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Hu M, Wu L, Wei E, Pan X, Zhu Q, Xiuyun X, Lv L, Dong X, Liu H, Liu Y. Sildenafil promotes osteogenic differentiation of human mesenchymal stem cells and inhibits bone loss by affecting the TGF-β signaling pathway. Stem Cell Res Ther 2025; 16:201. [PMID: 40264229 PMCID: PMC12016470 DOI: 10.1186/s13287-025-04320-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Accepted: 04/07/2025] [Indexed: 04/24/2025] Open
Abstract
BACKGROUND Osteoporosis, a common bone disorder, is primarily managed pharmacologically. However, existing medications are associated with non-trivial side-effects. Sildenafil, which already finds many clinical applications, promotes angiogenesis and cellular differentiation. Osteoporotic patients often exhibit a reduced intraosseous vasculature and impaired cellular differentiation; sildenafil may thus usefully treat osteoporosis. METHODS Here, the effects of sildenafil on the osteogenic differentiation of human mesenchymal stem cells (hMSCs) were explored, as were the molecular mechanisms in play. We treated hMSCs with varying concentrations of sildenafil and measured cell proliferation and osteogenic differentiation in vitro. We used a mouse model of subcutaneous ectopic osteogenesis to assess sildenafil's effect on hMSC osteogenic differentiation in vivo. We also explored the effects of sildenafil on bone loss in tail-suspended (TS) and ovariectomized (OVX) mice. Mechanistically, we employed RNA-sequencing to define potentially relevant molecular pathways. RESULTS The appropriate concentrations of sildenafil significantly enhanced osteogenic hMSC differentiation; the optimal sildenafil concentration may be 10 mg/L. Sildenafil mitigated osteoporosis in OVX and TS mice. The appropriate concentrations of sildenafil probably promoted hMSC osteogenic differentiation by acting on the transforming growth factor-β (TGF-β) signaling pathway. CONCLUSIONS In conclusion, sildenafil enhanced hMSC osteogenic differentiation and inhibited bone loss. Sildenafil may usefully treat osteoporosis. Our findings offer new insights into the physiological effects of the medicine.
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Affiliation(s)
- Menglong Hu
- Department of Prosthodontics, Peking University School and Hospital of StomatologyPeking University School and Hospital of Stomatology, Beijing, 100081, China
- National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, NMPA Key Laboratory for Dental Materials, Beijing, 100081, China
| | - Likun Wu
- Department of Prosthodontics, Peking University School and Hospital of StomatologyPeking University School and Hospital of Stomatology, Beijing, 100081, China
- National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, NMPA Key Laboratory for Dental Materials, Beijing, 100081, China
| | - Erfan Wei
- Department of Prosthodontics, Peking University School and Hospital of StomatologyPeking University School and Hospital of Stomatology, Beijing, 100081, China
- National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, NMPA Key Laboratory for Dental Materials, Beijing, 100081, China
| | - Xingtong Pan
- Department of Prosthodontics, Peking University School and Hospital of StomatologyPeking University School and Hospital of Stomatology, Beijing, 100081, China
- National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, NMPA Key Laboratory for Dental Materials, Beijing, 100081, China
| | - Qiyue Zhu
- Department of Prosthodontics, Peking University School and Hospital of StomatologyPeking University School and Hospital of Stomatology, Beijing, 100081, China
- National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, NMPA Key Laboratory for Dental Materials, Beijing, 100081, China
| | - Xv Xiuyun
- Department of Prosthodontics, Peking University School and Hospital of StomatologyPeking University School and Hospital of Stomatology, Beijing, 100081, China
- National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, NMPA Key Laboratory for Dental Materials, Beijing, 100081, China
| | - Letian Lv
- The Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, 100081, China
- National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, NMPA Key Laboratory for Dental Materials, Beijing, 100081, China
| | - Xinyi Dong
- Department of Prosthodontics, Peking University School and Hospital of StomatologyPeking University School and Hospital of Stomatology, Beijing, 100081, China
- National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, NMPA Key Laboratory for Dental Materials, Beijing, 100081, China
| | - Hao Liu
- The Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, 100081, China.
- National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, NMPA Key Laboratory for Dental Materials, Beijing, 100081, China.
- Peking University School and Hospital of StomatologyPeking University School and Hospital of Stomatology, No.22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, China.
| | - Yunsong Liu
- Department of Prosthodontics, Peking University School and Hospital of StomatologyPeking University School and Hospital of Stomatology, Beijing, 100081, China.
- National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, NMPA Key Laboratory for Dental Materials, Beijing, 100081, China.
- Peking University School and Hospital of StomatologyPeking University School and Hospital of Stomatology, No.22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, China.
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Lee WC, Lu S, Su CH, Tain YL, Wu KLH, Hsu CN, Tzeng HT. Tadalafil Ameliorates Chronic Ischemia-Associated Bladder Overactivity in Fructose-Fed Rats by Exerting Pelvic Angiogenesis and Enhancing p-eNOS Expression. Int J Mol Sci 2025; 26:1363. [PMID: 39941129 PMCID: PMC11818424 DOI: 10.3390/ijms26031363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 02/03/2025] [Accepted: 02/03/2025] [Indexed: 02/16/2025] Open
Abstract
Metabolic syndrome (MetS) can contribute to a chronic ischemia-relative overactive bladder (OAB). Using fructose-fed rats (FFRs), a rat model of MetS, we investigated the effects of tadalafil (a phosphodiesterase-5 inhibitor) on MetS-associated chronic bladder ischemia and bladder overactivity. Phenotypes of the OAB, including increased micturition frequency and a shortened intercontractile interval in cystometry, were observed in FFRs, together with reduced bladder blood perfusion (in empty bladders) via laser color Doppler imaging and elevated serum nitrite levels, suggesting chronic ischemia-related bladder dysfunction. Treatment with tadalafil (2 mg/kg) promoted pelvic angiogenesis, as shown by magnetic resonance imaging, and increased VEGF and p-eNOS overexpression in the bladder. This treatment restored bladder perfusion and alleviated bladder overactivity without significantly altering most MetS parameters. At the molecular level, FFRs exhibited increased ischemia markers (NGF, HIF-2α, and AMPK-α2) and decreased p-AMPK-α2, along with elevated proinflammatory mediators (ICAM-1, nuclear NF-κB, COX-2, IL-1β, IL-6, and TNF-α), enhanced mitochondria biogenesis (PGC-1α, TFAM, and mitochondria DNA copy number), oxidative stress (decreased nuclear NRF2, increase MnSOD and 8-OHdG staining), and tissue fibrosis (increased TGF-β1, collagen I, and fibronectin). Tadalafil treatment improved these effects. Together, these findings suggest that tadalafil may promote VEGF-associated angiogenesis, enhance p-eNOS staining in the bladder vasculature, normalize bladder perfusion in microcirculation, and reduce serum nitrite levels. Consequently, tadalafil mitigates the adverse effects of chronic ischemia/hypoxia, improving bladder overactivity. We elucidated the mechanisms underlying the tadalafil-mediated amelioration of MetS-associated OAB symptoms.
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Affiliation(s)
- Wei-Chia Lee
- Division of Urology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan;
| | - Steve Lu
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan; (S.L.); (K.L.H.W.)
- Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Chia-Hao Su
- Center for General Education, Chang Gung University, Taoyuan 333, Taiwan;
- Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - You-Lin Tain
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan;
| | - Kay L. H. Wu
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan; (S.L.); (K.L.H.W.)
| | - Chien-Ning Hsu
- Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan;
- School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Hong-Tai Tzeng
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan; (S.L.); (K.L.H.W.)
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Hong JM, Shin HS. Reinforcement of Transdural Angiogenesis: A Novel Approach to Treating Ischemic Stroke With Cerebral Perfusion Impairment. J Stroke 2025; 27:30-40. [PMID: 39916452 PMCID: PMC11834342 DOI: 10.5853/jos.2024.02810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 10/07/2024] [Accepted: 10/21/2024] [Indexed: 02/20/2025] Open
Abstract
Cerebral hypoperfusion plays a critical role in early neurological deterioration and long-term outcomes in patients with acute ischemic stroke, which remains a major global health challenge. This review explored transdural angiogenesis as a promising therapeutic strategy to restore cerebral perfusion in patients with ischemic stroke. The multiple burr hole procedure has been preliminarily used as an indirect revascularization method to induce transdural arteriogenesis. Theoretically, its efficacy could be enhanced by combining it with angiogenic boosters, such as erythropoietin. Recent clinical and preclinical studies have revealed that this combination therapy promotes angiogenesis and arteriogenesis, leading to successful revascularization across the dura mater and improved cerebral blood flow. This strategy may be particularly beneficial for high-risk patients with recurrent ischemic events, such as those with moyamoya disease or intracranial arterial occlusion, representing an effective strategy when conventional medical treatments are insufficient. This review highlights the potential of transdural angiogenesis enhancement as a novel intervention for ischemic stroke, offering an alternative to thrombolysis or endovascular treatment, particularly in acute stroke patients with impaired cerebral perfusion. This approach has the potential to bridge the treatment gap for patients outside the therapeutic window for acute stroke interventions. Although further research is required to refine this technique and validate its efficacy in broader clinical settings, early results have revealed promising outcomes at reducing stroke-related complications and improving patient prognosis. This review indicates that this novel strategy may offer hope for managing ischemic stroke and related conditions associated with significant cerebral hypoperfusion.
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Affiliation(s)
- Ji Man Hong
- Department of Neurology, Ajou University Medical Center, Ajou University School of Medicine, Suwon, Korea
- Department of Biomedical Science, Ajou University Medical Center, Ajou University School of Medicine, Suwon, Korea
| | - Hee Sun Shin
- Department of Biomedical Science, Ajou University Medical Center, Ajou University School of Medicine, Suwon, Korea
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Fu Q, Wang Y, Yan C, Xiang YK. Phosphodiesterase in heart and vessels: from physiology to diseases. Physiol Rev 2024; 104:765-834. [PMID: 37971403 PMCID: PMC11281825 DOI: 10.1152/physrev.00015.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 10/17/2023] [Accepted: 11/08/2023] [Indexed: 11/19/2023] Open
Abstract
Phosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyze cyclic nucleotides, including cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both cyclic nucleotides are critical secondary messengers in the neurohormonal regulation in the cardiovascular system. PDEs precisely control spatiotemporal subcellular distribution of cyclic nucleotides in a cell- and tissue-specific manner, playing critical roles in physiological responses to hormone stimulation in the heart and vessels. Dysregulation of PDEs has been linked to the development of several cardiovascular diseases, such as hypertension, aneurysm, atherosclerosis, arrhythmia, and heart failure. Targeting these enzymes has been proven effective in treating cardiovascular diseases and is an attractive and promising strategy for the development of new drugs. In this review, we discuss the current understanding of the complex regulation of PDE isoforms in cardiovascular function, highlighting the divergent and even opposing roles of PDE isoforms in different pathogenesis.
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Affiliation(s)
- Qin Fu
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- The Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
| | - Ying Wang
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Chen Yan
- Aab Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, New York, United States
| | - Yang K Xiang
- Department of Pharmacology, University of California at Davis, Davis, California, United States
- Department of Veterans Affairs Northern California Healthcare System, Mather, California, United States
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Kurt V, Guner S, Kayacan AM, Eronat O. The effect of Sildenafil, a phosphodiesterase-5 inhibitor, on tendon healing: an experimental study in rat model of achilles tendon injury. Arch Orthop Trauma Surg 2024; 144:1107-1115. [PMID: 38148369 DOI: 10.1007/s00402-023-05178-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 12/06/2023] [Indexed: 12/28/2023]
Abstract
INTRODUCTION Sildenafil Citrate has various effects on the body, including widening blood vessels, inhibiting platelet aggregation, promoting the growth of blood vessels, stimulating apoptosis and adhesion of fibroblasts, and reducing inflammation. This research aims to explore how Sildenafil Citrate affects surgically treated Achilles tendons, both in terms of tissue structure and mechanical properties. MATERIALS AND METHODS Forty-eight Wistar-albino rats weighing 350-400 g were randomly divided into groups, 6 in each group, as the study group was given Sildenafil Citrate and the control group given saline, respectively. The Achilles tendon rupture model was created under ketamine and xylazine anesthesia. During the entire experiment, rats were housed in eight separate cages, six of them each. The study group and control group of the first group were sacrificed at the end of 1 week, and Achilles tendon samples were taken. After that, Achilles tendon samples were taken after sacrificing the second group at 14 days, the third group at 21 days, and the fourth group at 28 days, respectively. Neovascularization, inflammation, fibrosis and fibroblastic activities of the harvested Achilles tendons were evaluated histopathologically. Biomechanically, stretching was applied to the Achilles tendons and continued until the tendon ruptured. the maximum force values at the moment of rupture were calculated. RESULTS The mean maximum strength value of group T21, which was given sildenafil citrate for 21 days, was 31.1 ± 4.36 N, and the mean maximum strength value of group C21, which was the control group, was 20.56 ± 6.92 N. A significant difference was observed between the groups (p: 0.008). Group T28 (45.17 ± 5.54 N) also demonstrated greater strength than group C28 (34.62 ± 3.21 N) in the comparison (p: 0.004). The study also noted significant differences between the groups in neovascularization, in the first week, 1 mild, 3 moderate and 2 prominent neovascularization was observed in group T7, in group T28, moderate neovascularization was observed in 4 specimens and prominent neovascularization was observed in 2 specimens (p: 0.001). Furthermore, the groups showed significant differences in their levels of fibrosis, inflammation and fibroblastic proliferation (p: 0.017, p: 0.036, (p: 0.035) respectively). CONCLUSIONS Study has demonstrated that sildenafil citrate can enhance the biomechanical and histopathological aspects of tendon healing, resulting in a stronger tendon.
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Affiliation(s)
- Vahap Kurt
- Department of Orthopedics and Traumatology, Abdulkadir Yuksel State Hospital, Perilikaya, Havaalanıyolu Cd. No: 302, 27100, Şahinbey/Gaziantep, Turkey.
| | - Savaş Guner
- Department of Orthopedics and Traumatology, Faculty of Medicine, Gaziantep University, 27310, Gaziantep, Turkey
| | - Ahmet Mesut Kayacan
- Department of Orthopedics and Traumatology, Faculty of Medicine, Gaziantep University, 27310, Gaziantep, Turkey
| | - Omer Eronat
- Department of Pathology, Faculty of Medicine, Gaziantep University, 27310, Gaziantep, Turkey
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Dhahri W, Dussault S, Raguema N, Desjarlais M, Rivard A. Stimulation of soluble guanylate cyclase activity with riociguat promotes angiogenesis and improves neovascularization after limb ischemia. Atherosclerosis 2023; 372:32-40. [PMID: 37023506 DOI: 10.1016/j.atherosclerosis.2023.03.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 03/21/2023] [Accepted: 03/22/2023] [Indexed: 04/08/2023]
Abstract
BACKGROUND AND AIMS The NO-cGMP pathway is essential for angiogenesis, vasculogenesis and post-natal neovascularization. The key enzyme responsible for the synthesis of cGMP following binding of NO is soluble guanylate cyclase (sGC). Riociguat is the first member of a novel class of compounds known as sGC stimulators. We tested the hypothesis that stimulation of sGC with riociguat might improve neovascularization in response to ischemia. METHODS In vitro, the angiogenic effect of riociguat was tested in human umbilical vein endothelial cells (HUVECs). In vivo, neovascularization was investigated in a mouse model of limb ischemia. C57Bl/6 mice were treated by gavage with 3 mg/kg/day of riociguat for a total of 28 days. After two weeks of treatment, hindlimb ischemia was surgically induced by femoral artery removal. RESULTS In a matrigel assay in vitro, riociguat dose-dependently stimulates tubule formation in HUVECs. Cell migration (scratch assay) is also increased in HUVECs treated with riociguat. At the molecular level, riociguat treatment leads to rapid activation of the p44/p42 MAP kinase pathway in HUVECs. Inhibition of protein kinase G (PKG) activity supresses both p44/p42 MAP kinase activation and angiogenesis in HUVECs treated with riociguat. In vivo, treatment with riociguat improves blood flow recovery after ischemia (Laser Doppler imaging), and increases capillary density in ischemic muscles (CD31 immunostaining). Clinically, this is associated with a significant decrease of ambulatory impairment and ischemic damages. Interestingly, mice treated with riociguat also show a 94% increase in the number of bone marrow-derived pro-angiogenic cells (PACs) compared to control mice. Moreover, riociguat treatment is associated with a significant improvement of PAC functions including migratory capacity, adhesion to an endothelial monolayer, and integration into endothelial tubular networks. CONCLUSIONS The sGC stimulator riociguat promotes angiogenesis and improves neovascularization after ischemia. The mechanism involves PKG-dependent activation of p44/p42 MAP kinase pathway, together with an improvement of PAC number and functions. sGC stimulation could constitute a novel therapeutic strategy to reduce tissue ischemia in patients with severe atherosclerotic diseases.
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Affiliation(s)
- Wahiba Dhahri
- Department of Medicine, Centre hospitalier de l'Université de Montréal (CHUM) Research Center, Montréal, Québec, Canada
| | - Sylvie Dussault
- Department of Medicine, Centre hospitalier de l'Université de Montréal (CHUM) Research Center, Montréal, Québec, Canada
| | - Nozha Raguema
- Department of Medicine, Centre hospitalier de l'Université de Montréal (CHUM) Research Center, Montréal, Québec, Canada
| | - Michel Desjarlais
- Department of Medicine, Centre hospitalier de l'Université de Montréal (CHUM) Research Center, Montréal, Québec, Canada
| | - Alain Rivard
- Department of Medicine, Centre hospitalier de l'Université de Montréal (CHUM) Research Center, Montréal, Québec, Canada.
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Shcheblykin DV, Bolgov AA, Pokrovskii MV, Stepenko JV, Tsuverkalova JM, Shcheblykina OV, Golubinskaya PA, Korokina LV. Endothelial dysfunction: developmental mechanisms and therapeutic strategies. RESEARCH RESULTS IN PHARMACOLOGY 2022. [DOI: 10.3897/rrpharmacology.8.80376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Introduction: Every year the importance of the normal functioning of the endothelial layer of the vascular wall in maintaining the health of the body becomes more and more obvious.
The physiological role of the endothelium: The endothelium is a metabolically active organ actively involved in the regulation of hemostasis, modulation of inflammation, maintenance of hemovascular homeostasis, regulation of angiogenesis, vascular tone, and permeability.
Risk factors for the development of endothelial dysfunction: Currently, insufficient bioavailability of nitric oxide is considered the most significant risk factor for endothelial dysfunction.
Mechanisms of development of endothelial dysfunction: The genesis of endothelial dysfunction is a multifactorial process. Among various complex mechanisms, this review examines oxidative stress, inflammation, hyperglycemia, vitamin D deficiency, dyslipidemia, excess visceral fat, hyperhomocysteinemia, hyperuricemia, as well as primary genetic defect of endotheliocytes, as the most common causes in the population underlying the development of endothelial dysfunction.
Markers of endothelial dysfunction in various diseases: This article discusses the main biomarkers of endothelial dysfunction currently used, as well as promising biomarkers in the future for laboratory diagnosis of this pathology.
Therapeutic strategies: Therapeutic approaches to the endothelium in order to prevent or reduce a degree of damage to the vascular wall are briefly described.
Conclusion: Endothelial dysfunction is a typical pathological process involved in the pathogenesis of many diseases. Thus, pharmacological agents with endothelioprotective properties can provide more therapeutic benefits than a drug without such an effect.
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Erectile Dysfunction Treatment Using Stem Cells: A Review. MEDICINES 2021; 8:medicines8010002. [PMID: 33419152 PMCID: PMC7825548 DOI: 10.3390/medicines8010002] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 12/27/2020] [Accepted: 12/31/2020] [Indexed: 12/31/2022]
Abstract
Erectile dysfunction (ED) is a disorder that affects the quality of life and the sexual relations of more than half of the male population aged over 40 years. The prediction regarding the incidence of ED is devastating as it is expected that this disorder will affect more than 300 million men in the next five years. Several studies have suggested the use of stem cells for the treatment of ED and showed that this type of treatment is promising in terms of damaged tissue repair as well as of clinical efficacy; however, there are several gaps in the knowledge and evidence is lacking. In order to highlight a few of them in this review, we performed a research of the literature focusing on currently available clinical studies regarding the clinical efficacy of stem cell administration for the treatment of ED. We reviewed the methods of administration, the cell types used in the performed clinical trials and the safety and efficiency of such procedures. We conclude that there are rapidly expanding and promising results from the reported clinical studies indicating that stem cells could indeed be a potential treatment for patients with ED although more studies are necessary.
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Wang X, Huang G, Mu J, Cong Z, Chen S, Fu D, Qi J, Li Z. Arrb2 promotes endothelial progenitor cell-mediated postischemic neovascularization. Am J Cancer Res 2020; 10:9899-9912. [PMID: 32863967 PMCID: PMC7449919 DOI: 10.7150/thno.45133] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 07/19/2020] [Indexed: 11/05/2022] Open
Abstract
Background and aim: Modulating biological functions of endothelial progenitor cells (EPCs) is essential for therapeutic angiogenesis in ischemic vascular diseases. This study aimed to explore the role and molecular mechanisms of β-arrestin 2 (Arrb2) in EPCs biology and angiogenic therapy. Methods: The influence of Arrb2 on postischemic neovascularization was evaluated in Arrb2-deficient mice. The proliferation, apoptosis, and various functions of EPCs were analyzed in vitro by manipulating the expression of Arrb2. Finally, the in vivo effect of Arrb2 on EPC-mediated neovascularization was investigated in a mouse model of hind-limb ischemia (HLI). Results: Arrb2-deficient mice exhibited impaired blood flow recovery based on laser Doppler measurements and reduced capillary density in the adductor muscle after unilateral HLI. Arrb2-deficient mice also showed restricted intraplug angiogenesis in subcutaneously implanted Matrigel plugs. In vitro, lentivirus-mediated Arrb2 overexpression promoted EPC proliferation, migration, adhesion, and tube formation, whereas Arrb2 knockdown had opposite effects. In addition, the overexpression of Arrb2 in EPCs protected them from hypoxia-induced apoptosis and improved intraplug angiogenesis ex vivo. Mechanistically, Arrb2 interacted with and activated extracellular signal-regulated kinase (ERK)1/2 and protein kinase B (Akt) signaling pathways. Finally, the transplantation of EPCs overexpressing Arrb2 resulted in a significantly higher blood flow restoration in ischemic hind limb and higher capillary density during histological analysis compared with control or Arrb2-knockdown EPC-treated nude mice. Conclusions: The data indicated that Arrb2 augmented EPC-mediated neovascularization through the activation of ERK and Akt signaling pathways. This novel biological function of Arrb2 might provide a potential therapeutic option to promote EPCs in the treatment of ischemic vascular diseases.
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Cheng LM, Li YJ, Chen XF, Li XL, Chen XS, Du YH. ClC-3 Deficiency Impairs the Neovascularization Capacity of Early Endothelial Progenitor Cells by Decreasing CXCR4/JAK-2 Signalling. Can J Cardiol 2019; 35:1546-1556. [DOI: 10.1016/j.cjca.2019.08.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 08/03/2019] [Accepted: 08/05/2019] [Indexed: 12/12/2022] Open
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Dincel YM, Alagoz E, Arikan Y, Caglar AK, Dogru SC, Ortes F, Arslan YZ. Biomechanical, histological, and radiological effects of different phosphodiesterase inhibitors on femoral fracture healing in rats. J Orthop Surg (Hong Kong) 2019; 26:2309499018777885. [PMID: 29848169 DOI: 10.1177/2309499018777885] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
PURPOSE To investigate the biomechanical, histological, and radiological effects of sildenafil and pentoxifylline on femoral fracture healing in rats. METHODS Forty-eight Sprague-Dawley rats were divided into three groups equally according to the pharmacological agents to be investigated. Femoral shaft fractures were formed in the left side. Group 1 (control group), group 2, and group 3 were administered with saline, sildenafil, and pentoxifylline during the fracture healing process, respectively. Eight rats from each group were euthanized on days 15 and 30. X-ray images of the rats were taken after euthanasia for radiographical examination. Femur samples were subjected to histopathological and biomechanical (three-point bending) examinations. RESULTS Radiologically, no difference between the Goldberg scores of the groups was found for day 15 ( p > 0.05), while higher Goldberg scores were obtained from group 2 than that of group 1 ( p > 0.05) and group 3 ( p < 0.05) for day 30. In the biomechanical analysis, higher mean breaking forces were found both for day 15 and day 30 from group 2 than those obtained from group 1 (for day 15 p > 0.05 and day 30 p > 0.05) and group 3 (for day 15 p < 0.05 and day 30 p < 0.01). Higher mean absorbed energy values were obtained from group 2 than those obtained from group 1 (for day 15 p > 0.05 and day 30 p < 0.05) and group 3 (for day 15 p < 0.01 and day 30 p < 0.01). A significant difference was not found between the histological scores of all groups ( p > 0.05) for day 15, while the histological score of group 1 on day 30 was found to be significantly lower than that of sildenafil and pentoxifylline groups ( p < 0.05). CONCLUSION Sildenafil had a positive effect on fracture healing, while pentoxifylline did not provide consistent positive effect.
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Affiliation(s)
- Yasar Mahsut Dincel
- 1 Department of Orthopaedics and Traumatology, Metin Sabancı Baltalimanı Bone Diseases Training and Research Hospital, Istanbul, Turkey
| | - Ender Alagoz
- 2 Department of Orthopaedics and Traumatology, İstanbul Bağcılar Training and Research Hospital, Istanbul, Turkey
| | - Yavuz Arikan
- 1 Department of Orthopaedics and Traumatology, Metin Sabancı Baltalimanı Bone Diseases Training and Research Hospital, Istanbul, Turkey
| | - Aysel Kara Caglar
- 3 Department of Pathology, İstanbul Bağcılar Training and Research Hospital, Istanbul, Turkey
| | - Suzan Cansel Dogru
- 4 Department of Mechanical Engineering, Faculty of Engineering, Istanbul University, Avcilar, Istanbul, Turkey
| | - Faruk Ortes
- 4 Department of Mechanical Engineering, Faculty of Engineering, Istanbul University, Avcilar, Istanbul, Turkey
| | - Yunus Ziya Arslan
- 4 Department of Mechanical Engineering, Faculty of Engineering, Istanbul University, Avcilar, Istanbul, Turkey
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12
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Tetsi L, Charles AL, Georg I, Goupilleau F, Lejay A, Talha S, Maumy-Bertrand M, Lugnier C, Geny B. Effect of the Phosphodiesterase 5 Inhibitor Sildenafil on Ischemia-Reperfusion-Induced Muscle Mitochondrial Dysfunction and Oxidative Stress. Antioxidants (Basel) 2019; 8:antiox8040093. [PMID: 30959961 PMCID: PMC6523910 DOI: 10.3390/antiox8040093] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 04/04/2019] [Accepted: 04/05/2019] [Indexed: 12/12/2022] Open
Abstract
Lower-limb ischemia-reperfusion (IR) is frequent and associated with significant morbidity and mortality. Phosphodiesterase 5 inhibitors demonstrated antioxidant and beneficial effects in several organs submitted to IR, but their effects on muscle mitochondrial functions after lower-limb IR are unknown. Unilateral hindlimb IR (2 h tourniquet followed by 2 h reperfusion) without or with sildenafil (1mg/kg ip 30 minutes before ischemia) was performed in 18 mice. Maximal oxidative capacity (VMax), relative contribution of the mitochondrial respiratory chain complexes, calcium retention capacity (CRC)—a marker of apoptosis—and reactive oxygen species (ROS) production were determined using high-resolution respirometry, spectrofluorometry, and electron paramagnetic resonance in gastrocnemius muscles from both hindlimbs. IR significantly reduced mitochondrial VMax (from 11.79 ± 1.74 to 4.65 ± 1.11 pmol/s*mg wet weight (ww), p < 0.05, −50.2 ± 16.3%) and CRC (from 2.33 ± 0.41 to 0.84 ± 0.18 µmol/mg dry weight (dw), p < 0.05; −61.1 ± 6.8%). ROS tended to increase in the ischemic limb (+64.3 ± 31.9%, p = 0.08). Although tending to reduce IR-related ROS production (−42.4%), sildenafil failed to reduce muscle mitochondrial dysfunctions (−63.3 ± 9.2%, p < 0.001 and −55.2 ± 7.6% p < 0.01 for VMax, and CRC, respectively). In conclusion, lower limb IR impaired skeletal muscle mitochondrial function, but, despite tending to reduce ROS production, pharmacological preconditioning with sildenafil did not show protective effects.
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Affiliation(s)
- Liliane Tetsi
- Unistra, Fédération de Médecine Translationnelle, Equipe d'Accueil 3072, « Mitochondrie, Stress oxydant et Protection Musculaire », Institut de Physiologie, 67000 CEDEX, France.
| | - Anne-Laure Charles
- Unistra, Fédération de Médecine Translationnelle, Equipe d'Accueil 3072, « Mitochondrie, Stress oxydant et Protection Musculaire », Institut de Physiologie, 67000 CEDEX, France.
| | - Isabelle Georg
- Unistra, Fédération de Médecine Translationnelle, Equipe d'Accueil 3072, « Mitochondrie, Stress oxydant et Protection Musculaire », Institut de Physiologie, 67000 CEDEX, France.
| | - Fabienne Goupilleau
- Unistra, Fédération de Médecine Translationnelle, Equipe d'Accueil 3072, « Mitochondrie, Stress oxydant et Protection Musculaire », Institut de Physiologie, 67000 CEDEX, France.
| | - Anne Lejay
- Unistra, Fédération de Médecine Translationnelle, Equipe d'Accueil 3072, « Mitochondrie, Stress oxydant et Protection Musculaire », Institut de Physiologie, 67000 CEDEX, France.
- Hôpitaux Universitaires de Strasbourg, Service de Physiologie et d'Explorations Fonctionnelles, 67000 Strasbourg, France.
- Hôpitaux Universitaires de Strasbourg, Service de Chirurgie vasculaire et de transplantation rénale, 67000 Strasbourg, France.
| | - Samy Talha
- Unistra, Fédération de Médecine Translationnelle, Equipe d'Accueil 3072, « Mitochondrie, Stress oxydant et Protection Musculaire », Institut de Physiologie, 67000 CEDEX, France.
- Hôpitaux Universitaires de Strasbourg, Service de Physiologie et d'Explorations Fonctionnelles, 67000 Strasbourg, France.
| | - Myriam Maumy-Bertrand
- IRMA, équipe MoCo et LabEx IRMIA, 7 rue René Descartes, 67084 Strasbourg CEDEX, France.
| | - Claire Lugnier
- Unistra, Fédération de Médecine Translationnelle, Equipe d'Accueil 3072, « Mitochondrie, Stress oxydant et Protection Musculaire », Institut de Physiologie, 67000 CEDEX, France.
| | - Bernard Geny
- Unistra, Fédération de Médecine Translationnelle, Equipe d'Accueil 3072, « Mitochondrie, Stress oxydant et Protection Musculaire », Institut de Physiologie, 67000 CEDEX, France.
- Hôpitaux Universitaires de Strasbourg, Service de Physiologie et d'Explorations Fonctionnelles, 67000 Strasbourg, France.
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Reneeta NP, Thiyonila B, Aathmanathan VS, Ramya T, Chandrasekar P, Subramanian N, Prajapati VK, Krishnan M. Encapsulation and Systemic Delivery of 5-Fluorouracil Conjugated with Silkworm Pupa Derived Protein Nanoparticles for Experimental Lymphoma Cancer. Bioconjug Chem 2018; 29:2994-3009. [DOI: 10.1021/acs.bioconjchem.8b00404] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
| | - Berchmans Thiyonila
- Department of Environmental Biotechnology, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | | | - Thangaraj Ramya
- Department of Environmental Biotechnology, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | - Ponnusamy Chandrasekar
- Department of Pharmaceutical Technology BIT Campus, Anna University, Tiruchirappalli 620024, India
| | - Natesan Subramanian
- Department of Pharmaceutical Technology BIT Campus, Anna University, Tiruchirappalli 620024, India
| | - Vijay Kumar Prajapati
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Bandarsindri, Kishangarh, Ajmer 305817, Rajasthan, India
| | - Muthukalingan Krishnan
- Department of Environmental Biotechnology, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Bandarsindri, Kishangarh, Ajmer 305817, Rajasthan, India
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Wobst J, Schunkert H, Kessler T. Genetic alterations in the NO-cGMP pathway and cardiovascular risk. Nitric Oxide 2018; 76:105-112. [PMID: 29601927 DOI: 10.1016/j.niox.2018.03.019] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Revised: 03/18/2018] [Accepted: 03/26/2018] [Indexed: 12/18/2022]
Abstract
In the past ten years, several chromosomal loci have been identified by genome-wide association studies to influence the risk of coronary artery disease (CAD) and its risk factors. The GUCY1A3 gene encoding the α1 subunit of the soluble guanylyl cyclase (sGC) resides at one of these loci and has been strongly associated with blood pressure and CAD risk. More recently, further genes in the pathway encoding the endothelial nitric oxide synthase, the phosphodiesterases 3A and 5A, and the inositol 1,4,5-trisphosphate receptor I-associated protein (IRAG), i.e., NOS3, PDE3A, PDE5A, and MRVI1, respectively, were likewise identified as CAD risk genes. In this review, we highlight the genetic findings linking variants in NO-cGMP signaling and cardiovascular disease, discuss the potential underlying mechanisms which might propagate the development of atherosclerosis, and speculate about therapeutic implications.
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Affiliation(s)
- Jana Wobst
- Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, Munich, Germany; Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) e.V., partner site Munich Heart Alliance, Munich, Germany
| | - Heribert Schunkert
- Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, Munich, Germany; Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) e.V., partner site Munich Heart Alliance, Munich, Germany
| | - Thorsten Kessler
- Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, Munich, Germany; Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) e.V., partner site Munich Heart Alliance, Munich, Germany.
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15
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Neonatal exposure to high oxygen levels leads to impaired ischemia-induced neovascularization in adulthood. Sci Rep 2017; 7:14143. [PMID: 29075011 PMCID: PMC5658429 DOI: 10.1038/s41598-017-14396-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 10/10/2017] [Indexed: 02/02/2023] Open
Abstract
Adverse perinatal conditions can lead to developmental programming of cardiovascular diseases. Prematurely born infants are often exposed to high oxygen levels, which in animal models has been associated with endothelial dysfunction, hypertension, and cardiac remodeling during adulthood. Here we found that adult mice that have been transiently exposed to O2 after birth show defective neovasculariation after hindlimb ischemia, as demonstrated by impaired blood flow recovery, reduced vascular density in ischemic muscles and increased tissue damages. Ischemic muscles isolated from mice exposed to O2 after birth exhibit increased oxidative stress levels and reduced expression of superoxide dismutase 1 (SOD1) and vascular endothelial growth factor (VEGF). Pro-angiogenic cells (PACs) have been shown to have an important role for postnatal neovascularisation. We found that neonatal exposure to O2 is associated with reduced number of PACs in adults. Moreover, the angiogenic activities of both PACs and mature mouse aortic endothelial cells (MAECs) are significantly impaired in mice exposed to hyperoxia after birth. Our results indicate that neonatal exposure to high oxygen levels leads to impaired ischemia-induced neovascularization during adulthood. The mechanism involves deleterious effects on oxidative stress levels and angiogenic signals in ischemic muscles, together with dysfunctional activities of PACs and mature endothelial cells.
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16
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Karizbodagh MP, Rashidi B, Sahebkar A, Masoudifar A, Mirzaei H. Implantation Window and Angiogenesis. J Cell Biochem 2017; 118:4141-4151. [DOI: 10.1002/jcb.26088] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 04/21/2017] [Indexed: 01/09/2023]
Affiliation(s)
- Mostafa Peyvandi Karizbodagh
- Department of Anatomical SciencesSchool of MedicineMashhad University of Medical SciencesMashhadIran
- Department of Anatomical SciencesSchool of MedicineBirjand University of Medical SciencesBirjandIran
| | - Bahman Rashidi
- Department of Anatomical Sciences and Molecular BiologySchool of MedicineIsfahan University of Medical SciencesIsfahanIran
| | | | - Aria Masoudifar
- Department of Molecular BiotechnologyCell Science Research CenterRoyan Institute for Biotechnology ACECRIsfahanIran
| | - Hamed Mirzaei
- Department of Medical BiotechnologySchool of MedicineMashhad University of Medical SciencesMashhadIran
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17
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Redox regulation of ischemic limb neovascularization - What we have learned from animal studies. Redox Biol 2017; 12:1011-1019. [PMID: 28505880 PMCID: PMC5430575 DOI: 10.1016/j.redox.2017.04.040] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Revised: 04/08/2017] [Accepted: 04/24/2017] [Indexed: 12/31/2022] Open
Abstract
Mouse hindlimb ischemia has been widely used as a model to study peripheral artery disease. Genetic modulation of the enzymatic source of oxidants or components of the antioxidant system reveal that physiological levels of oxidants are essential to promote the process of arteriogenesis and angiogenesis after femoral artery occlusion, although mice with diabetes or atherosclerosis may have higher deleterious levels of oxidants. Therefore, fine control of oxidants is required to stimulate vascularization in the limb muscle. Oxidants transduce cellular signaling through oxidative modifications of redox sensitive cysteine thiols. Of particular importance, the reversible modification with abundant glutathione, called S-glutathionylation (or GSH adducts), is relatively stable and alters protein function including signaling, transcription, and cytoskeletal arrangement. Glutaredoxin-1 (Glrx) is an enzyme which catalyzes reversal of GSH adducts, and does not scavenge oxidants itself. Glrx may control redox signaling under fluctuation of oxidants levels. In ischemic muscle increased GSH adducts through Glrx deletion improves in vivo limb revascularization, indicating endogenous Glrx has anti-angiogenic roles. In accordance, Glrx overexpression attenuates VEGF signaling in vitro and ischemic vascularization in vivo. There are several Glrx targets including HIF-1α which may contribute to inhibition of vascularization by reducing GSH adducts. These animal studies provide a caution that excess antioxidants may be counter-productive for treatment of ischemic limbs, and highlights Glrx as a potential therapeutic target to improve ischemic limb vascularization.
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18
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Dhahri W, Dussault S, Haddad P, Turgeon J, Tremblay S, Rolland K, Desjarlais M, Cáceres-Gorriti KY, Mathieu R, Rivard A. Reduced expression of let-7f activates TGF-β/ALK5 pathway and leads to impaired ischaemia-induced neovascularization after cigarette smoke exposure. J Cell Mol Med 2017; 21:2211-2222. [PMID: 28345812 PMCID: PMC5571564 DOI: 10.1111/jcmm.13144] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2016] [Accepted: 01/30/2017] [Indexed: 12/20/2022] Open
Abstract
This study sought to determine the potential role of microRNAs (miRNAs) in the detrimental effects of cigarette smoke on angiogenesis and neovascularization. Using large-scale miRNA profiling and qRT-PCR analyses, we identified let-7f as a pro-angiogenic miRNA which expression is significantly reduced in HUVECs treated with cigarette smoke extracts (CSE), and in the ischemic muscles of mice that are exposed to cigarette smoke (MES). In a mouse model of hindlimb ischaemia, intramuscular injection of let-7f mimic restored ischaemia-induced neovascularization in MES. Doppler flow ratios and capillary density in ischemic muscles were significantly improved in MES treated with let-7f mimic. Clinically, this was associated with reduced ambulatory impairment and hindlimb ischaemic damage. Treatment with let-7f mimic could also rescue pro-angiogenic cell (PAC) number and function (attachment, proliferation, migration) in MES. ALK5 (TGF-βR1), an important modulator of angiogenesis, is a target of let-7f. Here we show that ALK5 is increased in HUVECs exposed to CSE and in the ischaemic muscles of MES. This is associated with a downstream activation of the anti-angiogenic factors SMAD2/3 and PAI-1. Importantly, treatment with let-7f mimic reduces the expression of ALK5, SMAD2/3 and PAI-1 both in vitro and in vivo. Moreover, let-7f overexpression or ALK5 inhibition can rescue angiogenesis in HUVECs exposed to CSE. Cigarette smoke exposure is associated with reduced expression of let-7f and activation of the anti-angiogenic TGF-β/ALK5 pathway. Overexpression of let-7f using a miRNA mimic could constitute a novel therapeutic strategy to improve ischaemia-induced neovascularization in pathological conditions.
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Affiliation(s)
- Wahiba Dhahri
- Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
| | - Sylvie Dussault
- Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
| | - Paola Haddad
- Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
| | - Julie Turgeon
- Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
| | - Sophie Tremblay
- Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
| | - Kevin Rolland
- Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
| | - Michel Desjarlais
- Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
| | - Katia Y Cáceres-Gorriti
- Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
| | - Raphael Mathieu
- Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
| | - Alain Rivard
- Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
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Almeida LSD, Barboza JR, Freitas FPS, Porto ML, Vasquez EC, Meyrelles SS, Gava AL, Pereira TMC. Sildenafil prevents renal dysfunction in contrast media-induced nephropathy in Wistar rats. Hum Exp Toxicol 2016; 35:1194-1202. [DOI: 10.1177/0960327115626582] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Contrast-induced nephropathy (CIN) is an iatrogenic medical event in stable cardiology patients that may lead to acute renal failure. There is no current successful therapy to manage CIN. Increasing evidence in experimental models and humans has suggested that this disease is associated with renal tubular and vascular injury triggered by oxidative stress. Considering the importance of reactive oxygen species (ROS) generation in the pathogenesis of CIN, the goal of the present study was to evaluate the effects of sildenafil on CIN development. Male Wistar rats were divided into control, CIN, and CIN pretreated with sildenafil (50 mg/kg/day). CIN was induced by water deprivation, NG-nitro-L-arginine methyl ester + indomethacin injections (10 mg/kg, intraperitoneally) and intravenous iohexol administration (3 g/kg). Renal function was evaluated through glomerular filtration rate (GFR), renal blood flow (RBF), plasma creatinine, uremia, and proteinuria. Oxidative stress was assessed by flow cytometry for intracellular ROS. Treatment with sildenafil attenuated the marked reduction of GFR and RBF in the CIN group. Moreover, sildenafil treatment in CIN rats reduced plasma creatinine, uremia, and proteinuria. Flow cytometry demonstrated that sildenafil attenuated the ROS production in the CIN group. These data suggest that sildenafil may be a new therapeutic agent to prevent CIN through its ability to preserve renal function and attenuate oxidative stress.
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Affiliation(s)
- Lais Salles de Almeida
- Physiological Sciences Graduate Program, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil
| | - Jamila Rodrigues Barboza
- Physiological Sciences Graduate Program, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil
| | - Flávia Priscila Santos Freitas
- Physiological Sciences Graduate Program, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil
| | - Marcella Leite Porto
- Physiological Sciences Graduate Program, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil
| | - Elisardo Corral Vasquez
- Physiological Sciences Graduate Program, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil
- Pharmaceutical Sciences Graduate Program, University of Vila Velha, Vila Velha, ES, Brazil
| | - Silvana Santos Meyrelles
- Physiological Sciences Graduate Program, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil
| | - Agata Lages Gava
- Physiological Sciences Graduate Program, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil
- Division of Nephrology, McMaster University, Hamilton, ON, Canada
| | - Thiago Melo Costa Pereira
- Pharmaceutical Sciences Graduate Program, University of Vila Velha, Vila Velha, ES, Brazil
- Federal Institute of Education, Science and Technology, Vila Velha, ES, Brazil
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Su JB. Vascular endothelial dysfunction and pharmacological treatment. World J Cardiol 2015; 7:719-741. [PMID: 26635921 PMCID: PMC4660468 DOI: 10.4330/wjc.v7.i11.719] [Citation(s) in RCA: 145] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 06/23/2015] [Accepted: 09/18/2015] [Indexed: 02/06/2023] Open
Abstract
The endothelium exerts multiple actions involving regulation of vascular permeability and tone, coagulation and fibrinolysis, inflammatory and immunological reactions and cell growth. Alterations of one or more such actions may cause vascular endothelial dysfunction. Different risk factors such as hypercholesterolemia, homocystinemia, hyperglycemia, hypertension, smoking, inflammation, and aging contribute to the development of endothelial dysfunction. Mechanisms underlying endothelial dysfunction are multiple, including impaired endothelium-derived vasodilators, enhanced endothelium-derived vasoconstrictors, over production of reactive oxygen species and reactive nitrogen species, activation of inflammatory and immune reactions, and imbalance of coagulation and fibrinolysis. Endothelial dysfunction occurs in many cardiovascular diseases, which involves different mechanisms, depending on specific risk factors affecting the disease. Among these mechanisms, a reduction in nitric oxide (NO) bioavailability plays a central role in the development of endothelial dysfunction because NO exerts diverse physiological actions, including vasodilation, anti-inflammation, antiplatelet, antiproliferation and antimigration. Experimental and clinical studies have demonstrated that a variety of currently used or investigational drugs, such as angiotensin-converting enzyme inhibitors, angiotensin AT1 receptors blockers, angiotensin-(1-7), antioxidants, beta-blockers, calcium channel blockers, endothelial NO synthase enhancers, phosphodiesterase 5 inhibitors, sphingosine-1-phosphate and statins, exert endothelial protective effects. Due to the difference in mechanisms of action, these drugs need to be used according to specific mechanisms underlying endothelial dysfunction of the disease.
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Freitas Lima LC, Braga VDA, do Socorro de França Silva M, Cruz JDC, Sousa Santos SH, de Oliveira Monteiro MM, Balarini CDM. Adipokines, diabetes and atherosclerosis: an inflammatory association. Front Physiol 2015; 6:304. [PMID: 26578976 PMCID: PMC4630286 DOI: 10.3389/fphys.2015.00304] [Citation(s) in RCA: 142] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 10/12/2015] [Indexed: 12/20/2022] Open
Abstract
Cardiovascular diseases can be considered the most important cause of death in diabetic population and diabetes can in turn increase the risk of cardiovascular events. Inflammation process is currently recognized as responsible for the development and maintenance of diverse chronic diseases, including diabetes and atherosclerosis. Considering that adipose tissue is an important source of adipokines, which may present anti and proinflammatory effects, the aim of this review is to explore the role of the main adipokines in the pathophysiology of diabetes and atherosclerosis, highlighting the therapeutic options that could arise from the manipulation of these signaling pathways both in humans and in translational models.
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Affiliation(s)
| | - Valdir de Andrade Braga
- Biotechnology Center, Federal University of Paraiba (Universidade Federal da Paraíba)Joao Pessoa, Brazil
| | | | - Josiane de Campos Cruz
- Biotechnology Center, Federal University of Paraiba (Universidade Federal da Paraíba)Joao Pessoa, Brazil
| | - Sérgio H. Sousa Santos
- Biological Sciences Institute, Federal University of Minas GeraisBelo Horizonte, Brazil
- Health Science Post-Graduate Program, State University of Montes ClarosMontes Claros, Brazil
| | | | - Camille de Moura Balarini
- Biotechnology Center, Federal University of Paraiba (Universidade Federal da Paraíba)Joao Pessoa, Brazil
- Health Sciences Center, Federal University of Paraiba (Universidade Federal da Paraíba)Joao Pessoa, Brazil
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Sradnick J, Rong S, Luedemann A, Parmentier SP, Bartaun C, Todorov VT, Gueler F, Hugo CP, Hohenstein B. Extrarenal Progenitor Cells Do Not Contribute to Renal Endothelial Repair. J Am Soc Nephrol 2015; 27:1714-26. [PMID: 26453608 DOI: 10.1681/asn.2015030321] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Accepted: 08/18/2015] [Indexed: 12/14/2022] Open
Abstract
Endothelial progenitor cells (EPCs) may be relevant contributors to endothelial cell (EC) repair in various organ systems. In this study, we investigated the potential role of EPCs in renal EC repair. We analyzed the major EPC subtypes in murine kidneys, blood, and spleens after induction of selective EC injury using the concanavalin A/anti-concanavalin A model and after ischemia/reperfusion (I/R) injury as well as the potential of extrarenal cells to substitute for injured local EC. Bone marrow transplantation (BMTx), kidney transplantation, or a combination of both were performed before EC injury to allow distinction of extrarenal or BM-derived cells from intrinsic renal cells. During endothelial regeneration, cells expressing markers of endothelial colony-forming cells (ECFCs) were the most abundant EPC subtype in kidneys, but were not detected in blood or spleen. Few cells expressing markers of EC colony-forming units (EC-CFUs) were detected. In BM chimeric mice (C57BL/6 with tandem dimer Tomato-positive [tdT+] BM cells), circulating and splenic EC-CFUs were BM-derived (tdT+), whereas cells positive for ECFC markers in kidneys were not. Indeed, most BM-derived tdT+ cells in injured kidneys were inflammatory cells. Kidneys from C57BL/6 donors transplanted into tdT+ recipients with or without prior BMTx from C57BL/6 mice were negative for BM-derived or extrarenal ECFCs. Overall, extrarenal cells did not substitute for any intrinsic ECs. These results demonstrate that endothelial repair in mouse kidneys with acute endothelial lesions depends exclusively on local mechanisms.
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Affiliation(s)
- Jan Sradnick
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; and
| | - Song Rong
- Division of Nephrology and Hypertension, Department of Internal Medicine, Hannover Medical School, Hannover, Germany
| | - Anika Luedemann
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; and
| | - Simon P Parmentier
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; and
| | - Christoph Bartaun
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; and
| | - Vladimir T Todorov
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; and
| | - Faikah Gueler
- Division of Nephrology and Hypertension, Department of Internal Medicine, Hannover Medical School, Hannover, Germany
| | - Christian P Hugo
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; and
| | - Bernd Hohenstein
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; and
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Desjarlais M, Dussault S, Dhahri W, Mathieu R, Rivard A. Direct renin inhibition with aliskiren improves ischemia-induced neovascularization: blood pressure-independent effect. Atherosclerosis 2015; 242:450-60. [PMID: 26295797 DOI: 10.1016/j.atherosclerosis.2015.08.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Revised: 07/27/2015] [Accepted: 08/06/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Renin is the rate limiting step for the activation of the renin-angiotensin-aldosterone system, which is linked to the development of endothelial dysfunction, hypertension and atherosclerosis. However, the specific role of renin during physiological responses to tissue ischemia is currently unknown. Aliskiren is the only direct renin inhibitor that is clinically used as an orally active antihypertensive drug. Here we tested the hypothesis that aliskiren might improve neovascularization in response to ischemia. METHODS AND RESULTS At a dose that did not modulate blood pressure (10 mg/kg), aliskiren led to improved blood flow recovery after hindlimb ischemia in C57BL/6 mice (Doppler flow ratios 0.71 ± 0.07 vs. 0.55 ± 0.03; P < 0.05). In ischemic muscles, treatment with aliskiren was associated with a significant increase of vascular density, reduced oxidative stress levels and increased expression of VEGF and eNOS. Aliskiren treatment also significantly increased the number of bone marrow-derived endothelial progenitor cells (EPCs) after hindlimb ischemia. Moreover, the angiogenic properties of EPCs (migration, adhesion, integration into tubules) were significantly improved in mice treated with aliskiren. In vitro, aliskiren improves cellular migration and tubule formation in HUVECs. This is associated with an increased expression of nitric oxide (NO), and a significant reduction of oxidative stress levels. Importantly, the angiogenic properties of aliskiren in vitro and in vivo are completely abolished following treatment with the NOS inhibitor l-NAME. CONCLUSION Direct renin inhibition with aliskiren leads to improved ischemia-induced neovascularization that is not dependant on blood pressure lowering. The mechanism involves beneficial effects of aliskiren on oxidative stress and NO angiogenic pathway, together with an increase in the number and the functional activities of EPCs.
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Affiliation(s)
- Michel Desjarlais
- Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
| | - Sylvie Dussault
- Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
| | - Wahiba Dhahri
- Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
| | - Raphael Mathieu
- Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
| | - Alain Rivard
- Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
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Xiao M, Lu X, Li J, Li L, Li Y. Physiologic ischaemic training induces endothelial progenitor cell mobilization and myocardial angiogenesis via endothelial nitric oxide synthase related pathway in rabbits. J Cardiovasc Med (Hagerstown) 2014; 15:280-7. [DOI: 10.2459/jcm.0b013e32836009fe] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Shah A, Pfaff MJ, Assi R, Wu W, Steinbacher DM. PDE-5 inhibition improves skin flap viability in rats that are exposed to nicotine. Microsurgery 2014; 34:390-7. [PMID: 24610727 DOI: 10.1002/micr.22237] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Revised: 02/02/2014] [Accepted: 02/14/2014] [Indexed: 02/02/2023]
Abstract
INTRODUCTION Nicotine causes ischemia and necrosis of skin flaps. Phosphodiesterase-5 (PDE-5) inhibition enhances blood flow and vasculogenesis. This study examines skin flap survival in rats exposed to nicotine that are treated with and without PDE-5 inhibition. MATERIALS AND METHODS Eighty six rats were divided into five groups. Group 1 received saline subcutaneous (SC) once per day. Group 2 received nicotine SC 2 mg/kg day. Group 3 received sildenafil intraperitoneal (IP) 10 mg/kg day. Group 4 received nicotine SC 2 mg/kg and sildenafil IP 10 mg/kg day. Group 5 received nicotine SC 2 mg/kg day and sildenafil IP 10 mg/kg two times daily. After 28 days of treatment, modified McFarlane flaps were created, silicone sheets were interposed, and flaps were sutured. Photographs were taken on postoperative days 1, 3, and 7 and fluorescence angiography was used on day 7, both to evaluate for skin flap necrosis. Rats were euthanized and flaps were harvested for Vascular Endothelial Growth Factor (VEGF) Western blot analysis. Images were analyzed by three blinded observers using ImageJ, and necrotic indices were calculated. RESULTS The nicotine and PDE-5 inhibition twice-daily group showed a 46% reduction in flap necrosis when compared to saline only (P < 0.05) and a 54% reduction when compared to nicotine only (P < 0.01). Fluorescence angiographic image analysis revealed reductions in flap necrosis (P < 0.01). VEGF analysis trended toward increased VEGF for all sildenafil-treated groups (P > 0.05). CONCLUSIONS PDE-5 inhibition exhibits a dose-dependent reduction in skin flap necrosis in rats exposed to nicotine. This suggests that PDE-5 inhibition may mitigate the ill effects of smoking on skin flaps.
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Affiliation(s)
- Ajul Shah
- Section of Plastic Surgery, Department of Surgery, Yale University School of Medicine, New Haven, CT
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Dias AT, Rodrigues BP, Porto ML, Gava AL, Balarini CM, Freitas FPS, Palomino Z, Casarini DE, Campagnaro BP, Pereira TMC, Meyrelles SS, Vasquez EC. Sildenafil ameliorates oxidative stress and DNA damage in the stenotic kidneys in mice with renovascular hypertension. J Transl Med 2014; 12:35. [PMID: 24502628 PMCID: PMC3922021 DOI: 10.1186/1479-5876-12-35] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Accepted: 02/04/2014] [Indexed: 12/01/2022] Open
Abstract
Background Oxidative stress and DNA damage have been implicated in the pathogenesis of renovascular hypertension induced by renal artery stenosis in the two-kidney, one-clip (2K1C) Goldblatt model. Considering our previous report indicating that the chronic blockade of phosphodiesterase 5 with sildenafil (Viagra®) has marked beneficial effects on oxidative stress and DNA damage, we tested the hypothesis that sildenafil could also protect the stenotic kidneys of 2K1C hypertensive mice against oxidative stress and genotoxicity. Methods The experiments were performed with C57BL6 mice subjected to renovascular hypertension by left renal artery clipping. Two weeks after clipping, the mice were treated with sildenafil (40 mg/kg/day for 2 weeks, 2K1C-sildenafil group) or the vehicle (2K1C). These mice were compared with control mice not subjected to renal artery clipping (Sham). After hemodynamic measurements, the stenotic kidneys were assessed using flow cytometry to evaluate cell viability and the comet assay to evaluate DNA damage. Measurements of intracellular superoxide anions and hydrogen peroxide levels as well as nitric oxide bioavailability were also obtained. Results Sildenafil treatment significantly reduced mean arterial pressure (15%), heart rate (8%), intrarenal angiotensin II (50%) and renal atrophy (36%). In addition, it caused a remarkable decrease of reactive oxygen species production. On the other hand, sildenafil increased nitric oxide levels relative to those in the nontreated 2K1C mice. Sildenafil treatment also significantly reduced the high level of kidney DNA damage that is a characteristic of renovascular hypertensive mice. Conclusions Our data reveal that sildenafil has a protective effect on the stenotic kidneys of 2K1C mice, suggesting a new use of phosphodiesterase 5 inhibitors for protection against the DNA damage observed in the hypoperfused kidneys of individuals with renovascular hypertension. Further translational research is necessary to delineate the mechanisms involved in the prevention of renal stenosis in the clinical setting.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Elisardo C Vasquez
- Laboratory of Translational Physiology, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil.
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Silvestre JS, Smadja DM, Lévy BI. Postischemic revascularization: from cellular and molecular mechanisms to clinical applications. Physiol Rev 2013; 93:1743-802. [PMID: 24137021 DOI: 10.1152/physrev.00006.2013] [Citation(s) in RCA: 181] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
After the onset of ischemia, cardiac or skeletal muscle undergoes a continuum of molecular, cellular, and extracellular responses that determine the function and the remodeling of the ischemic tissue. Hypoxia-related pathways, immunoinflammatory balance, circulating or local vascular progenitor cells, as well as changes in hemodynamical forces within vascular wall trigger all the processes regulating vascular homeostasis, including vasculogenesis, angiogenesis, arteriogenesis, and collateral growth, which act in concert to establish a functional vascular network in ischemic zones. In patients with ischemic diseases, most of the cellular (mainly those involving bone marrow-derived cells and local stem/progenitor cells) and molecular mechanisms involved in the activation of vessel growth and vascular remodeling are markedly impaired by the deleterious microenvironment characterized by fibrosis, inflammation, hypoperfusion, and inhibition of endogenous angiogenic and regenerative programs. Furthermore, cardiovascular risk factors, including diabetes, hypercholesterolemia, hypertension, diabetes, and aging, constitute a deleterious macroenvironment that participates to the abrogation of postischemic revascularization and tissue regeneration observed in these patient populations. Thus stimulation of vessel growth and/or remodeling has emerged as a new therapeutic option in patients with ischemic diseases. Many strategies of therapeutic revascularization, based on the administration of growth factors or stem/progenitor cells from diverse sources, have been proposed and are currently tested in patients with peripheral arterial disease or cardiac diseases. This review provides an overview from our current knowledge regarding molecular and cellular mechanisms involved in postischemic revascularization, as well as advances in the clinical application of such strategies of therapeutic revascularization.
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Rodrigues BP, Campagnaro BP, Balarini CM, Pereira TMC, Meyrelles SS, Vasquez EC. Sildenafil ameliorates biomarkers of genotoxicity in an experimental model of spontaneous atherosclerosis. Lipids Health Dis 2013; 12:128. [PMID: 23981672 PMCID: PMC3766097 DOI: 10.1186/1476-511x-12-128] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2013] [Accepted: 08/23/2013] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND It is well known that enhanced production of reactive oxygen species (ROS) leads to oxidative stress observed in atherosclerosis and that ROS can also cause damage in cellular macromolecules, including DNA. Considering previous report that sildenafil, an inhibitor of phosphodiesterase 5 (PDE5), has antioxidant effects, in the present study we evaluated the effect of this drug on genotoxicity of blood mononuclear cells (MNC) and liver cells from atherosclerotic apolipoprotein E knockout mice (apoE(-/-)). METHODS ROS production in MNC was evaluated by flow cytometry with the fluorescent dye dihydroethidium (DHE), a method that has been used to quantify the production of superoxide anion, and DNA damage was evaluated in both MNC and liver cells using the alkaline comet assay. Sildenafil-administered apoE(-/-) mice were compared with strain-matched mice administered with vehicle and with C57BL/6 wild-type (WT) mice. RESULTS MNC from apoE(-/-) vehicle exhibited a 2-fold increase in production of superoxide anion in comparison with WT. In contrast, sildenafil-administered apoE(-/-) mice showed superoxide anion levels similar to those observed in WT mice. Similarly, MNC and liver cells from apoE(-/-) vehicle mice showed a 4-fold and 2-fold augmented DNA fragmentation compared with WT, respectively, and sildenafil-administered apoE(-/-) mice exhibited minimal DNA damage in those cells similar to WT mice. CONCLUSIONS ApoE(-/-) mice chronically administered with sildenafil exhibited reduced levels of superoxide anion in MNC and less DNA fragmentation in MNC and liver cells, which are biomarkers of genotoxicity. Therefore, sildenafil may offer a new perspective to the use of PDE5 inhibitors to protect against DNA damage, in cells involved in the inflammatory and dyslipidemic processes that accompany atherosclerosis.
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Affiliation(s)
- Bianca P Rodrigues
- Laboratory of Translational Physiology, Health Sciences Center, Federal University of Espirito Santo (UFES), Vitoria, Brazil
| | - Bianca P Campagnaro
- Laboratory of Translational Physiology, Health Sciences Center, Federal University of Espirito Santo (UFES), Vitoria, Brazil
- Pharmaceutical Sciences Graduate Program, University of Vila Velha (UVV), Vila Velha, ES, Brazil
| | - Camille M Balarini
- Laboratory of Translational Physiology, Health Sciences Center, Federal University of Espirito Santo (UFES), Vitoria, Brazil
| | - Thiago M C Pereira
- Pharmaceutical Sciences Graduate Program, University of Vila Velha (UVV), Vila Velha, ES, Brazil
- Federal Institute of Education, Science and Technology (IFES), Vila Velha, ES, Brazil
| | - Silvana S Meyrelles
- Laboratory of Translational Physiology, Health Sciences Center, Federal University of Espirito Santo (UFES), Vitoria, Brazil
| | - Elisardo C Vasquez
- Laboratory of Translational Physiology, Health Sciences Center, Federal University of Espirito Santo (UFES), Vitoria, Brazil
- Pharmaceutical Sciences Graduate Program, University of Vila Velha (UVV), Vila Velha, ES, Brazil
- Emescam School of Health Sciences, Vitoria, Brazil
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Ichim TE, Warbington T, Cristea O, Chin JL, Patel AN. Intracavernous administration of bone marrow mononuclear cells: a new method of treating erectile dysfunction? J Transl Med 2013; 11:139. [PMID: 23758954 PMCID: PMC3718667 DOI: 10.1186/1479-5876-11-139] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 04/23/2013] [Indexed: 02/06/2023] Open
Abstract
While PDE5 inhibitors have revolutionized treatment of ED, approximately 30% of patients are non-responsive. A significant cause of this is vascular and smooth muscle dysfunction, as well as nerve atrophy. Autologous administration of bone marrow mononuclear cells (BMMC) has been performed in over 2000 cardiac patients without adverse effects, for stimulation of angiogenesis/regeneration. Despite its ease of access, and dependence on effective vasculature for function, comparatively little has been perform in terms of BMMC therapy for ED. Here we outline the rationale for use of autologous BMMC in patients with ED, as well as provide early safety data on the first use of this procedure clinically.
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Affiliation(s)
- Thomas E Ichim
- Institute for Molecular Medicine, Huntington Beach, CA, USA.
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Condorelli RA, Calogero AE, Vicari E, Favilla V, Morgia G, Cimino S, La Vignera S. Vascular regenerative therapies for the treatment of erectile dysfunction: current approaches. Andrology 2013; 1:533-40. [DOI: 10.1111/j.2047-2927.2013.00087.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2013] [Revised: 03/01/2013] [Accepted: 03/09/2013] [Indexed: 12/20/2022]
Affiliation(s)
- R. A. Condorelli
- Section of Endocrinology; Andrology and Internal Medicine; Department of Medical and Pediatric Sciences; University of Catania; Catania; Italy
| | - A. E. Calogero
- Section of Endocrinology; Andrology and Internal Medicine; Department of Medical and Pediatric Sciences; University of Catania; Catania; Italy
| | - E. Vicari
- Section of Endocrinology; Andrology and Internal Medicine; Department of Medical and Pediatric Sciences; University of Catania; Catania; Italy
| | - V. Favilla
- Department of Urology; University of Catania; Catania; Italy
| | - G. Morgia
- Department of Urology; University of Catania; Catania; Italy
| | - S. Cimino
- Department of Urology; University of Catania; Catania; Italy
| | - S. La Vignera
- Section of Endocrinology; Andrology and Internal Medicine; Department of Medical and Pediatric Sciences; University of Catania; Catania; Italy
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Balarini CM, Leal MA, Gomes IBS, Pereira TMC, Gava AL, Meyrelles SS, Vasquez EC. Sildenafil restores endothelial function in the apolipoprotein E knockout mouse. J Transl Med 2013; 11:3. [PMID: 23289368 PMCID: PMC3551739 DOI: 10.1186/1479-5876-11-3] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2012] [Accepted: 01/02/2013] [Indexed: 11/25/2022] Open
Abstract
Background Atherosclerosis is an inflammatory process of the arterial walls and is initiated by endothelial dysfunction accompanied by an imbalance in the production of reactive oxygen species (ROS) and nitric oxide (NO). Sildenafil, a selective phosphodiesterase-5 (PDE5) inhibitor used for erectile dysfunction, exerts its cardiovascular effects by enhancing the effects of NO. The aim of this study was to investigate the influence of sildenafil on endothelial function and atherosclerosis progression in apolipoprotein E knockout (apoE−/−) mice. Methods ApoE−/− mice treated with sildenafil (Viagra®, 40 mg/kg/day, for 3 weeks, by oral gavage) were compared to the untreated apoE−/− and the wild-type (WT) mice. Aortic rings were used to evaluate the relaxation responses to acetylcholine (ACh) in all of the groups. In a separate set of experiments, the roles of NO and ROS in the relaxation response to ACh were evaluated by incubating the aortic rings with L-NAME (NO synthase inhibitor) or apocynin (NADPH oxidase inhibitor). In addition, the atherosclerotic lesions were quantified and superoxide production was assessed. Results Sildenafil restored the vasodilator response to acetylcholine (ACh) in the aortic rings of the apoE−/− mice. Treatment with L-NAME abolished the vasodilator responses to ACh in all three groups of mice and revealed an augmented participation of NO in the endothelium-dependent vasodilation in the sildenafil-treated animals. The normalized endothelial function in sildenafil-treated apoE−/− mice was unaffected by apocynin highlighting the low levels of ROS production in these animals. Moreover, morphological analysis showed that sildenafil treatment caused approximately a 40% decrease in plaque deposition in the aorta. Conclusion This is the first study demonstrating the beneficial effects of chronic treatment with sildenafil on endothelial dysfunction and atherosclerosis in a model of spontaneous hypercholesterolemia. These data indicate that the main mechanism of the beneficial effect of sildenafil on the endothelial function appears to involve an enhancement of the NO pathway along with a reduction in oxidative stress.
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Affiliation(s)
- Camille M Balarini
- Dept, of Physiological Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil
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Gammella E, Leuenberger C, Gassmann M, Ostergaard L. Evidence of synergistic/additive effects of sildenafil and erythropoietin in enhancing survival and migration of hypoxic endothelial cells. Am J Physiol Lung Cell Mol Physiol 2012. [PMID: 23204066 DOI: 10.1152/ajplung.00112.2012] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Endothelial cell dysfunction is a common event to several pathologies including pulmonary hypertension, which is often associated with hypoxia. As the endothelium plays an essential role in regulating the dynamic interaction between pulmonary vasodilatation and vasoconstriction, this cell type is fundamental in the development of vascular remodeling and increased vascular resistance. We investigated the protective effects of sildenafil, a phosphodiesterase type 5 inhibitor, given in combination with erythropoietin (Epo), as it has been demonstrated that both drugs have antiapoptotic effects on several cell types. Specifically, we examined the viability and angiogenic properties of rat pulmonary artery endothelial cells upon exposure to either 21% or 1% oxygen, in presence of sildenafil (1 and 100 nM) and Epo (5 and 20 U/ml) alone or in combination (1 nM and 20 U/ml). Cell proliferation and viability were analyzed by Trypan blue staining, MTT assay, and Annexin V/propidium iodide stainings. In all assays, the ability of the combination treatment in improving cell viability was superior to that of either drug alone. The angiogenic properties were studied using a migration and a 3D collagen assay, and the results revealed increases in the migration potential of endothelial cells as well as the ability to form tube-like structures in response to sildenafil and the combination treatment. We therefore conclude that both drugs exert protective effects on endothelial cells on hypoxia and that sildenafil enhances the migratory and angiogenic properties, especially in hypoxic conditions. Furthermore, we present evidence of possible additive or synergistic effects of both drugs.
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Affiliation(s)
- Elena Gammella
- Department of Human Morphology and Biomedical Sciences, Città Studi, Università degli Studi di Milano, Milan, Italy
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Pinocembrin, a major flavonoid in propolis, improves the biological functions of EPCs derived from rat bone marrow through the PI3K-eNOS-NO signaling pathway. Cytotechnology 2012. [PMID: 23179089 DOI: 10.1007/s10616-012-9502-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Abstract
The number and quality of endothelial progenitor cells (EPCs) are damaged to varying degrees in patients at risk for developing atherosclerosis. The improvement of the quantity and functions of EPCs can enhance repair of injured endothelial monolayer resulting in inhibiting atherosclerosis. The purpose of this study was to investigate the effect of pinocembrin (PIN), a major flavonoid in propolis on the differentiation and biological functions of EPCs and the potential mechanisms of these effects. Flow cytometry analysis revealed that PIN treatment increased the number of CD34(+), CD133(+), FLK-1(+), CD133(+)/FLK-1(+) and CD34(+)/FLK-1(+) mononuclear cells (MNCs) in the peripheral blood of apoE(-/-) mice compared to untreated control mice. In vitro PIN treatment significantly increased the number of CD34(+), CD133(+), FLK-1(+) and CD133(+)/FLK-1(+) MNCs derived from SD bone marrow compared to untreated controls by 42.1, 84.6, 165.9 and 23.1 %, respectively. Additionally, PIN can improve biological functions of EPCs, such as proliferation, migration, adhesion, and in vitro tube formation and NO release. All of these improvements were inhibited by LY294002, while L-NAME only inhibited the PIN-induced increase in EPC proliferation and adhesion. We conclude that PIN can both promote the differentiation of EPCs in vitro and ex vivo and improve the biological functions of EPCs. The PI3K-eNOS-NO signaling pathway may be involved in the PIN-induced increase in the proliferation and adhesion of EPCs.
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Herraiz S, Pellicer B, Serra V, Cauli O, Cortijo J, Felipo V, Pellicer A. Sildenafil citrate improves perinatal outcome in fetuses from pre-eclamptic rats. BJOG 2012; 119:1394-402. [DOI: 10.1111/j.1471-0528.2012.03430.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Meyrelles SS, Peotta VA, Pereira TMC, Vasquez EC. Endothelial dysfunction in the apolipoprotein E-deficient mouse: insights into the influence of diet, gender and aging. Lipids Health Dis 2011; 10:211. [PMID: 22082357 PMCID: PMC3247089 DOI: 10.1186/1476-511x-10-211] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2011] [Accepted: 11/14/2011] [Indexed: 02/07/2023] Open
Abstract
Since the early 1990s, several strains of genetically modified mice have been developed as models for experimental atherosclerosis. Among the available models, the apolipoprotein E-deficient (apoE⁻/⁻) mouse is of particular relevance because of its propensity to spontaneously develop hypercholesterolemia and atherosclerotic lesions that are similar to those found in humans, even when the mice are fed a chow diet. The main purpose of this review is to highlight the key achievements that have contributed to elucidating the mechanisms pertaining to vascular dysfunction in the apoE⁻/⁻ mouse. First, we summarize lipoproteins and atherosclerosis phenotypes in the apoE⁻/⁻ mouse, and then we briefly discuss controversial evidence relative to the influence of gender on the development of atherosclerosis in this murine model. Second, we discuss the main mechanisms underlying the endothelial dysfunction of conducting vessels and resistance vessels and examine how this vascular defect can be influenced by diet, aging and gender in the apoE⁻/⁻ mouse.
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Affiliation(s)
- Silvana S Meyrelles
- Departament of Physiological Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil
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Histing T, Marciniak K, Scheuer C, Garcia P, Holstein JH, Klein M, Matthys R, Pohlemann T, Menger MD. Sildenafil accelerates fracture healing in mice. J Orthop Res 2011; 29:867-73. [PMID: 21246617 DOI: 10.1002/jor.21324] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2010] [Accepted: 11/08/2010] [Indexed: 02/04/2023]
Abstract
Sildenafil, a cyclic guanosine monophosphate (cGMP)-dependent phospodiesterase-5 inhibitor, has been shown to be a potent stimulator of angiogenesis through upregulation of pro-angiogenic factors and control of cGMP concentration. Herein, we determined whether sildenafil also influences angiogenic growth factor expression and bone formation during the process of fracture healing. Bone healing was studied in a murine closed femur fracture model using radiological, biomechanical, histomorphometric, and protein biochemical analysis at 2 and 5 weeks after fracture. Thirty mice received 5 mg/kg body weight sildenafil p.o. daily. Controls (n = 30) received equivalent amounts of vehicle. After 2 weeks of fracture healing sildenafil significantly increased osseous fracture bridging, as determined radiologically and histologically. This resulted in an increased biomechanical stiffness compared to controls. A smaller callus area with a slightly reduced amount of cartilaginous tissue indicated an accelerated healing process. After 5 weeks the differences were found blunted, demonstrating successful healing in both groups. Western blot analysis showed a significantly higher expression of the pro-angiogenic and osteogenic cysteine-rich protein (CYR) 61, confirming the increase of bone formation. We show for the first time that sildenafil treatment accelerates fracture healing by enhancing bone formation, most probably by a CYR61-associated pathway.
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Affiliation(s)
- Tina Histing
- Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, Homburg/Saar, Germany.
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Curatola AM, Xu J, Hendricks-Munoz KD. Cyclic GMP protects endothelial progenitors from oxidative stress. Angiogenesis 2011; 14:267-79. [PMID: 21499920 DOI: 10.1007/s10456-011-9211-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2010] [Accepted: 03/30/2011] [Indexed: 12/24/2022]
Abstract
Endothelial progenitor cells (EPCs) play a critical role in the repair of damaged blood vessels and/or in the growth of new ones in ischemic tissues. Elevated levels of oxygen radicals, which accumulate in the ischemic tissue, could compromise the angiogenic potential of EPCs. To determine if oxidative stress alters the angiogenic response of EPCs and to identify possible cellular targets that protect EPCs from the damaging effects of oxidative stress, we have investigated vascular development in embryonic bodies (EBs) under hyperoxic conditions. Murine EBs at differentiaton day 2 were cultured for 3 days under normoxic (21% O(2)) or hyperoxic (60% O(2)) conditions. Hyperoxic EBs showed a moderate reduction in Pecam-1, Vegfr-2, eNOS and Tie2 mRNA levels compared to normoxic EBs. However, immunostaining of hyperoxic EBs with antibodies against PECAM-1 after 1 week recovery at room air revealed a defective vasculature completely deficient in branches, while normoxic EBs developed a normal vascular plexus. Oxygen-induced defective vascular development correlated with a dramatic decrease in soluble guanylyl cyclase, phosphodiesterase (Pde) 4B and Pde4C mRNAs. Oxidative stress did not affect the expression of adenylyl cyclase 6 and Pde5. The abnormal vascular development caused by hyperoxia was reverted by pharmacological treatments that increased cGMP levels, such as 8-bromo-cGMP or 4-{[3',4'-(methylenedioxy)benzyl]amino}-6-methoxyquinazoline, a specific inhibitor of PDE5. These results indicated that oxidative stress inhibits vascular development from EPCs through its effects on levels of cyclic nucleotides and suggested that therapies that target cyclic nucleotide turnover may be useful in protecting vascular repair under oxidative conditions.
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Affiliation(s)
- Anna Maria Curatola
- Division of Neonatology, Department of Pediatrics, New York University School of Medicine, NY 10016, USA.
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Pellicer B, Herraiz S, Cauli O, Rodrigo R, Asensi M, Cortijo J, Serra V, Morcillo E, Felipo V, Simón C, Pellicer A. Haemodynamic effects of long-term administration of sildenafil in normotensive pregnant and non-pregnant rats. BJOG 2011; 118:615-23. [PMID: 21244618 DOI: 10.1111/j.1471-0528.2010.02839.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To determine the effects of chronic administration of sildenafil citrate on healthy pregnant rats. DESIGN In vivo animal experimental study. SETTING Fundación IVI-Instituto Universitario IVI, Valencia, Spain. SAMPLE Pregnant and non-pregnant Wistar rats exposed to chronic administration of sildenafil. METHODS Placental cross-barrier and feto-maternal relationship levels, maternal blood pressure, and haemodymamic effects on uterine arteries were evaluated. The effect of growth on weight and fetal tissues, and on perinatal outcome, was investigated. MAIN OUTCOME MEASURES Maternal blood pressure, blood viscosity, vascular indices of uterine arteries and fetal ductus venosus, plasmatic levels of sildenafil, embryo/fetal and litter weights, perinatal/postnatal survival rates. RESULTS Sildenafil citrate crossed the placenta. The maternal and fetal levels of sildenafil, and its metabolite desmethyl-sildenafil, demonstrated a positive linear correlation in treated pregnant animals versus controls; a selective maternal hypotensive effect without changes in uterine vascular resistance was noted on days E8 and E11 (embryonic day). The lower pulsatility index of the ductus venosus on day E18 suggests fetal overflow at the end of the pregnancy. Effects on offspring were placental and liver enlargement, and increased fetal weight gain in the second half of pregnancy (irrespective of liver enlargement) and at birth. Perinatal and postnatal survival rates in the sildenafil group remained unaltered. No haemodynamic effects were evident in non-pregnant animals. CONCLUSIONS In normotensive rats, sildenafil appears to have a selective effect at the onset of pregnancy, implying increased fetal blood supply, and increased fetal weight, and placental and liver enlargement, but no increased perinatal mortality.
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Affiliation(s)
- B Pellicer
- Hospital de Manises, C/Roses s/n, Manises, Valencia, Spain.
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Treprostinil increases the number and angiogenic potential of endothelial progenitor cells in children with pulmonary hypertension. Angiogenesis 2010; 14:17-27. [PMID: 21049284 PMCID: PMC3040815 DOI: 10.1007/s10456-010-9192-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2010] [Accepted: 10/19/2010] [Indexed: 02/05/2023]
Abstract
Background Pulmonary vasodilators in general and prostacyclin therapy in particular, have markedly improved the outcome of patients with pulmonary arterial hypertension (PAH). As endothelial dysfunction is a key feature of PAH, and as endothelial progenitor cells (EPC) may contribute to vascular repair in PAH, we suspected that prostacyclin therapy might enhance EPC numbers and functions. In the present study, objectives were to determine whether EPC may contribute to vasodilator treatment efficacy in PAH. Methods We quantified CD34+ cells, CFU-Hill and ECFC (endothelial colony forming cells) in peripheral blood from children with idiopathic PAH (n = 27) or PAH secondary to congenital heart disease (n = 52). CD34+ were enumerated by flow cytometry, CFU-Hill and ECFC by a culture assay. ECFC grown ex vivo were tested for their angiogenic capacities before and after prostacyclin analog therapy (subcutaneous treprostinil). Results ECFC counts were significantly enhanced in the 8 children treated with treprostinil, while no change was observed in children receiving oral therapy with endothelin antagonists and/or PDE5 inhibitors. CD34+ cell and CFU-Hill counts were unaffected. ECFC from patients treated with treprostinil had a hyperproliferative phenotype and showed enhanced angiogenic potential in a nude mouse preclinical model of limb ischemia. Conclusions ECFC may partly mediate the clinical benefits of prostanoids in pulmonary arterial hypertension.
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Tousoulis D, Papageorgiou N, Androulakis E, Paroutoglou K, Stefanadis C. Novel therapeutic strategies targeting vascular endothelium in essential hypertension. Expert Opin Investig Drugs 2010; 19:1395-1412. [PMID: 20923260 DOI: 10.1517/13543784.2010.522989] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
IMPORTANCE OF THE FIELD Several studies have demonstrated the high prevalence of hypertension and the crucial role of the association between endothelial function and hypertension. Thus, in depth investigation of the pathophysiological mechanisms linking endothelial dysfunction and hypertension, as well as evaluation of the efficacy of therapeutic approaches targeting vascular endothelium in states of essential hypertension seems to be of great interest. AREAS COVERED IN THIS REVIEW The association of essential hypertension and endothelial function are discussed in depth. In addition to the classical anti-hypertensive agents, agents such as statins, tetrahydrobiopterin, l-arginine, antioxidants, sildenafil, third generation beta blockers and NO-release related agents have been found to be beneficial by improving endothelial dysfunction in essential hypertension. WHAT THE READER WILL GAIN Important aspects regarding the association of hypertension and endothelial dysfunction will be highlighted. In addition, classical and novel agents especially, will be reported thoroughly according to their effects on endothelial function in hypertension. TAKE HOME MESSAGE There is a strong bidirectional association between essential hypertension and endothelial dysfunction. Moreover, novel agents appear to be beneficial and promising in improving endothelial function in states of hypertension. However, more studies are required to evaluate their role, as the literature lacks large scale studies.
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Affiliation(s)
- Dimitris Tousoulis
- Athens University Medical School, Hippokration Hospital, First Cardiology Unit, Athens, Greece.
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Everaert BR, Van Craenenbroeck EM, Hoymans VY, Haine SE, Van Nassauw L, Conraads VM, Timmermans JP, Vrints CJ. Current perspective of pathophysiological and interventional effects on endothelial progenitor cell biology: focus on PI3K/AKT/eNOS pathway. Int J Cardiol 2010; 144:350-66. [PMID: 20444511 DOI: 10.1016/j.ijcard.2010.04.018] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2010] [Accepted: 04/04/2010] [Indexed: 12/24/2022]
Abstract
For more than a decade, endothelial progenitor cells (EPCs) have been implicated in cardiovascular homeostasis. EPCs are believed to reside within the bone marrow in close contact with surrounding stromal cells, and, under stimulation of pro-inflammatory cytokines, EPCs are mobilized out of the bone marrow. Hereafter circulating EPCs home to peripheral tissues, undergoing further proliferation and differentiation. Under certain pathophysiologic conditions this process seems to be blunted, resulting in a reduced capacity of EPCs to engage in vasculogenesis at sites of endothelial injury or tissue ischemia. In this review, we focus on the effects of traditional cardiovascular risk factors on EPC biology and we explore whether pharmacological, dietary and lifestyle interventions can favorably restore EPC mobilization, differentiation, homing and angiogenic properties. Because the PI3K/Akt/eNOS pathway plays a pivotal role in the process of EPC mobilization, migration and homing, we specifically emphasize the involvement of PI3K, Akt and eNOS in EPC biology under these different (patho)physiologic conditions. (Pre)clinically used drugs or lifestyle interventions that have been shown to ameliorate EPC biology are reviewed. These treatment strategies remain attractive targets to restore the regenerative capacity of EPCs in cardiovascular diseases.
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Affiliation(s)
- Bert R Everaert
- Laboratory of Cell Biology and Histology, University of Antwerp, Antwerp, Belgium
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