regulated after exposure to simulated microgravity. However, the specific inhibitor of PI3K not only significantly downregulated the expression of phosphorylated Akt, but also downregulated the phosphorylation of eNOS. This suggested that the PI3K-Akt signal pathway might participate in modulating the activity of eNOS. In conclusion, the present study indicates that 24 h of exposure to simulated microgravity promote angiogenesis among HUVEC-C and that this process is mediated through the PI3K-Akt-eNOS signal pathway.
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Yazawa H, Miyachi M, Furukawa M, Takahashi K, Takatsu M, Tsuboi K, Ohtake M, Murase T, Hattori T, Kato Y, Murohara T, Nagata K. Angiotensin-Converting Enzyme Inhibition Promotes Coronary Angiogenesis in the Failing Heart of Dahl Salt-Sensitive Hypertensive Rats. J Card Fail 2011; 17:1041-50. [DOI: 10.1016/j.cardfail.2011.09.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2011] [Revised: 08/18/2011] [Accepted: 09/01/2011] [Indexed: 01/01/2023]
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20
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Thebault S, González C, García C, Zamarripa DA, Nava G, Vaca L, López-Casillas F, de la Escalera GM, Clapp C. Vasoinhibins Prevent Bradykinin-Stimulated Endothelial Cell Proliferation by Inactivating eNOS via Reduction of both Intracellular Ca2+ Levels and eNOS Phosphorylation at Ser1179. Pharmaceuticals (Basel) 2011. [PMCID: PMC4058677 DOI: 10.3390/ph4071052] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Stéphanie Thebault
- Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Campus UNAM-Juriquilla, Querétaro 76230, Mexico; E-Mails: (C.G.); (C.G.); (D.A.Z.); (G.N.); (G.M.E.); (C.C.)
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +52-442-238-1029; Fax: +52-442-238-1005
| | - Carmen González
- Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Campus UNAM-Juriquilla, Querétaro 76230, Mexico; E-Mails: (C.G.); (C.G.); (D.A.Z.); (G.N.); (G.M.E.); (C.C.)
| | - Celina García
- Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Campus UNAM-Juriquilla, Querétaro 76230, Mexico; E-Mails: (C.G.); (C.G.); (D.A.Z.); (G.N.); (G.M.E.); (C.C.)
| | - David Arredondo Zamarripa
- Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Campus UNAM-Juriquilla, Querétaro 76230, Mexico; E-Mails: (C.G.); (C.G.); (D.A.Z.); (G.N.); (G.M.E.); (C.C.)
| | - Gabriel Nava
- Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Campus UNAM-Juriquilla, Querétaro 76230, Mexico; E-Mails: (C.G.); (C.G.); (D.A.Z.); (G.N.); (G.M.E.); (C.C.)
| | - Luis Vaca
- Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, Del. Coyoacán, México, D.F., 04510, Mexico; E-Mails: (L.V.); (F.L.-C.)
| | - Fernando López-Casillas
- Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, Del. Coyoacán, México, D.F., 04510, Mexico; E-Mails: (L.V.); (F.L.-C.)
| | - Gonzalo Martínez de la Escalera
- Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Campus UNAM-Juriquilla, Querétaro 76230, Mexico; E-Mails: (C.G.); (C.G.); (D.A.Z.); (G.N.); (G.M.E.); (C.C.)
| | - Carmen Clapp
- Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Campus UNAM-Juriquilla, Querétaro 76230, Mexico; E-Mails: (C.G.); (C.G.); (D.A.Z.); (G.N.); (G.M.E.); (C.C.)
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21
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Moyes AJ, Maldonado-Pérez D, Gray GA, Denison FC. Enhanced angiogenic capacity of human umbilical vein endothelial cells from women with preeclampsia. Reprod Sci 2011; 18:374-82. [PMID: 20962332 DOI: 10.1177/1933719110385131] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Maternal and placental angiogenic abnormalities are a common feature of preeclampsia. The aim of this study was to determine if endothelial cells from women with preeclampsia exhibit different angiogenic responses compared to healthy cells. Using the endothelial tube formation assay, we have shown that primary human umbilical vein endothelial cells (HUVECs) isolated from women with preeclampsia display greater levels of in vitro angiogenic branching compared to cells from healthy women. A comparable increase in tube formation was observed in healthy cells cultured at 0.5% O(2). Vascular endothelial growth factor (VEGF) receptor inhibition resulted in a decrease in angiogenesis in both healthy hypoxic cells and cells from women with preeclampsia. These findings demonstrate that HUVECs from women with preeclampsia exhibit inherent differences in their angiogenic capacity which are apparent in the absence of placental or maternal factors.
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Affiliation(s)
- Amie J Moyes
- Centre for Reproductive Biology, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
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22
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Valdés G, Corthorn J. Review: The angiogenic and vasodilatory utero-placental network. Placenta 2011; 32 Suppl 2:S170-5. [DOI: 10.1016/j.placenta.2011.01.008] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2010] [Revised: 12/31/2010] [Accepted: 01/11/2011] [Indexed: 01/23/2023]
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23
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Sinha S, Sridhara SRC, Srinivasan S, Muley A, Majumder S, Kuppusamy M, Gupta R, Chatterjee S. NO (nitric oxide): the ring master. Eur J Cell Biol 2010; 90:58-71. [PMID: 20800929 DOI: 10.1016/j.ejcb.2010.07.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2010] [Revised: 07/02/2010] [Accepted: 07/07/2010] [Indexed: 11/24/2022] Open
Abstract
The migration and proliferation of endothelial cells affect the process of angiogenesis or the formation of blood vessels. Endothelial cells interact with each other to form ring-like structures in monolayers and tubular structures in matrigels. However, the transit phase between the individual endothelial cells and fully formed tubular structures is yet to be established. Guided by imaging, Western blot analysis, drug perturbation studies and siRNA studies we validate that endothelial ring structures are the fundamental and monomeric units of capillary tubes and nitric oxide is implicated in their fabrication. Giving input from experimental data, we used bagging classifier and information-gain to determine some of the physical and chemical parameters that define these biological structures. Further, we elucidated the implications of endothelial nitric oxide synthase and the NO/sGC/cGMP pathway in the formation of endothelial rings. We conclude that, formation of endothelial ring structure is important for angiogenesis and is mediated by the NO/sGC/cGMP pathway; and further endothelial rings can be used as in vitro models to study angiogenesis.
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Affiliation(s)
- Swaraj Sinha
- Vascular Biology Lab, AU-KBC Research Centre, MIT Campus, Anna University, Chennai 600 004, Tamil Nadu, India
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Chao J, Shen B, Gao L, Xia CF, Bledsoe G, Chao L. Tissue kallikrein in cardiovascular, cerebrovascular and renal diseases and skin wound healing. Biol Chem 2010; 391:345-55. [PMID: 20180644 DOI: 10.1515/bc.2010.042] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Tissue kallikrein (KLK1) processes low-molecular weight kininogen to produce vasoactive kinins, which exert biological functions via kinin receptor signaling. Using various delivery approaches, we have demonstrated that tissue kallikrein through kinin B2 receptor signaling exhibits a wide spectrum of beneficial effects by reducing cardiac and renal injuries, restenosis and ischemic stroke, and by promoting angiogenesis and skin wound healing, independent of blood pressure reduction. Protection by tissue kallikrein in oxidative organ damage is attributed to the inhibition of apoptosis, inflammation, hypertrophy and fibrosis. Tissue kallikrein also enhances neovascularization in ischemic heart and limb. Moreover, tissue kallikrein/kinin infusion not only prevents but also reverses kidney injury, inflammation and fibrosis in salt-induced hypertensive rats. Furthermore, there is a wide time window for kallikrein administration in protection against ischemic brain infarction, as delayed kallikrein infusion for 24 h after cerebral ischemia in rats is effective in reducing neurological deficits, infarct size, apoptosis and inflammation. Importantly, in the clinical setting, human tissue kallikrein has been proven to be effective in the treatment of patients with acute brain infarction when injected within 48 h after stroke onset. Finally, kallikrein promotes skin wound healing and keratinocyte migration by direct activation of protease-activated receptor 1.
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Affiliation(s)
- Julie Chao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, 29425, USA.
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Clapp C, Thebault S, Jeziorski MC, Martínez De La Escalera G. Peptide hormone regulation of angiogenesis. Physiol Rev 2009; 89:1177-215. [PMID: 19789380 DOI: 10.1152/physrev.00024.2009] [Citation(s) in RCA: 124] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
It is now apparent that regulation of blood vessel growth contributes to the classical actions of hormones on development, growth, and reproduction. Endothelial cells are ideally positioned to respond to hormones, which act in concert with locally produced chemical mediators to regulate their growth, motility, function, and survival. Hormones affect angiogenesis either directly through actions on endothelial cells or indirectly by regulating proangiogenic factors like vascular endothelial growth factor. Importantly, the local microenvironment of endothelial cells can determine the outcome of hormone action on angiogenesis. Members of the growth hormone/prolactin/placental lactogen, the renin-angiotensin, and the kallikrein-kinin systems that exert stimulatory effects on angiogenesis can acquire antiangiogenic properties after undergoing proteolytic cleavage. In view of the opposing effects of hormonal fragments and precursor molecules, the regulation of the proteases responsible for specific protein cleavage represents an efficient mechanism for balancing angiogenesis. This review presents an overview of the actions on angiogenesis of the above-mentioned peptide hormonal families and addresses how specific proteolysis alters the final outcome of these actions in the context of health and disease.
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Affiliation(s)
- Carmen Clapp
- Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Mexico.
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26
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Liesmaa I, Leskinen HK, Kokkonen JO, Ruskoaho H, Kovanen PT, Lindstedt KA. Hypoxia-induced expression of bradykinin type-2 receptors in endothelial cells triggers NO production, cell migration, and angiogenesis. J Cell Physiol 2009; 221:359-66. [DOI: 10.1002/jcp.21861] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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The role of the renin-angiotensin-aldosterone system in cardiovascular progenitor cell function. Clin Sci (Lond) 2009; 116:301-14. [PMID: 19138171 DOI: 10.1042/cs20080157] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Intervention in the RAAS (renin-angiotensin-aldosterone system) is one of the leading pharmacotherapeutic strategies, among others, used for the treatment of cardiovascular disease to improve the prognosis after myocardial infarction and to reduce hypertension. Recently, regenerative progenitor cell therapy has emerged as a possible alternative for pharmacotherapy in patients after myocardial infarction or ischaemic events elsewhere, e.g. in the limbs. Angiogenic cell therapy to restore the vascular bed in ischaemic tissues is currently being tested in a multitude of clinical studies. This has prompted researchers to investigate the effect of modulation of the RAAS on progenitor cells. Furthermore, the relationship between hypertension and endothelial progenitor cell function is being studied. Pharmacotherapy by means of angiotensin II type 1 receptor antagonists or angiotensin-converting enzyme inhibitors has varying effects on progenitor cell levels and function. These controversial effects may be explained by involvement of multiple mediators, e.g. angiotensin II and angiotensin-(1-7), that have differential effects on mesenchymal stem cells, haematopoietic progenitor cells and endothelial progenitor cells. Importantly, angiotensin II can either stimulate endothelial progenitor cells by improvement of vascular endothelial growth factor signalling, or invoke excessive production of reactive oxygen species causing premature senescence of these cells. On the other hand, angiotensin-(1-7) stimulates haematopoietic cells and possibly also endothelial progenitor cells. Furthermore, aldosterone, bradykinin and Ac-SDKP (N-acetyl-Ser-Asp-Lys-Pro) may also affect progenitor cell populations. Alternatively, the variability in effects of angiotensin II type 1 receptor and angiotensin-converting enzyme inhibition on cardiovascular progenitor cells might reflect differences between the various models or diseases with respect to circulating and local tissue RAAS activation. In the present review we discuss what is currently known with respect to the role of the RAAS in the regulation of cardiovascular progenitor cells.
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Martins-Green M, Petreaca M, Yao M. An assay system for in vitro detection of permeability in human "endothelium". Methods Enzymol 2009; 443:137-53. [PMID: 18772015 DOI: 10.1016/s0076-6879(08)02008-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The molecular mechanisms by which endothelial permeability occurs are often studied more readily in vitro, underscoring the importance of the use of systems that mimic human endothelium in vivo. We present an assay that accurately models human endothelium by use of primary human microvascular endothelial cells (hMVEC), because permeability primarily occurs at the microvascular level, and transwell filter units coated with Matrigel, extracellular matrix that mimics basal lamina, the matrix that is tightly associated with endothelium and is critical for its proper function. As a tracer molecule, we used 3-kDa dextran-FITC to detect leakage through the small gaps present in the early stages of permeability induction. The permeability-inducing agents IL-8 and VEGF were added to the lower chamber of the transwell units to mimic inflammatory conditions in vivo. After optimization, we were able to minimize basal permeability and to detect rapid changes in permeability stimulated by IL-8 and VEGF, similar to that observed in vivo. Furthermore, we have used this system to delineate the importance of the transactivation of VEGFR2 in IL-8-induced permeability and have confirmed the relevance of this signaling in vivo, suggesting that our permeability assay system adequately mimics the in vivo situation. Therefore, this system can be used to better understand the molecular mechanisms of human vascular permeability in a more in vivo-like setting and, thus, may be used to test effective therapeutics to prevent and treat diseases involving persistent permeability.
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Affiliation(s)
- Manuela Martins-Green
- Department of Cell Biology and Neuroscience, University of California, Riverside, California, USA
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Kränkel N, Katare RG, Siragusa M, Barcelos LS, Campagnolo P, Mangialardi G, Fortunato O, Spinetti G, Tran N, Zacharowski K, Wojakowski W, Mroz I, Herman A, Manning Fox JE, MacDonald PE, Schanstra JP, Bascands JL, Ascione R, Angelini G, Emanueli C, Madeddu P. Role of kinin B2 receptor signaling in the recruitment of circulating progenitor cells with neovascularization potential. Circ Res 2008; 103:1335-43. [PMID: 18927465 PMCID: PMC2821015 DOI: 10.1161/circresaha.108.179952] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Reduced migratory function of circulating angiogenic progenitor cells (CPCs) has been associated with impaired neovascularization in patients with cardiovascular disease (CVD). Previous findings underline the role of the kallikrein-kinin system in angiogenesis. We now demonstrate the involvement of the kinin B2 receptor (B(2)R) in the recruitment of CPCs to sites of ischemia and in their proangiogenic action. In healthy subjects, B(2)R was abundantly present on CD133(+) and CD34(+) CPCs as well as cultured endothelial progenitor cells (EPCs) derived from blood mononuclear cells (MNCs), whereas kinin B1 receptor expression was barely detectable. In transwell migration assays, bradykinin (BK) exerts a potent chemoattractant activity on CD133(+) and CD34(+) CPCs and EPCs via a B(2)R/phosphoinositide 3-kinase/eNOS-mediated mechanism. Migration toward BK was able to attract an MNC subpopulation enriched in CPCs with in vitro proangiogenic activity, as assessed by Matrigel assay. CPCs from cardiovascular disease patients showed low B(2)R levels and decreased migratory capacity toward BK. When injected systemically into wild-type mice with unilateral limb ischemia, bone marrow MNCs from syngenic B(2)R-deficient mice resulted in reduced homing of sca-1(+) and cKit(+)flk1(+) progenitors to ischemic muscles, impaired reparative neovascularization, and delayed perfusion recovery as compared with wild-type MNCs. Similarly, blockade of the B(2)R by systemic administration of icatibant prevented the beneficial effect of bone marrow MNC transplantation. BK-induced migration represents a novel mechanism mediating homing of circulating angiogenic progenitors. Reduction of BK sensitivity in progenitor cells from cardiovascular disease patients might contribute to impaired neovascularization after ischemic complications.
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Affiliation(s)
- Nicolle Kränkel
- Experimental Cardiovascular Medicine, Bristol Heart Institute, UK
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Lam CF, Chang PJ, Huang YS, Sung YH, Huang CC, Lin MW, Liu YC, Tsai YC. Prolonged use of high-dose morphine impairs angiogenesis and mobilization of endothelial progenitor cells in mice. Anesth Analg 2008; 107:686-92. [PMID: 18633053 DOI: 10.1213/ane.0b013e31817e6719] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND Morphine is one of the most commonly prescribed analgesics for treating wound pain. Using a mouse model of excisional wound injury, we determined the effects of high-dose morphine on angiogenesis and mobilization of endothelial progenitor cells. METHODS An excisional wound was created on mice treated with placebo or morphine (20 mg/kg, i.p. injection for 14 days). Wound healing was compared by measuring the final-to-initial wound area ratio. Generation of superoxide anions in the wound was determined by luminol-enhanced chemiluminescence. Circulating mononuclear cells were isolated and measured for endothelial progenitor cell (defined as CD34+/CD133+ cell) counts. In vivo and in vitro measurements of angiogenesis after morphine treatment were performed using the Matrigel assay. RESULTS Mice treated with morphine had reduced wound closure and higher wound superoxide ions concentrations than control mice. Morphine reduced the number of postwound circulating endothelial progenitor cells. Matrigel assay showed impaired angiogenesis in animals and reduced capillary tube formation in cultured endothelial cells treated with morphine. CONCLUSION High-dose morphine impaired angiogenesis, increased systemic oxidative stress, and impaired mobilization of endothelial progenitor cells. This study emphasizes the potential detrimental effect of high-dose morphine on angiogenesis after systemic administration.
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Affiliation(s)
- Chen-Fuh Lam
- Department of Anesthesiology, National Cheng Kung University, Medical College and Hospital, Tainan City, Taiwan
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Yao YY, Yin H, Shen B, Smith RS, Liu Y, Gao L, Chao L, Chao J. Tissue kallikrein promotes neovascularization and improves cardiac function by the Akt-glycogen synthase kinase-3beta pathway. Cardiovasc Res 2008; 80:354-64. [PMID: 18689794 DOI: 10.1093/cvr/cvn223] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
AIMS We investigated the role of the Akt-glycogen synthase kinase (GSK)-3beta signalling pathway in mediating the protective effects of tissue kallikrein on myocardial injury by promoting angiogenesis and blood flow in rats after myocardial infarction (MI). METHODS AND RESULTS Human tissue kallikrein gene in an adenoviral vector, with or without co-administration of dominant-negative Akt (Ad.DN-Akt) or constitutively active GSK-3beta (Ad.GSK-3betaS9A), was injected into rat myocardium after MI. The expression of recombinant human kallikrein in rat heart significantly improved cardiac function and reduced infarct size 10 days after gene delivery. Kallikrein administration significantly increased myocardial blood flow as well as capillary and arteriole densities in the infarcted myocardium. Kallikrein increased cardiac Akt and GSK-3beta phosphorylation in conjunction with decreased GSK-3beta activity and the upregulation of vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2). All of kallikrein's effects on the myocardium were abrogated by Ad.DN-Akt and Ad.GSK-3betaS9A. Moreover, in cultured human aortic endothelial cells, tissue kallikrein stimulated capillary tube formation and promoted cell migration; however, these effects were blocked by Ad.DN-Akt, Ad.GSK-3betaS9A, icatibant (a kinin B2 receptor antagonist), Tki (a VEGF receptor tyrosine kinase inhibitor), and a neutralizing VEGF antibody. In addition, tissue kallikrein decreased GSK-3beta activity via the phosphatidylinositol 3-kinase-Akt pathway and enhanced VEGF and VEGFR-2 expression in endothelial cells. CONCLUSION These data provide the first direct evidence that tissue kallikrein protects against acute-phase MI by promoting neovascularization, restoring regional blood flow and improving cardiac function through the kinin B2 receptor-Akt-GSK-3beta and VEGF signalling pathways.
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Affiliation(s)
- Yu-Yu Yao
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210029, People's Republic of China
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Yeh JC, Otte LA, Frangos JA. Regulation of G protein-coupled receptor activities by the platelet-endothelial cell adhesion molecule, PECAM-1. Biochemistry 2008; 47:9029-39. [PMID: 18672896 DOI: 10.1021/bi8003846] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
It is becoming increasingly evident that the cell-cell junction is a major signaling center. Here we show that the Galphaq/11 subunit of heterotrimeric G proteins forms a complex with platelet-endothelial cell adhesion molecule 1 (PECAM-1), a junctional protein that has been shown to be involved in mechanosignaling in endothelial cells. To understand the role of PECAM-1 in this complex, we determined the critical regions of PECAM-1 involved in this interaction. By expressing truncated forms of PECAM-1 in human embryonic kidney (HEK293) cells, we found that the cytoplasmic domain of PECAM-1 is not required for its association with Galphaq/11. Domain swapping of PECAM-1 with intracellular cell adhesion molecule 1 (ICAM-1), a protein that does not form a complex with Galphaq/11, provides evidence that the extracellular domain of PECAM-1 is critical for this interaction. This result also suggests that PECAM-1 does not directly interact with Galphaq/11. Coexpression of bradykinin receptor B2 (BKRB2), a Galphaq/11-coupled receptor, with PECAM-1 enhances formation of the PECAM-1-Galphaq/11 complex, suggesting an interaction between PECAM-1 and BKRB2. Co-immunoprecipitation experiments indicate that these two molecules indeed form a complex when expressed in HEK293 cells. Activation of ERK1/2 by bradykinin in HUVEC is enhanced when PECAM-1 expression is inhibited by transfection of small interference RNA against PECAM-1. Taken together, our results provide evidence of interaction of PECAM-1 with BKRB2 and of its possible role in regulating G protein-coupled receptor (GPCR) and G protein functions.
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Affiliation(s)
- Jiunn-chern Yeh
- La Jolla Bioengineering Institute, 505 Coast Boulevard South, Suite 406, La Jolla, California 92037, USA
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Wright JK, Botha JH, Naidoo S. Influence of the kallikrein-kinin system on prostate and breast tumour angiogenesis. Tumour Biol 2008; 29:130-6. [PMID: 18577888 DOI: 10.1159/000141918] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2008] [Accepted: 04/18/2008] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS Angiogenesis is important for the growth and progression of cancer cells. There is some evidence that the kallikrein-kinin system (KKS) is involved in cancer and angiogenesis. The present study investigated the effect of increasing concentrations of prostate and breast tumour cell metabolites on the proliferation of cultured endothelial cells, their tissue kallikrein (TK) secretion and KKS expression. METHODS Expression of TK and kinin receptors was investigated by immunochemistry, and secretion of TK by ELISA. Cell proliferation was measured by a chromogenic assay. KKS proteins were also immunolocalised in an endothelial tumour co-culture model. RESULTS KKS proteins were found in projections of all cell types as well as at points of heterogeneous contact. Tumour metabolites increased the secretion of TK from endothelial cells, with corresponding decreases in intracellular amounts, while also increasing proliferation of the endothelial cells. CONCLUSIONS These findings indicate that the KKS may be one of the more important players in angiogenesis associated with prostate and breast tumours.
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Affiliation(s)
- Jaclyn K Wright
- Department of Therapeutics and Medicines Management, Nelson R Mandela School of Medicine Durban, South Africa
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Sanchez de Miguel L, Neysari S, Jakob S, Petrimpol M, Butz N, Banfi A, Zaugg CE, Humar R, Battegay EJ. B2-kinin receptor plays a key role in B1-, angiotensin converting enzyme inhibitor-, and vascular endothelial growth factor-stimulated in vitro angiogenesis in the hypoxic mouse heart. Cardiovasc Res 2008; 80:106-13. [PMID: 18566101 DOI: 10.1093/cvr/cvn170] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
AIMS Angiotensin converting enzyme (ACE) inhibition reduces heart disease and vascular stiffness in hypertension and leads to kinin accumulation. In this study, we analysed the role and importance of two kinin receptor subtypes in angiogenesis during ACE inhibition in an in vitro model of angiogenesis of the mouse heart. METHODS AND RESULTS First, we analysed the angiogenic properties of bradykinin and enalapril on wild-type C57Bl/6 and B2 receptor(-/-) mouse heart under normoxia (21% O(2)) and hypoxia (1% O(2)) in vitro and the contribution of B1 and B2 kinin receptors to this effect. Bradykinin induced dose-dependent endothelial sprout formation in vitro in adult mouse heart only under hypoxia (1.7 fold, n = 6, P < 0.05). The B2 receptor mediated sprouting that was induced by bradykinin and vascular endothelial growth factor (VEGF(164); n = 6, P < 0.05), but did not mediate sprouting that was induced by growth factors bFGF or PDGF-BB. Enalapril induced sprouting through both the B1 and B2 kinin receptors, but it required the presence of the B2 receptor in both scenarios and was dependent on BK synthesis. B1-receptor agonists induced sprout formation via the B1 receptor (2.5 fold, n = 6, P < 0.05), but it required the presence of the B2 receptor for them to do so. Both B2-receptor and B1-receptor agonist-induced angiogenesis required nitric oxide biosynthesis. CONCLUSION The kinin B2 receptor plays a crucial role in angiogenesis that is induced by different vasoactive molecules, namely bradykinin, ACE inhibitors, B1-stimulating kinin metabolites, and VEGF164 in an in vitro model of angiogenesis of mouse heart under hypoxia. Therapeutic treatment of hypertensive patients by using ACE inhibitors may potentially benefit the ischaemic heart through inducing B2-dependent heart neovascularization.
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Kitajima K, Miura SI, Mastuo Y, Uehara Y, Saku K. Newly developed PPAR-alpha agonist (R)-K-13675 inhibits the secretion of inflammatory markers without affecting cell proliferation or tube formation. Atherosclerosis 2008; 203:75-81. [PMID: 18606415 DOI: 10.1016/j.atherosclerosis.2008.05.055] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2007] [Revised: 05/22/2008] [Accepted: 05/29/2008] [Indexed: 11/28/2022]
Abstract
Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a key regulator of lipid and glucose metabolism and has been implicated in inflammation. The vascular effects of activator for PPARs, particularly PPAR-alpha, on vascular cells remain to be fully elucidated. Therefore, we analyzed the hypothesis that newly developed (R)-K-13675 decreases the secretion of inflammatory markers without affecting cell proliferation or tube formation. Human coronary endothelial cells (HCECs) were maintained in different doses of (R)-K-13675 under serum starvation. After 20h, the levels of monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T expressed and secreted (RANTES), interleukin-6 (IL-6) and interferon-gamma (INF-gamma) secreted in the medium and nuclear factor kappa B (NFkappaB) in cell lysate were analyzed using enzyme-linked immunosorbent assays (ELISA). Upon treatment with (R)-K-13675 at 0, 10, 20, 50 and 100nM, with the inflammatory markers at 0nM as 100 (arbitrary units), MCP-1 levels were significantly suppressed (94+/-9, 88+/-2, 80+/-5 and 74+/-11, respectively). RANTES, IL-6 and INF-gamma levels were also significantly suppressed (RANTES: 92+/-2, 74+/-9, 64+/-7 and 60+/-2, respectively, IL-6: 97+/-2, 89+/-10, 82+/-1 and 66+/-7, respectively, INF-gamma: 98+/-7, 94+/-3, 76+/-8 and 64+/-8, respectively). NFkappaB levels were also decreased to 91+/-5, 90+/-5, 84+/-7 and 82+/-8, respectively. In addition, (R)-K-13675 did not affect HCEC proliferation or tube formation at up to 100nM. Thus, (R)-K-13675 was associated with the inhibition of inflammatory responses without affecting cell proliferation or angiogenesis, and subsequently may induce an anti-atherosclerotic effect.
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Affiliation(s)
- Ken Kitajima
- Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
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Imaizumi S, Miura SI, Nakamura K, Kiya Y, Uehara Y, Zhang B, Matsuo Y, Urata H, Ideishi M, Rye KA, Sata M, Saku K. Antiarrhythmogenic effect of reconstituted high-density lipoprotein against ischemia/reperfusion in rats. J Am Coll Cardiol 2008; 51:1604-12. [PMID: 18420105 DOI: 10.1016/j.jacc.2007.12.040] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2007] [Revised: 12/04/2007] [Accepted: 12/10/2007] [Indexed: 11/19/2022]
Abstract
OBJECTIVES This study analyzed the antiarrhythmogenic effect of reconstituted high-density lipoprotein (rHDL) against ischemia/reperfusion in vivo. BACKGROUND Recent studies have suggested that a reduction in the plasma HDL level may contribute to cardiac sudden death. Although there are currently only a few therapeutic strategies for increasing HDL, an exciting new therapeutic option, rHDL, has recently been developed to prevent coronary artery disease. METHODS To analyze the suppression of reperfusion arrhythmia by rHDL (apolipoprotein A-I with 1-palmitoyl-2-oleoyl-phosphatidyl-choline), 92 male Wistar rats were divided into 10 groups: rats that had been pre-treated with or without rHDL, apolipoprotein A-I, or 1-palmitoyl-2-oleoyl-phosphatidyl-choline in the presence or absence of inhibitors of Akt protein kinase, nitric oxide (NO), or extracellular-signal-regulated kinase (ERK) administered intravenously before left coronary artery occlusion. We also used human coronary artery endothelial cells and adenosine triphosphate-binding cassette transporter (ABC) A1-, ABCG1-, or scavenger receptor class B, type I-transfected ldlA7 cells systems. RESULTS The duration of ventricular tachycardia or ventricular fibrillation after reperfusion in rHDL-pre-treated rats was much shorter than that in untreated rats. Apolipoprotein A-I or 1-palmitoyl-2-oleoyl-phosphatidyl-choline alone had no effect. The effect of rHDL was blocked by inhibitors of Akt, NO, and ERK. Plasma NO concentration in the rHDL group was significantly higher. In addition, rHDL activated phospho(p)-Akt, p-ERK, and p-endothelial NO synthesis in endothelial cells. The rHDL activated p-ERK in ABCA1- or ABCG1-transfected but not scavenger receptor class B, type I-transfected ldlA7 cells. CONCLUSIONS The rHDL-induced NO production, probably mediated by ABCA1 or ABCG1 through an Akt/ERK/NO pathway in endothelial cells, may suppress reperfusion-induced arrhythmias. The HDL-based therapy may hold the promise of reducing the incidence of such arrhythmias after ischemia/reperfusion.
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Affiliation(s)
- Satoshi Imaizumi
- Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan
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Miura SI, Matsuo Y, Saku K. Jun N-terminal kinase inhibitor blocks angiogenesis by blocking VEGF secretion and an MMP pathway. J Atheroscler Thromb 2008; 15:69-74. [PMID: 18385538 DOI: 10.5551/jat.e496] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
AIM The excessive proliferation and migration of vascular smooth muscle cells (SMCs) and angiogenesis of endothelial cells (ECs) participate in the growth and instability of atherosclerotic plaques. It is unclear whether Jun N-terminal kinase (JNK) is pro-or anti-atherogenic. METHODS We examined the direct effect of JNK inhibitor (JNK-I) on the proliferation and formation of tubes by human coronary SMCs and human coronary ECs. RESULTS Culture medium from JNK-I-treated SMCs prevented ECs from forming tubes in an in vitro model of angiogenesis indirectly by reducing the amount of vascular endothelial growth factor (VEGF) released from SMCs. In addition, JNK-I attenuated the expression of pro-matrix metalloproteinase-2 in ECs. When added back to the medium of SMCs treated with JNK-I, VEGF blocked the inhibitory effect on the formation of tubes. CONCLUSION Our results indicate JNK-I to have a direct anti-atherogenic effect in SMCs and ECs.
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Affiliation(s)
- Shin-ichiro Miura
- Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, Japan.
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Valdés G, Erices R, Chacón C, Corthorn J. Angiogenic, hyperpermeability and vasodilator network in utero-placental units along pregnancy in the guinea-pig (Cavia porcellus). Reprod Biol Endocrinol 2008; 6:13. [PMID: 18371207 PMCID: PMC2291058 DOI: 10.1186/1477-7827-6-13] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2007] [Accepted: 03/27/2008] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND The angiogenic and invasive properties of the cytotrophoblast are crucial to provide an adequate area for feto-maternal exchange. The present study aimed at identifying the localization of interrelated angiogenic, hyperpermeability and vasodilator factors in the feto-maternal interface in pregnant guinea-pigs. METHODS Utero-placental units were collected from early to term pregnancy. VEGF, Flt-1, KDR, B2R and eNOS were analyzed by immunohistochemistry, and the intensity of the signals in placenta and syncytial streamers was digitally analysed. Flt1 and eNOS content of placental homogenates was determined by western blotting. Statistical analysis used one-way analysis of variance and Tukey's Multiple Comparison post-hoc test. RESULTS In the subplacenta, placental interlobium and labyrinth VEGF, Flt-1, KDR, B2R and eNOS were expressed in all stages of pregnancy. Syncytial streamers in all stages of gestation, and cytotrophoblasts surrounding myometrial arteries in early and mid pregnancy - and replacing the smooth muscle at term - displayed immunoreactivity for VEGF, Flt-1, KDR, eNOS and B2R. In partly disrupted mesometrial arteries in late pregnancy cytotrophoblasts and endothelial cells expressed VEGF, Flt-1, KDR, B2R and eNOS. Sections incubated in absence of the first antibody, or in presence of rabbit IgG fraction and mouse IgG serum, yielded no staining. According to the digital analysis, Flt-1 increased in the placental interlobium in days 40 and 60 as compared to day 20 (P = 0.016), and in the labyrinth in day 60 as compared to days 20 and 40 (P = 0.026), while the signals for VEGF, KDR, B2R, and eNOS showed no variations along pregnancy. In syncytial streamers the intensity of VEGF immunoreactivity was increased in day 40 in comparison to day 20 (P = 0.027), while that of B2R decreased in days 40 and 60 as compared to day 20 (P = 0.011); VEGF, Flt-1, KDR, B2R and eNOS expression showed no variations. Western blots for eNOS and Flt-1 in placental homogenates showed no significant temporal differences along pregnancy. CONCLUSION The demonstration of different angiogenic, hyperpermeability and vasodilator factors in the same cellular protagonists of angiogenesis and invasion in the pregnant guinea-pig, supports the presence of a functional network, and strengthens the argument that this species provides an adequate model to understand human pregnancy.
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Affiliation(s)
- Gloria Valdés
- Departamento de Nefrología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 391, 8330024 Santiago, Chile
- Centro de Investigaciones Médicas, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Rafaela Erices
- Centro de Investigaciones Médicas, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Cecilia Chacón
- Centro de Investigaciones Médicas, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Jenny Corthorn
- Departamento de Nefrología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 391, 8330024 Santiago, Chile
- Centro de Investigaciones Médicas, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
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Li P, Kondo T, Numaguchi Y, Kobayashi K, Aoki M, Inoue N, Okumura K, Murohara T. Role of Bradykinin, Nitric Oxide, and Angiotensin II Type 2 Receptor in Imidapril-Induced Angiogenesis. Hypertension 2008; 51:252-8. [DOI: 10.1161/hypertensionaha.107.097394] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The angiotensin II (Ang II)-Ang II type 1 receptor pathway is proangiogenic, whereas studies showed that some angiotensin-converting enzyme inhibitors also stimulate angiogenesis in the setting of tissue ischemia, leaving a controversy of Ang II-mediated angiogenesis. We investigated whether an angiotensin-converting enzyme inhibitor imidapril-induced angiogenesis might be mediated via the tissue bradykinin pathway. To rule out the conventional effects of Ang II on angiogenesis, we used Ang II type 1a receptor knockout (AT1aKO) mice. We examined the effects of the angiotensin-converting enzyme inhibitor imidapril on angiogenesis in a hindlimb ischemia model using AT1aKO mice. After induction of hindlimb ischemia, AT1aKO mice were treated with or without imidapril (1.0 or 0.1 mg/kg per day for 21 days). Angiogenesis was quantified by laser Doppler blood flowmetry and capillary density. Angiogenesis was reduced in AT1aKO mice compared with wild-type mice. Imidapril with either low or high doses enhanced angiogenesis in AT1aKO mice (
P
<0.01). Ang II type 2 receptor antagonist (PD123319; 30 mg/kg per day) and B1 receptor antagonist (DesArg9-[Leu8]-bradykinin; 50 nmol/kg per day) suppressed the imidapril-induced angiogenesis in AT1aKO mice to an extent even lower than that of nontreated AT1aKO mice. B2 receptor antagonist (Hoechst 140; 100 μg/kg/d) and NO synthase inhibitor (
N
G
-nitro-
l
-arginine methyl ester; 20 mg/kg per day) moderately attenuated the imidapril-mediated angiogenesis. RT-PCR revealed that vascular endothelial growth factor receptor 2 mRNA was reduced with PD123319, DesArg9-[Leu8]-bradykinin, or Hoechst 140, and vascular endothelial growth factor mRNA abundance was suppressed with PD123319 or DesArg9-[Leu8]-bradykinin. In conclusion, imidapril elicited angiogenesis in the setting of tissue ischemia in AT1aKO mice. This angiogenic effect might involve the Ang II-Ang II type 2 receptor pathway in addition to the bradykinin-B1 and bradykinin-B2 receptor/NO-dependent pathways.
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Affiliation(s)
- Ping Li
- From the Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takahisa Kondo
- From the Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasushi Numaguchi
- From the Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Koichi Kobayashi
- From the Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mika Aoki
- From the Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Natsuo Inoue
- From the Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kenji Okumura
- From the Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Toyoaki Murohara
- From the Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Greenberg Y, King M, Kiosses WB, Ewalt K, Yang X, Schimmel P, Reader JS, Tzima E. The novel fragment of tyrosyl tRNA synthetase, mini-TyrRS, is secreted to induce an angiogenic response in endothelial cells. FASEB J 2007; 22:1597-605. [PMID: 18165356 DOI: 10.1096/fj.07-9973com] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Aminoacyl tRNA synthetases--enzymes that catalyze the first step of protein synthesis--in mammalian cells are now known to have expanded functions, including activities in signal transduction pathways, such as those for angiogenesis and inflammation. The native synthetases themselves are procytokines, having no signal transduction activities. After alternative splicing or natural proteolysis, specific fragments that are potent cytokines and that interact with specific receptors on cell surfaces are released. In this manner, a natural fragment of human tyrosyl tRNA synthetase (TyrRS), mini-TyrRS, has been shown to act as a proangiogenic cytokine. The mechanistic basis for the action of mini-TyrRS in angiogenesis has yet to be established. Here, we show that mini-TyrRS is exported from endothelial cells when they are treated with tumor necrosis factor-alpha. Mini-TyrRS binds to vascular endothelial cells and activates an array of angiogenic signal transduction pathways. Mini-TyrRS-induced angiogenesis requires the activation of vascular endothelial growth factor receptor-2 (VEGFR2/Flk-1/KDR). Mini-TyrRS stimulates VEGFR2 phosphorylation in a VEGF-independent manner, suggesting VEGFR2 transactivation. Transactivation of VEGFR2 and downstream angiogenesis require an intact Glu-Leu-Arg (ELR) motif in mini-TyrRS, which is important for its cytokine activity. These studies therefore suggest a mechanism by which mini-TyrRS induces angiogenesis in endothelial cells and provide further insight into the role of mini-TyrRS as a link between translation and angiogenesis.
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Affiliation(s)
- Y Greenberg
- Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, 103 Mason Farm Rd., Chapel Hill, NC 27599-7545, USA
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Petreaca ML, Yao M, Liu Y, DeFea K, Martins-Green M. Transactivation of vascular endothelial growth factor receptor-2 by interleukin-8 (IL-8/CXCL8) is required for IL-8/CXCL8-induced endothelial permeability. Mol Biol Cell 2007; 18:5014-23. [PMID: 17928406 PMCID: PMC2096609 DOI: 10.1091/mbc.e07-01-0004] [Citation(s) in RCA: 168] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2007] [Revised: 09/28/2007] [Accepted: 10/02/2007] [Indexed: 12/30/2022] Open
Abstract
Interleukin-8 (IL-8/CXCL8) is a chemokine that increases endothelial permeability during early stages of angiogenesis. However, the mechanisms involved in IL-8/CXCL8-induced permeability are poorly understood. Here, we show that permeability induced by this chemokine requires the activation of vascular endothelial growth factor receptor-2 (VEGFR2/fetal liver kinase 1/KDR). IL-8/CXCL8 stimulates VEGFR2 phosphorylation in a VEGF-independent manner, suggesting VEGFR2 transactivation. We investigated the possible contribution of physical interactions between VEGFR2 and the IL-8/CXCL8 receptors leading to VEGFR2 transactivation. Both IL-8 receptors interact with VEGFR2 after IL-8/CXCL8 treatment, and the time course of complex formation is comparable with that of VEGFR2 phosphorylation. Src kinases are involved upstream of receptor complex formation and VEGFR2 transactivation during IL-8/CXCL8-induced permeability. An inhibitor of Src kinases blocked IL-8/CXCL8-induced VEGFR2 phosphorylation, receptor complex formation, and endothelial permeability. Furthermore, inhibition of the VEGFR abolishes RhoA activation by IL-8/CXCL8, and gap formation, suggesting a mechanism whereby VEGFR2 transactivation mediates IL-8/CXCL8-induced permeability. This study points to VEGFR2 transactivation as an important signaling pathway used by chemokines such as IL-8/CXCL8, and it may lead to the development of new therapies that can be used in conditions involving increases in endothelial permeability or angiogenesis, particularly in pathological situations associated with both IL-8/CXCL8 and VEGF.
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Affiliation(s)
- Melissa L. Petreaca
- *Graduate Program in Cell, Molecular, and Developmental Biology
- Department of Cell Biology and Neuroscience, and
| | - Min Yao
- Department of Cell Biology and Neuroscience, and
| | - Yan Liu
- Department of Cell Biology and Neuroscience, and
| | - Kathryn DeFea
- *Graduate Program in Cell, Molecular, and Developmental Biology
- Division of Biomedical Sciences, University of California, Riverside, Riverside, CA 92521
| | - Manuela Martins-Green
- *Graduate Program in Cell, Molecular, and Developmental Biology
- Department of Cell Biology and Neuroscience, and
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42
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Yao YY, Yin H, Shen B, Chao L, Chao J. Tissue kallikrein and kinin infusion rescues failing myocardium after myocardial infarction. J Card Fail 2007; 13:588-96. [PMID: 17826650 PMCID: PMC4519013 DOI: 10.1016/j.cardfail.2007.04.009] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2007] [Revised: 03/26/2007] [Accepted: 04/23/2007] [Indexed: 10/22/2022]
Abstract
BACKGROUND Tissue kallikrein is a serine proteinase that generates the vasoactive kinin peptide, which produces vasodilatory, angiogenic, and antiapoptotic effects. In this study, we investigated the effect of a stable supply of kallikrein and kinin on ventricular remodeling and blood vessel growth in rats after myocardial infarction. METHODS AND RESULTS At 1 week after coronary artery ligation, tissue kallikrein or kinin was infused through a minipump for 4 weeks. At 5 weeks after myocardial infarction, kallikrein and kinin infusion significantly improved cardiac contractility and reduced diastolic dysfunction without affecting systolic blood pressure. Kallikrein and kinin infusion significantly increased capillary density in the noninfarcted region. Kallikrein and kinin infusion also reduced heart weight/body weight ratio, cardiomyocyte size, and atrial natriuretic peptide and brain natriuretic peptide expression in the noninfarcted area. Moreover, kallikrein and kinin infusion inhibited interstitial collagen deposition, collagen fraction volume, and collagen I and collagen III mRNA levels, transforming growth factor (TGF)-beta1 and plasminogen activator inhibitor-1 expression, and Smad2 phosphorylation. The effects of kallikrein and kinin on cardiac remodeling were associated with increased nitric oxide levels and reduced NADPH oxidase expression and activity, superoxide formation, and malondialdehyde levels. Furthermore, in cultured cardiac fibroblasts, kinin inhibited angiotensin II-stimulated TGF-beta1 production, and the effect was blocked by icatibant. CONCLUSION These results indicate that a subdepressor dose of kallikrein or kinin can restore impaired cardiac function in rats with postinfarction heart failure by inhibiting hypertrophy and fibrosis and promoting angiogenesis through increased nitric oxide formation and suppression of oxidative stress and TGF-beta1 expression.
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Affiliation(s)
- Yu-Yu Yao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA
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43
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Dimitropoulou C, Chatterjee A, McCloud L, Yetik-Anacak G, Catravas JD. Angiotensin, bradykinin and the endothelium. Handb Exp Pharmacol 2007:255-94. [PMID: 16999222 DOI: 10.1007/3-540-32967-6_8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
Angiotensins and kinins are endogenous peptides with diverse biological actions; as such, they represent current and future targets of therapeutic intervention. The field of angiotensin biology has changed significantly over the last 50 years. Our original understanding of the crucial role of angiotensin II in the regulation of vascular tone and electrolyte homeostasis has been expanded to include the discovery of new angiotensins, their important role in cardiovascular inflammation and the development of clinically useful synthesis inhibitors and receptor antagonists. While less applied progress has been achieved in the kinin field, there are continuous discoveries in bradykinin physiology and in the complexity of kinin interactions with other proteins. The present review focuses on mechanisms and interactions of angiotensins and kinins that deal specifically with vascular endothelium.
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Affiliation(s)
- C Dimitropoulou
- Vascular Biology Center and Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912-2500, USA
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44
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Altin T, Kilickap M, Tutar E, Turhan S, Atmaca Y, Gulec S, Oral D, Erol C. The Relationship of Chronic Angiotensin Converting Enzyme Inhibitor Use and Coronary Collateral Vessel Development. Int Heart J 2007; 48:435-42. [PMID: 17827815 DOI: 10.1536/ihj.48.435] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
BACKGROUND Angiotensin II induces various growth factors such as vascular endothelial growth factor, platelet-derived growth factor, and fibroblast growth factor, and recent studies suggest that the expression of these growth factors promotes collateral growth. We hypothesized that the blockage of angiotensin II production by ACE inhibitors might interfere with collateral development in patients with coronary occlusion. METHODS The study group consisted of 187 patients (114 males, mean ages, 62 +/- 11 years) who had chronic (> 1 month) coronary occlusion (TIMI flow grade < or = 1) in one of 3 epicardial coronary arteries. Collaterals were graded using the Rentrop classification, and the patients were divided into 2 groups according to having good (grade 2 and 3) or poor (grade 0 and 1) collaterals (n = 127 and 60, respectively). Clinical and angiographic characteristics were compared in the 2 groups. RESULTS ACE inhibitor use (52% versus 35%, P = 0.04) and the prevalence of diabetes mellitus (DM) (43% versus 27%, P = 0.02) was higher in patients with poor collaterals. Patients with poor collaterals had a higher frequency of circumflex artery (Cx) occlusion, worse wall motion, and lower ejection fraction. In multivariate analysis, ACE inhibitor use (OR: 2.4; 95% CI = 1.23-4.68, P = 0.01) and the occlusion of Cx (OR: 3.3, 95% CI; 1.33-8.12, P = 0.01) were found to be independent predictors for poor collateral development, whereas there was a trend for DM as a predictor for poor collaterals (OR: 1.9, 95% CI = 0.97-3.8, P = 0.06). CONCLUSION The findings suggest that ACE inhibitor therapy may contribute to poor collateral development in patients with coronary occlusion.
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Affiliation(s)
- Timucin Altin
- Department of Cardiology, Ankara University School of Medicine, Ankara, Turkey
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45
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Hamada H, Ebata R, Higashi K, Tateno S, Niwa K, Honda T, Yasukawa K, Terai M. Serum vascular endothelial growth factor in cyanotic congenital heart disease functionally contributes to endothelial cell kinetics in vitro. Int J Cardiol 2006; 120:66-71. [PMID: 17126928 DOI: 10.1016/j.ijcard.2006.08.106] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2006] [Revised: 08/03/2006] [Accepted: 08/10/2006] [Indexed: 01/19/2023]
Abstract
BACKGROUND Remarkable amounts of neovascularization develop in patients with cyanotic congenital heart disease who have low pulmonary blood flow and systemic cyanosis, but the factors functionally responsible for angiogenesis in cyanotic congenital heart disease have not been determined. METHODS AND RESULTS To investigate the functional angiogenic molecules in serum from these patients, serum angiogenic activity was studied in 21 patients (systemic oxygen saturation: 82+/-1.9%) and in 17 healthy controls. Patient serum was more active in stimulating the tube formation of human umbilical vein endothelial cells (HUVECs) into capillary-like structures than control serum (150% vs 104% of internal control; p<0.001). This increased serum angiogenic activity normalized after total cardiac repair (p<0.001). The migration activity of HUVECs was also accelerated in patient serum (p=0.007). To identify the molecules in patient serum affecting tube formation of HUVECs, we examined the effects of an inhibitor or a neutralizing antibody against various angiogenic molecules on in vitro angiogenesis. Both the soluble vascular endothelial growth factor (VEGF) receptor 1 and the VEGF receptor 2 tyrosine kinase inhibitor SU5416 reduced the basal serum angiogenic activity of patients and this was reversed by a supplement of recombinant human VEGF. CONCLUSION Our results indicate that serum VEGF functionally contributes to vascular endothelial cell kinetics in patients with cyanotic congenital heart disease.
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Affiliation(s)
- Hiromichi Hamada
- Department of Pediatrics, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8670, Japan
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46
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Matsuo Y, Miura SI, Kawamura A, Uehara Y, Rye KA, Saku K. Newly developed reconstituted high-density lipoprotein containing sphingosine-1-phosphate induces endothelial tube formation. Atherosclerosis 2006; 194:159-68. [PMID: 17118370 DOI: 10.1016/j.atherosclerosis.2006.10.020] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2006] [Revised: 10/11/2006] [Accepted: 10/18/2006] [Indexed: 11/24/2022]
Abstract
Reconstituted high-density lipoprotein (rHDL) has been shown to produce a rapid regression of atherosclerosis in animal models and humans. Sphingosine-1-phosphate (S1P), which is a bioactive lipid in HDL, plays a role in mitogenesis, endothelial cell motility, and cell survival, as well as organization and differentiation into a vessel. In this study, we examined the direct role of a newly developed rHDL, [POPC(1-palmitoyl-2-oleoyl phosphatidylcholine)/S1P/apolipoproteinA-I(A-I)]rHDL containing S1P in tube formation in endothelial cells (ECs) as well as cholesterol efflux in macrophage. The effect of (POPC/S1P/A-I)rHDL on cholesterol efflux in macrophage was similar to that of conventional rHDL, (POPC/A-I)rHDL. In addition, (POPC/S1P/A-I)rHDL induced EC proliferation through the activation of phospho-Akt and phospho-extracellular-signal-regulated kinases (p-ERK) 1/2 and EC tube formation, and this effect was blocked by inhibitors of Akt, ERK and endothelial nitric-oxide synthase (eNOS). In addition, (POPC/S1P/A-I)rHDL-induced p-ERK1/2 activation and EC tube formation can be mainly attributed to S1P-stimulated signaling through S1P2 and S1P3 as determined by an anti-sense strategy. In conclusion, (POPC/S1P/A-I)rHDL induces cholesterol efflux independently of S1P but has additional S1P-mediated effects on EC tube formation mediated by Akt/ERK/NO through S1P2 and S1P3. In the future, these new discs may be useful for the treatment of atherosclerotic and ischemic cardiovascular disease, such as acute coronary syndrome and atherosclerosis obliterans.
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Affiliation(s)
- Yoshino Matsuo
- Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-Ku, Fukuoka 810-0180, Japan
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Leung T, Chen H, Stauffer AM, Giger KE, Sinha S, Horstick EJ, Humbert JE, Hansen CA, Robishaw JD. Zebrafish G protein gamma2 is required for VEGF signaling during angiogenesis. Blood 2006; 108:160-6. [PMID: 16537812 PMCID: PMC1895829 DOI: 10.1182/blood-2005-09-3706] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
Abstract
Vascular endothelial growth factor (VEGF) is a major mediator of pathologic angiogenesis, a process necessary for the formation of new blood vessels to support tumor growth. Historically, VEGF has been thought to signal via receptor tyrosine kinases, which are not typically considered to be G protein dependent. Here, we show that targeted knockdown of the G protein gng2 gene (Ggamma2) blocks the normal angiogenic process in developing zebrafish embryos. Moreover, loss of gng2 function inhibits the ability of VEGF to promote the angiogenic sprouting of blood vessels by attenuating VEGF induced phosphorylation of phospholipase C-gamma1 (PLCgamma1) and serine/threonine kinase (AKT). Collectively, these results demonstrate a novel interaction between Ggamma2- and VEGF-dependent pathways to regulate the angiogenic process in a whole-animal model. Blocking VEGF function using a humanized anti-VEGF antibody has emerged as a promising treatment for colorectal, non-small lung cell, and breast cancers. However, this treatment may cause considerable side effects. Our findings provide a new opportunity for cotargeting G protein- and VEGF-dependent pathways to synergistically block pathologic angiogenesis, which may lead to a safer and more efficacious therapeutic regimen to fight cancer.
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Affiliation(s)
- Tinchung Leung
- Weis Center for Research, Geisinger Health System, Danville, PA 17822, USA
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48
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Imaizumi S, Miura SI, Nishikawa H, Iwata A, Zhang B, Kawamura A, Tsuchiya Y, Kumagai K, Matsuo K, Saku K. Angiotensin II Type 1 Receptor Blockers Do Not Promote Coronary Collateral Circulation in Patients with Coronary Artery Disease. Hypertens Res 2006; 29:135-41. [PMID: 16755148 DOI: 10.1291/hypres.29.135] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
We previously reported that angiotensin-converting enzyme inhibitors (ACE-Is) promote collateral circulation in patients with coronary artery disease (CAD). There have been many reports on the beneficial effects of angiotensin II type 1 receptor blockers (ARBs) on the cardiac microvasculature. Therefore, the following studies were performed to evaluate the association between treatment with an ARB and the enhancement of coronary collateral circulation as assessed by the Rentrop Score (RS) (Study 1) and to compare these results to those obtained with an ACE-I (Study 2). The subjects were 456 patients with angina who underwent coronary angiography. Study 1: Those who had one (1-V), two (2-V) or three significantly stenosed vessels (3-V) and who received only an ARB without any other anti-hypertensive medication were defined as the ARB group (n=81), and age-, sex- and body mass index-matched subjects (n=146) were selected as a comparative group. There were no significant differences in the percentage of patients with RS>or=1 between the two groups. Study 2: Those who received an ACE-I as the only anti-hypertensive treatment were defined as the ACE-I group (n=67), which was matched to the ARB group in Study 1. The percentage of patients with RS>or=1 in the ACE-I group was significantly higher than that in the ARB group as assessed by a Cochran-Mantel-Haenszel analysis. In addition, patients with 3-V disease who were treated with an ACE-I, but not an ARB, were most likely (odds ratio [confidence Interval]): 27.7 [4.8-161.0]) to show enhanced collateral circulation, as assessed by a multiple logistic regression analysis. These results suggest that treatment with an ACE-I, but not treatment with an ARB, was associated with the enhancement of collateral circulation in patients with CAD.
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Affiliation(s)
- Satoshi Imaizumi
- Department of Cardiology, Fukuoka University School of Medicine, Japan
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49
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Giusti B, Serratì S, Margheri F, Papucci L, Rossi L, Poggi F, Magi A, Del Rosso A, Cinelli M, Guiducci S, Kahaleh B, Matucci-Cerinic M, Abbate R, Fibbi G, Del Rosso M. The antiangiogenic tissue kallikrein pattern of endothelial cells in systemic sclerosis. ACTA ACUST UNITED AC 2005; 52:3618-28. [PMID: 16255054 DOI: 10.1002/art.21383] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Postnatal angiogenesis relies on a proper response of endothelial cells to angiogenic stimuli. In systemic sclerosis (SSc), endothelial cells are unresponsive to angiogenic factors. Since circumstantial and experimental evidence points to tissue kallikreins as powerful effectors of the angiogenic response, we undertook this study to investigate the kallikrein pattern of normal and SSc endothelial cells in order to identify differences that can account for defective angiogenesis. METHODS Expression of 14 tissue kallikreins was studied by a microarray approach, by reverse transcription-polymerase chain reaction, and by Western blotting in endothelial cells isolated from the skin of clinically healthy subjects and SSc patients. Cell proliferation was quantified by direct cell counting. Invasion and capillary morphogenesis were evaluated in a Boyden chamber and in culture flasks layered with Matrigel. Cyclic nucleotide production was measured by enzyme immunoassay. MAP kinase and ERK activation were measured by Western blotting. RESULTS Endothelial cells from SSc patients showed poor expression of kallikreins 9, 11, and 12 compared with endothelial cells from normal subjects. Antibodies against the relevant kallikreins on normal endothelial cells revealed that while kallikreins 9, 11, and 12 induced cell growth, only kallikrein 12 regulated invasion and capillary morphogenesis. Buffering of kallikrein 12 with antibodies resulted in the acquisition of an SSc-like pattern by normal cells in in vitro angiogenesis. Reduction of cAMP and cGMP production and of ERK phosphorylation upon administration of antikallikrein antibodies revealed that the activity of kallikreins 9, 11, and 12 was mediated by kinins. CONCLUSION Reduction of tissue kallikreins 9, 11, and 12 may be relevant to reduced angiogenesis in SSc patients.
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MESH Headings
- Antibodies, Blocking/pharmacology
- Blotting, Western
- Cell Count
- Cell Proliferation
- Cells, Cultured
- Endothelial Cells/cytology
- Endothelial Cells/drug effects
- Endothelial Cells/metabolism
- Extracellular Signal-Regulated MAP Kinases/metabolism
- Female
- Gene Expression Profiling
- Gene Expression Regulation
- Humans
- Male
- Microcirculation/cytology
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Nucleotides, Cyclic/metabolism
- Oligonucleotide Array Sequence Analysis
- Phosphorylation
- RNA, Messenger/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Scleroderma, Systemic/metabolism
- Scleroderma, Systemic/pathology
- Scleroderma, Systemic/physiopathology
- Skin/blood supply
- Tissue Kallikreins/genetics
- Tissue Kallikreins/immunology
- Tissue Kallikreins/metabolism
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Affiliation(s)
- Betti Giusti
- Department of Experimental Pathology and Oncology, University of Florence, Viale G M Morgagni 50, 50134 Florence, Italy
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50
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Parker SL, Parker MS, Sah R, Sallee F. Angiogenesis and rhodopsin-like receptors: a role for N-terminal acidic residues? Biochem Biophys Res Commun 2005; 335:983-92. [PMID: 16023616 DOI: 10.1016/j.bbrc.2005.06.158] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2005] [Accepted: 06/23/2005] [Indexed: 12/22/2022]
Abstract
Numerous rhodopsin-like G-protein coupling receptors induce or inhibit angiogenesis. The active human receptors include several chemokine receptors, apelin APJ receptor, neuropeptide Y Y2 receptor, Duffy antigen, and herpes virus-8 receptor. A common and striking feature of these receptors is the large fraction (up to 42%) of residues with anionic sidechains (Asp, Glu, and benzene anions Tyr, Trp, and Phe) in the N-terminal extracellular domain. These residues (which are frequently clustered) can assist the binding of ligand peptides, but should also support interactions that help tubular arraying of cells, e.g., via cationic bridges and/or hydrogen bonding with cell-connecting receptors such as integrins, or with proteins of the extracellular matrix.
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Affiliation(s)
- Steven L Parker
- Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
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