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      Mechanisms of Vascular Smooth Muscle Contraction and the Basis for Pharmacologic Treatment of Smooth Muscle Disorders

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          Abstract

          The smooth muscle cell directly drives the contraction of the vascular wall and hence regulates the size of the blood vessel lumen. We review here the current understanding of the molecular mechanisms by which agonists, therapeutics, and diseases regulate contractility of the vascular smooth muscle cell and we place this within the context of whole body function. We also discuss the implications for personalized medicine and highlight specific potential target molecules that may provide opportunities for the future development of new therapeutics to regulate vascular function.

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

          Robert F. Furchgott, John Zawadzki (1980)
          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.
          Article 0 comments Cited 753 times – based on 0 reviews     Review now
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            Mammalian sirtuins: biological insights and disease relevance.

            Marcia Haigis, David A Sinclair (2010)
            Aging is accompanied by a decline in the healthy function of multiple organ systems, leading to increased incidence and mortality from diseases such as type II diabetes mellitus, neurodegenerative diseases, cancer, and cardiovascular disease. Historically, researchers have focused on investigating individual pathways in isolated organs as a strategy to identify the root cause of a disease, with hopes of designing better drugs. Studies of aging in yeast led to the discovery of a family of conserved enzymes known as the sirtuins, which affect multiple pathways that increase the life span and the overall health of organisms. Since the discovery of the first known mammalian sirtuin, SIRT1, 10 years ago, there have been major advances in our understanding of the enzymology of sirtuins, their regulation, and their ability to broadly improve mammalian physiology and health span. This review summarizes and discusses the advances of the past decade and the challenges that will confront the field in the coming years.
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              Sirtuins in mammals: insights into their biological function.

              Shaday Michan, David. Sinclair (2007)
              Sirtuins are a conserved family of proteins found in all domains of life. The first known sirtuin, Sir2 (silent information regulator 2) of Saccharomyces cerevisiae, from which the family derives its name, regulates ribosomal DNA recombination, gene silencing, DNA repair, chromosomal stability and longevity. Sir2 homologues also modulate lifespan in worms and flies, and may underlie the beneficial effects of caloric restriction, the only regimen that slows aging and extends lifespan of most classes of organism, including mammals. Sirtuins have gained considerable attention for their impact on mammalian physiology, since they may provide novel targets for treating diseases associated with aging and perhaps extend human lifespan. In this review we describe our current understanding of the biological function of the seven mammalian sirtuins, SIRT1-7, and we will also discuss their potential as mediators of caloric restriction and as pharmacological targets to delay and treat human age-related diseases.
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                Author and article information

                Contributors
                Stephanie W. Watts: Role: ASSOCIATE EDITOR
                Journal
                Journal ID (nlm-ta): Pharmacol Rev
                Journal ID (iso-abbrev): Pharmacol. Rev
                Journal ID (hwp): pharmrev
                Journal ID (pmc): Pharmacol Rev
                Journal ID (publisher-id): PharmRev
                Title: Pharmacological Reviews
                Publisher: The American Society for Pharmacology and Experimental Therapeutics (Bethesda, MD )
                ISSN (Print): 0031-6997
                ISSN (Electronic): 1521-0081
                Publication date (Print): April 2016
                Publication date (Electronic): April 2016
                Publication date PMC-release: April 2016
                Volume: 68
                Issue: 2
                Pages: 476-532
                Affiliations
                [1]Department of Health Sciences, Boston University, Boston, Massachusetts (C.J.N., Y.Z.G., M.A., K.G.M.); Department of Medicine, Mayo Clinic, Rochester, Minnesota (F.V.B.); and Paracelsus Medical University Salzburg, Salzburg, Austria (C.V.D.)
                Author notes
                Address correspondence to: Kathleen G. Morgan, Department of Health Sciences, Boston University, Boston MA 02215. E-mail: kmorgan@ 123456bu.edu
                Article
                Publisher ID: PHARMREV_010652
                DOI: 10.1124/pr.115.010652
                PMC ID: 4819215
                PubMed ID: 27037223
                SO-VID: 79cde5ec-2d2e-4b24-808e-2e23e3bb3886
                Copyright © Copyright © 2016 The Author(s)
                License:

                This is an open access article distributed under the CC-BY Attribution 4.0 International license.

                History
                Page count
                Figures: 10, Tables: 1, Equations: 1, References: 693, Pages: 57
                Categories
                Subject: Review Articles
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