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

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Mechanisms of Vascular Smooth Muscle Contraction and the Basis for Pharmacologic Treatment of Smooth Muscle Disorders 1521-0081/68/2/476–532$25.00 http://dx.doi.org/10.1124/pr.115.010652 PHARMACOLOGICAL REVIEWS Pharmacol Rev 68:476–532, April 2016 Copyright © 2016 The Author(s) This is an open access article distributed under the CC-BY Attribution 4.0 International license. ASSOCIATE EDITOR: STEPHANIE W. WATTS Mechanisms of Vascular Smooth Muscle Contraction and the Basis for Pharmacologic Treatment of Smooth Muscle Disorders F.V. Brozovich, C.J. Nicholson, C.V. Degen, Yuan Z. Gao, M. Aggarwal, and K.G. Morgan 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.) Abstract ...................................................................................478 I. Introduction . ..............................................................................478 A. Scope and Limitations..................................................................478 B. Overview of Regulation of Blood Pressure/Vascular Tone. ...............................478 1. Guyton View of Regulation Blood Pressure, Kidney Role, Volume Regulation. .......478 2. Recent Direct Confirmation of Changes in Vascular Tone/Resistance Related to Changes in Systemic Vascular Resistance and Blood Pressure and Downloaded from the Importance of Vascular Smooth Muscle Contraction in both Normal Physiology and Pathophysiology—Hypertension......................................479 3. Racial Differences/Personalized Medicine. ..........................................479 II. Regulation of Ca2+ .........................................................................480 A. Ca2+ Determines Vascular Smooth Muscle Cell Contractility and Phenotype.............480 B. Compartmentalization of Ca2+ Signaling................................................480 by guest on October 1, 2021 1. Ca2+ Sparklets. ..................................................................480 2. Ca2+ Sparks.........................................................................482 a. Ca2+-dependent K+ channel-coupled sparks. .....................................482 b. Ca2+ gated Cl2 channel-coupled sparks. ..........................................483 3. Ca2+ Waves. ........................................................................483 4. Store-Operated Calcium Entry.......................................................483 C. Excitation-Transcription Coupling ......................................................484 D. Conclusion .............................................................................485 III. Vascular Smooth Muscle Signal Transduction ..............................................485 A. Signaling Pathways—Overview. ......................................................485 1. Major Pathways Leading to Changes in the Activity of Smooth Muscle Myosin. ......485 2. Pathways Leading to Changes in Actin Availability for Interaction with Myosin. .....487 3. Tyrosine Phosphorylation of Smooth Muscle Proteins. ...............................488 4. Calcium Sensitization of the Contractile Apparatus. ...............................488 B. Subcellular Spatial Organization of Signaling Pathways . ...............................488 1. Extracellular Regulated Kinase Scaffolds (Calponin, SmAV, Paxillin, Caveolin, FAK, IQGAP). ......................................................................489 2. Myosin Phosphatase Scaffolds. ......................................................490 C. Link to Hypertension ..................................................................490 D. Potential Novel Therapeutic Targets/Approaches/Critical Analysis of Pathway-Specific Inhibitors ............................................................490 1. Rho Kinase Inhibitors. ............................................................490 2. Endothelin Inhibitors. ............................................................490 3. Beta Adrenergic Receptor Mediated Inhibition. .....................................490 IV. Regulation of Smooth Muscle Myosin. ......................................................491 Address correspondence to: Kathleen G. Morgan, Department of Health Sciences, Boston University, Boston MA 02215. E-mail: [email protected] dx.doi.org/10.1124/pr.115.010652. 476 Mechanisms of Vascular Smooth Muscle Contraction 477 A. Overview of Regulation of the Smooth Muscle Actomyosin ATPase and 20kda light chain Phosphorylation/Smooth Muscle Activation . ..........................................491 B. Guanine Nucleotide Exchange Factor Signaling, Rac/Rho, and Analysis of Inhibitors . 492 C. Phenotypic Switching of Contractile Proteins during Development and Disease: Role of MYPT1 in Ca2+ Sensitization/Desensitization ...................................494 1. Smooth Muscle Myosin Heavy Chain. ...............................................494 2. ELC17..............................................................................494 3. MYPT1.............................................................................495 D. Implications for Disease and Treatment ................................................496 1. Pressurized Resistance Vessels, Implications of the Myogenic Response for Hypertension, and Critical Analysis of Inhibitors. ...............................496 2. Smooth Muscle Myosin versus Nonmuscle Myosin, Implications for Force Maintanance and Vascular Tone.....................................................497 3. Force Maintenance/Latch and the Regulation of Vascular Tone: The Tonic versus Phasic Contractile Phenotype and Contributions to Pathogenesis of Hypertension. 499 4. Autoregulation of Vascular Resistance/Flow-Mediated Vasodilatation and Nitric Oxide Signaling with Analysis of Current Inhibitors. .........................500 5. Mouse Models (Contractile Protein Knockout) and Implications for Hypertension. 500 E. Summary of Contractile Phenotype and Contributions to Pathogenesis of Hypertension with Analysis of Current Therapies for Hypertension . ...................502 F. Potential Novel Targets for Treatment of Essential Hypertension .......................502 V. Cytoskeletal Regulation . ..................................................................503 A. Intermediate Filaments, Dystrophin, Utrophin, and Microtubules .......................503 1. Dystrophin/Utrophin. ............................................................504 B. Actin ..................................................................................504 C. Focal Adhesion Remodeling ............................................................505 D. Link to Hypertension ..................................................................505 VI. Identifying Therapeutic Targets in Vascular Smooth Muscle through Biomechanical Studies 506 A. Arterial Stiffness as a Predictor of Negative Cardiovascular Events with Aging. .......506 1. Pulse Wave Velocity: The Clinical Standard .........................................506 2. The Importance of Ex Vivo Material Stiffness. .....................................506 B. Regulation of Arterial Stiffness by Vascular Smooth Muscle.............................507 1. Homeostatic Interactions between Cellular and Extracellular Components of the Arterial Wall. ..................................................................507 2. The Focal Adhesion and Actin Cytoskeleton as Regulatory Sites of Arterial Material Stiffness...........................................................507 VII. Regulation of Vascular Smooth Muscle Cell Function by Epigenetic Mechanisms ............508 A. DNA Methylation ......................................................................509 B. Histone Modifications ..................................................................509 1. Histone Acetylases and Histone Deacetylases. .....................................510 a. Histone deacetylases and link to hypertension. ...................................510 2. Sirtuins. ............................................................................510 ABBREVIATIONS: ACE, angiotensin converting enzyme; AM, rigor state; Ang II, angiotensin II; ARB, angiotensin receptor blocker; AT1, 2+ + 2+ 2 angiotensin type 1; BK, Ca -dependent K channels; BP, blood pressure; CaCC, Ca gated Cl channel; CaD, caldesmon; Cae, extracellular Ca2+; CaP, calponin; CCB, calcium channel blocker; CCt, C-terminal end of the LTCC; CI, central insert; CICR, Ca2+-induced Ca2+ release; CO, cardiac output; CRAC, calcium release activated calcium channel; CREB, cAMP response element-binding protein; CVD, cardiovascular disease; EC, endothelial cells; ECM, extracellular matrix; ELC17, 17-kDa essential myosin light chain; eNOS, endothelial nitric oxide synthase; ERK, extracellular regulated kinase; FA, focal adhesion; FAK, focal adhesion kinase; GAP, GTPase activating protein; GEF, guanine nucleotide exchange factor; GWAS, genome wide-association studies; HAT, histone acetylase; HDAC, histone deacetylase; HF, heart failure; IL, interleukin; KLF, Kruppel-like factor; KO, knockout; LTCC, L-type Ca2+ channels; LncRNA, long noncoding RNA; LZ, leucine zipper; MHC; muscle myosin heavy chain; miR, microRNAs; MLCK, myosin light chain kinase; MP, myosin phosphatase; NAD, nicotinamide adenine dinucleotide; NM, nonmuscle; NO, nitric oxide; PAH, pulmonary arterial hypertension; PASMC, pulmonary artery smooth muscle cells; PKGI, protein kinase G; pre-miRNA, preliminary miRNA; PWV, pulse wave velocity; RISC, RNA-induced silencing complex; RLC, regulatory myosin light
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