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      Direct Current Electric Field Stimulates Nitric Oxide Production and Promotes NO-Dependent Angiogenesis: Involvement of the PI3K/Akt Signaling Pathway

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          Electric fields (EFs) promote angiogenesis in vitro and in vivo. These results indicate the feasibility of the application of EFs to modulate angiogenesis. Nitric oxide (NO) derived from endothelial nitric oxide synthase (eNOS) is an important regulator of angiogenesis. However, the role of direct current EFs in eNOS activity and expression in association with angiogenesis of endothelial cells has not been investigated. In the present study, we stimulated human umbilical vein endothelial cells (HUVECs) with EFs and evaluated the activity and expression of eNOS. EFs induced significant phosphorylation of eNOS, upregulation of the expression of eNOS protein, and an increase in NO production from HUVECs. L-NAME, a specific inhibitor of eNOS, abolished EF-induced HUVEC angiogenesis. EFs stimulated Akt activation. Inhibition of PI3K activity inhibited EF-mediated Akt and eNOS activation and inhibited NO production in the endothelial cells. Moreover, EFs stimulated HUVEC proliferation and enhanced the S phase cell population of the cell cycle. We conclude that EFs stimulate eNOS activation and NO production via a PI3K/Akt-dependent pathway. Thus, activation of eNOS appears to be one of the key signaling pathways necessary for EF-mediated angiogenesis. These novel findings suggest that NO signaling may have an important role in EF-mediated endothelial cell function.

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          Most cited references 38

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          Angiogenesis in life, disease and medicine.

          The growth of blood vessels (a process known as angiogenesis) is essential for organ growth and repair. An imbalance in this process contributes to numerous malignant, inflammatory, ischaemic, infectious and immune disorders. Recently, the first anti-angiogenic agents have been approved for the treatment of cancer and blindness. Angiogenesis research will probably change the face of medicine in the next decades, with more than 500 million people worldwide predicted to benefit from pro- or anti-angiogenesis treatments.
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            Nitric oxide synthase modulates angiogenesis in response to tissue ischemia.

            We tested the hypothesis that endothelial nitric oxide synthase (eNOS) modulates angiogenesis in two animal models in which therapeutic angiogenesis has been characterized as a compensatory response to tissue ischemia. We first administered L-arginine, previously shown to augment endogenous production of NO, to normal rabbits with operatively induced hindlimb ischemia. Angiogenesis in the ischemic hindlimb was significantly improved by dietary supplementation with L-arginine, compared to placebo-treated controls; angiographically evident vascularity in the ischemic limb, hemodynamic indices of limb perfusion, capillary density, and vasomotor reactivity in the collateral vessel-dependent ischemic limb were all improved by oral L-arginine supplementation. A murine model of operatively induced hindlimb ischemia was used to investigate the impact of targeted disruption of the gene encoding for ENOS on angiogenesis. Angiogenesis in the ischemic hindlimb was significantly impaired in eNOS-/- mice versus wild-type controls evaluated by either laser Doppler flow analysis or capillary density measurement. Impaired angiogenesis in eNOS-/- mice was not improved by administration of vascular endothelial growth factor (VEGF), suggesting that eNOS acts downstream from VEGF. Thus, (a) eNOS is a downstream mediator for in vivo angiogenesis, and (b) promoting eNOS activity by L-arginine supplementation accelerates in vivo angiogenesis. These findings suggest that defective endothelial NO synthesis may limit angiogenesis in patients with endothelial dysfunction related to atherosclerosis, and that oral L-arginine supplementation constitutes a potential therapeutic strategy for accelerating angiogenesis in patients with advanced vascular obstruction.
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              Nitric oxide signaling in the central nervous system.


                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                July 2020
                06 May 2020
                : 57
                : 4
                : 195-205
                aLaboratory of Genetic Disease and Perinatal Medicine and Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
                bDepartment of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
                cDivision of Peptides Related to Human Disease, West China Hospital, Sichuan University, Chengdu, China
                dDepartment of Biochemistry and Molecular Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, China
                Author notes
                *Huai Bai, MD, PhD, Laboratory of Genetic Disease and Perinatal Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041 (PR China),
                506517 J Vasc Res 2020;57:195–205
                © 2020 S. Karger AG, Basel

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                Page count
                Figures: 9, Pages: 11
                Research Article


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