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      Nitric oxide synthases, S-nitrosylation and cardiovascular health: From molecular mechanisms to therapeutic opportunities (Review)

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          Abstract

          The understanding of nitric oxide (NO) signaling has grown substantially since the identification of endothelial derived relaxing factor (EDRF). NO has emerged as a ubiquitous signaling molecule involved in diverse physiological and pathological processes. Perhaps the most significant function, independent of EDRF, is that of NO signaling mediated locally in signaling modules rather than relying upon diffusion. In this context, NO modulates protein function via direct post-translational modification of cysteine residues. This review explores NO signaling and related reactive nitrogen species involved in the regulation of the cardiovascular system. A critical concept in the understanding of NO signaling is that of the nitroso-redox balance. Reactive nitrogen species bioactivity is fundamentally linked to the production of reactive oxygen species. This interaction occurs at the chemical, enzymatic and signaling effector levels. Furthermore, the nitroso-redox equilibrium is in a delicate balance, involving the cross-talk between NO and oxygen-derived species signaling systems, including NADPH oxidases and xanthine oxidase.

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          Most cited references132

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          The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.

          Despite its very potent vasodilating action in vivo, acetylcholine (ACh) does not always produce relaxation of isolated preparations of blood vessels in vitro. For example, in the helical strip of the rabbit descending thoracic aorta, the only reported response to ACh has been graded contractions, occurring at concentrations above 0.1 muM and mediated by muscarinic receptors. Recently, we observed that in a ring preparation from the rabbit thoracic aorta, ACh produced marked relaxation at concentrations lower than those required to produce contraction (confirming an earlier report by Jelliffe). In investigating this apparent discrepancy, we discovered that the loss of relaxation of ACh in the case of the strip was the result of unintentional rubbing of its intimal surface against foreign surfaces during its preparation. If care was taken to avoid rubbing of the intimal surface during preparation, the tissue, whether ring, transverse strip or helical strip, always exhibited relaxation to ACh, and the possibility was considered that rubbing of the intimal surface had removed endothelial cells. We demonstrate here that relaxation of isolated preparations of rabbit thoracic aorta and other blood vessels by ACh requires the presence of endothelial cells, and that ACh, acting on muscarinic receptors of these cells, stimulates release of a substance(s) that causes relaxation of the vascular smooth muscle. We propose that this may be one of the principal mechanisms for ACh-induced vasodilation in vivo. Preliminary reports on some aspects of the work have been reported elsewhere.
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            Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension

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              Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability.

              Nitric oxide (NO) plays a critical role in vascular endothelial growth factor (VEGF)-induced angiogenesis and vascular hyperpermeability. However, the relative contribution of different NO synthase (NOS) isoforms to these processes is not known. Here, we evaluated the relative contributions of endothelial and inducible NOS (eNOS and iNOS, respectively) to angiogenesis and permeability of VEGF-induced angiogenic vessels. The contribution of eNOS was assessed by using an eNOS-deficient mouse, and iNOS contribution was assessed by using a selective inhibitor [l-N(6)-(1-iminoethyl) lysine, l-NIL] and an iNOS-deficient mouse. Angiogenesis was induced by VEGF in type I collagen gels placed in the mouse cranial window. Angiogenesis, vessel diameter, blood flow rate, and vascular permeability were proportional to NO levels measured with microelectrodes: Wild-type (WT) > or = WT with l-NIL or iNOS(-/-) > eNOS(-/-) > or = eNOS(-/-) with l-NIL. The role of NOS in VEGF-induced acute vascular permeability increase in quiescent vessels also was determined by using eNOS- and iNOS-deficient mice. VEGF superfusion significantly increased permeability in both WT and iNOS(-/-) mice but not in eNOS(-/-) mice. These findings suggest that eNOS plays a predominant role in VEGF-induced angiogenesis and vascular permeability. Thus, selective modulation of eNOS activity is a promising strategy for altering angiogenesis and vascular permeability in vivo.
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                Author and article information

                Journal
                Mol Med Rep
                Mol Med Rep
                Molecular Medicine Reports
                D.A. Spandidos
                1791-2997
                1791-3004
                March 2015
                18 November 2014
                18 November 2014
                : 11
                : 3
                : 1555-1565
                Affiliations
                [1 ]Laboratory of Organic Synthesis, Institute of Chemistry of Natural Resources, University of Talca, Talca 3460000, Chile
                [2 ]Department of Biomedical Basic Sciences, School of Health Sciences, University of Talca, Talca 3460000, Chile
                [3 ]Interdisciplinary Excellence Research Program on Healthy Aging (Interdisciplinary Excellence Research Program on Healthy Aging), University of Talca, Talca 3460000, Chile
                Author notes
                Correspondence to: Dr Daniel R. Gonzalez, Department of Biomedical Basic Sciences, School of Health Sciences, University of Talca, Avenida Lircay s/n, Talca 3460000, Chile, E-mail: dagonzalez@ 123456utalca.cl
                Article
                mmr-11-03-1555
                10.3892/mmr.2014.2968
                4270315
                25405382
                5af3faad-7a42-4a68-9ce7-8a54d5a949bb
                Copyright © 2015, Spandidos Publications

                This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

                History
                : 06 August 2013
                : 05 August 2014
                Categories
                Articles

                s-nitrosylation,cardiovascular,nitric oxide synthase,heart

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