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      ROK and Arteriolar Myogenic Tone Generation: Molecular Evidence in Health and Disease

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          Abstract

          The myogenic response is an inherent property of resistance arteries that warrants a relatively constant blood flow in response to changes in perfusion pressure and protect delicate organs from vascular insufficiencies and excessive blood flow. This fundamental phenomenon has been extensively studied aiming to elucidate the underlying mechanisms triggering smooth muscle contraction in response to intraluminal pressure elevation, particularly, Rho-associated kinase (ROK)-mediated Ca 2+-independent mechanisms. The size of the resistance arteries limits the capacity to examine changes in protein phosphorylation/expression levels associated with ROK signaling. A highly sensitive biochemical detection approach was beneficial in examining the role of ROK in different force generation mechanisms along the course of myogenic constriction. In this mini review, we summarize recent results showing direct evidence for the contribution of ROK in development of myogenic response at the level of mechanotransduction, myosin light chain phosphatase inhibition and dynamic actin cytoskeleton reorganization. We will also present evidence that alterations in ROK signaling could underlie the progressive loss in myogenic response in a rat model of type 2 diabetes.

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          Most cited references83

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          Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase.

          Ca2+ sensitivity of smooth muscle and nonmuscle myosin II reflects the ratio of activities of myosin light-chain kinase (MLCK) to myosin light-chain phosphatase (MLCP) and is a major, regulated determinant of numerous cellular processes. We conclude that the majority of phenotypes attributed to the monomeric G protein RhoA and mediated by its effector, Rho-kinase (ROK), reflect Ca2+ sensitization: inhibition of myosin II dephosphorylation in the presence of basal (Ca2+ dependent or independent) or increased MLCK activity. We outline the pathway from receptors through trimeric G proteins (Galphaq, Galpha12, Galpha13) to activation, by guanine nucleotide exchange factors (GEFs), from GDP. RhoA. GDI to GTP. RhoA and hence to ROK through a mechanism involving association of GEF, RhoA, and ROK in multimolecular complexes at the lipid cell membrane. Specific domains of GEFs interact with trimeric G proteins, and some GEFs are activated by Tyr kinases whose inhibition can inhibit Rho signaling. Inhibition of MLCP, directly by ROK or by phosphorylation of the phosphatase inhibitor CPI-17, increases phosphorylation of the myosin II regulatory light chain and thus the activity of smooth muscle and nonmuscle actomyosin ATPase and motility. We summarize relevant effects of p21-activated kinase, LIM-kinase, and focal adhesion kinase. Mechanisms of Ca2+ desensitization are outlined with emphasis on the antagonism between cGMP-activated kinase and the RhoA/ROK pathway. We suggest that the RhoA/ROK pathway is constitutively active in a number of organs under physiological conditions; its aberrations play major roles in several disease states, particularly impacting on Ca2+ sensitization of smooth muscle in hypertension and possibly asthma and on cancer neoangiogenesis and cancer progression. It is a potentially important therapeutic target and a subject for translational research.
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            Genetic and cell biological analysis of integrin outside-in signaling.

            Integrins are cell surface transmembrane receptors that recognize and bind to extracellular matrix proteins and counter receptors. Binding of activated integrins to their ligands induces a vast number of structural and signaling changes within the cell. Large, multimolecular complexes assemble onto the cytoplasmic tails of activated integrins to engage and organize the cytoskeleton, and activate signaling pathways that ultimately lead to changes in gene expression. Additionally, integrin-mediated signaling intersects with growth factor-mediated signaling through various levels of cross-talk. This review discusses recent work that has tremendously broadened our understanding of the complexity of integrin-mediated signaling.
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              On the local reactions of the arterial wall to changes of internal pressure.

              M. Bayliss (1902)
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                23 February 2017
                2017
                : 8
                : 87
                Affiliations
                [1] 1Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut Beirut, Lebanon
                [2] 2Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University Alexandria, Egypt
                [3] 3Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa Ottawa, ON, Canada
                Author notes

                Edited by: Issy Laher, University of British Columbia, Canada

                Reviewed by: Marilyn J. Cipolla, University of Vermont, USA; Joseph Brayden, University of Vermont, USA; Ulf Simonsen, Aarhus University, Denmark; Christian Aalkjaer, Aarhus University, Denmark

                *Correspondence: Ahmed F. El-Yazbi, ae88@ 123456aub.edu.lb

                This article was submitted to Cardiovascular and Smooth Muscle Pharmacology, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2017.00087
                5322222
                1f401930-1f09-4eda-8447-3be25c9474bc
                Copyright © 2017 El-Yazbi and Abd-Elrahman.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 28 November 2016
                : 10 February 2017
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 94, Pages: 10, Words: 0
                Categories
                Pharmacology
                Mini Review

                Pharmacology & Pharmaceutical medicine
                rho-associated kinase,myogenic response,calcium sensitization,actin polymerization,integrins,type 2 diabetes

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