Vascular Smooth Muscle: Structure And Function In Health And Disease

Structure and Function in Health and Disease

Chi-Ming Hai

• Publisher: WSPC
• Year: 2016
• ISBN:
  9789813144071
• Topic: Biological Sciences
• Subtopic: Cell Biology
• Index: Biological Sciences

This book presents key concepts in the structure and function of vascular smooth muscle cells in health and disease. Supplemental reading may be drawn from the extensive references listed at the end of each chapter. Vascular smooth muscle cell is the majo

Chapter 1

Introduction

Chi-Ming Hai

Department of Molecular Pharmacology,
Physiology and Biotechnology,
Brown University Providence, Rhode Island 02912, USA
[email protected]

This book covers core concepts in the structure and function of vascular smooth muscle cells in health and disease. Supplemental reading may be drawn from the extensive number of references listed at the end of each chapter. Vascular smooth muscle cell is the major cell type in blood vessels. Dysfunction of vascular smooth muscle cells is an important cause of vascular diseases — for example, atherosclerosis, hypertension, and circulatory shock. Vascular smooth muscle cells are phenotypically plastic, capable of switching between two major phenotypes — contractile/differentiated phenotype and invasive/ proliferative phenotype — in response to environmental clues. This book is organized in three sections. Section I (chapters 2 to 4) addresses the structure and function of the contractile/differentiated phenotype of vascular smooth muscle cell. Section II (chapters 5 and 6) addresses the developmental basis of vascular smooth muscle cell phenotype and structure and function of podosomes (invasive organelles) in the invasive/proliferative phenotype of vascular smooth muscle cell. Section III (chapters 7 to 9) addresses the role of vascular smooth muscle cell dysfunction in three vascular diseases — atherosclerosis, hypertension, and circulatory shock.

1.Section I (Chapters 2 to 4)

Structure and Function of Contractile/Differentiated Phenotype of Vascular Smooth Muscle Cell. In Chapter 2, Dr. Thomas Eddinger discusses the structure of blood vessel and contractile phenotype of vascular smooth muscle cell at multiple layers of organization — blood vessel, smooth muscle cell, contractile filaments, cytoskeleton, membrane associated proteins, nucleoskeleton, regulatory proteins, organelles, and extracellular matrix. Contractile filaments include thin and thick filaments, and the associated proteins and isoforms — for example, tropomyosin, myosin heavy chain and light chain isoforms. Cytoskeleton includes actin, intermediate filament (vimentin and desmin), microtubules, and their associated proteins — for example, plectin, filamin, cadherins, and catenins. Regulatory proteins include tropomyosin, caldesmon, calponin, myosin light chain kinase and myosin light chain phosphatase. Organelles include sarcoplasmic reticulum and nucleus. Dr. Eddinger concludes his chapter by posing some unanswered questions on vascular smooth muscle structure and function.

In Chapter 3, Dr. Paul Ratz discusses receptor signaling mechanisms for vascular smooth muscle contraction and relaxation. Dr. Ratz first provides an overview of the classification of smooth muscle cells into fast, phasic and slow, tonic subtypes, and their differential muscle mechanics, intracellular [Ca²⁺] regulation, and cell signaling. He then discusses extracellular stimuli (neurotransmitters, hormones and local mediators) that regulate smooth muscle contraction and the canonical control of smooth muscle contraction through regulation of myosin light chain phosphorylation. In particular, he discusses the phosphorylation of myosin light chain by Ca²⁺, calmodulin-dependent myosin light chain kinase and the modulation of Ca²⁺-sensitivity of myosin light chain phosphorylation by myosin light chain phosphatase. He further details the roles of small GTPases (rac and rhoA), rho-activated kinase (ROCK), calmodulin-dependent kinase II (CaMKII), mitogen activated kinase (Erk), and PKC in the regulation of myosin light chain phosphorylation and contraction. He concludes the chapter by discussing the function of multiple phosphorylation sites of myosin light chain and non-canonical myosin light chain kinases in the regulation of smooth muscle contraction.

In Chapter 4, Drs. William Cole and Michael Walsh discuss the function of actin filament dynamics during vascular smooth muscle contraction. Drs. Cole and Walsh first discuss the contribution of vascular smooth muscle contraction to the control of blood flow and the concepts of Ca²⁺-induced vasoconstriction and Ca²⁺-sensitization of vasoconstriction. Specific Ca²⁺-sensitization mechanisms include RhoA, Rho-associated coiled-coil kinase (ROCK), myosin targeting subunit of myosin light chain phosphatase (MYPT1) and a 17-kDa cytosolic protein (CPI-17). They then discuss recent findings on the function of actin polymerization in Ca²⁺ sensitization of vasoconstriction and signal transduction pathways mediating stimulus-evoked actin polymerization. Specific signaling mechanisms include Src family kinases (SFK), focal adhesion kinase (FAK), Pyk2, p130CAS and PKC. Specific cytoskeletal proteins include α-actinin, vinculin, talin and paxillin. They conclude the chapter by discussing the potential pathophysiological significance of actin polymerization in vascular dysfunction such as hypertension and cerebral vasospasm following subarachnoid hemorrhage.

2.Section II (Chapters 5 and 6)

Developmental Basis of Vascular Smooth Muscle Cell Phenotype, and Structure and Function of Podosomes (Invasive Organelles) in the Invasive/Proliferative Phenotype of Vascular Smooth Muscle Cell. In Chapter 5, Drs. Christine Cheung and B C Narmada discuss the developmental basis of vascular smooth muscle cell phenotype by first emphasizing the diverse embryonic lineages of vascular smooth muscle cells from different blood vessels and even different regions within the same blood vessel. This observation suggests the hypothesis that lineage differences among vascular smooth muscle cells at different regions of the vasculature can explain region-specific vascular disease development. They then discuss the following specific topics: (a) triggers of phenotypic modulation, (b) influence of embryonic origins on regional differences of vascular smooth muscle cells, and (c) molecular basis of lineage-specific differences in vascular smooth muscle subtypes — embryonic smooth muscle cells, postnatal smooth muscle cells, and human pluripotent stem cell-derived smooth muscle cells. They conclude the chapter by suggesting that stem cell-derived vascular smooth muscle cells hold great potential for tissue engineering applications and regenerative medicine, high throughput drug screening and pharmacokinetic testing, and targeted therapeutic interventions for restoration of vascular health.

In Chapter 6, Dr. Alan Mak discusses the structure and function of podosomes — invasive organelles that enable vascular smooth muscle cells to degrade and invade the extracellular matrix. He begins the chapter by emphasizing the remarkable plasticity of vascular smooth muscle cells in switching between contractile and synthetic phenotypes and highlighting the importance of acquiring the migratory and invasive phenotype for vascular smooth muscle cells to degrade the extracellular matrix and cross the basement membrane in the process of reaching the intima. He then discusses the following specific topics: (a) podosomes in non-smooth muscle and vascular smooth muscle cells, (b) regulation of podosome formation in vascular smooth muscle cells by the PKC and cSrc-dependent pro-podosome and p53-dependent anti-podosome signaling pathways, and (c) regulators of podosome-mediated extracellular matrix adhesion and degradation. He concludes the chapter by suggesting future directions for research on the structure and function of podosomes in vascular smooth muscle cells in relation to the specific roles of vascular smooth muscle cells in the pathogenesis and progression of atherosclerotic plaques.

3.Section III (Chapters 7 to 9)

Role of Vascular Smooth Muscle Cells in Vascular Diseases — Atherosclerosis, Hypertension, and Circulatory Shock. In Chapter 7, I discuss the role of vascular smooth muscle cell proliferation and invasion in atherosclerosis. I first emphasize the important role of vascular smooth muscle cells in atherosclerosis by highlighting the observation that vascular smooth muscle-rich regions of coronary arteries are more prone to the development of atherosclerosis, whereas vascular smooth muscle-sparse regions are more resistant to the development of atherosclerosis. I then discuss the multiple stages of atherosclerosis progression and the specific roles of vascular smooth muscle cells in promoting atherosclerosis development and plaque stabilization at each stage of atherosclerosis. I conclude the chapter by suggesting that there is emerging consensus that vascular smooth muscle cells are a central player in all stages of atherosclerosis and re-emphasizing the two opposing roles of vascular smooth muscle cells in atherosclerosis — detrimental role in promoting plaque development during early stage of atherosclerosis but beneficial role in promoting plaque stabilization during later stage of atherosclerosis.

In Chapter 8, Drs. Christopher Nicholson and Kathleen Morgan discuss the role of non-coding RNA in the control of vascular contractility and disease. They begin the chapter by introducing the general structure and function of microRNAs and long non-coding RNAs. In the first section, they discuss the following topics on the molecular biology of non-coding RNA: (a) microRNA biogenesis, (b) RNA-induced silencing complex, (c) microRNA target recognition, and (d) control of microRNA expression. In the second section, they discuss the following topics on the function of microRNA in vascular smooth muscle cells: (a) microRNA-dependent contractile differentiation of vascular smooth muscle cells, (b) role of microRNAs in vascular smooth muscle pathways of contraction, and (c) microRNA dysfunction in hypertension, hyperlipidemia and diabetes, atherosclerosis, and pulmonary vascular disease. They conclude the chapter by discussing the function of microRNA in extracellular communication in vascular cells, function of long non-coding RNAs in vascular smooth muscle, and modulating microRNAs in the treatment of vascular disease.

In Chapter 9, Drs. Liangming Liu, Tao Li, and Chengyang Duan discuss the potential of vascular smooth muscle cells as therapeutic target for the treatment of circulatory shock. They first discuss the clinical significance of circulatory shock, function of vascular smooth muscle cells in vasodilation and vasoconstriction, and the contribution of reduced vascular reactivity to circulatory shock. They then discuss the general concepts of inducing factors of vascular smooth muscle cell damage and features of vascular dysfunction during circulatory shock. Third, they discuss the following topics on hemorrhagic shock: (a) biphasic change of vascular reactivity, (b) vasculature, gender, and age-differences of vascular reactivity, (c) metabolic diseases suffering from hemorrhagic shock, and (d) similarities and differences between endotoxin/septic shock and hemorrhagic shock. Fourth, they discuss the following topics on shock-induced vascular smooth muscle cell damage and vascular hypo-reactivity: (a) receptor desensitization, (b) membrane hyperpolarization, and (c) calcium desensitization. They conclude the chapter by discussing treatments of circulatory shock based on mechanisms of vascular smooth muscle cell damage and vascular hypo-reactivity.

Chapter 2

Structure of Differentiated/Contractile Vascular Smooth Muscle Cells

Thomas J. Eddinger

Biological Sciences Department,
Marquette University, Milwaukee, WI 53233, USA
[email protected]

The study of structure and its relationship to function has been, and will continue to be, significant for advancing our understanding of organismal, systems, organ, tissue, cell and sub-cellular physiology. While novel organismal anatomical observations have become rather rare at the gross level, this is far from true at the molecular level where new data on molecular structures continue to expedite advancement of our understanding of their function. William Harvey (1578–1657) is credited with significant advances in our understanding of cardiovascular function through his “exercises” where he applied quantitative reasoning with cardiac and vascular anatomy to derive physiological significance. In so doing he resolved major questions that had no answers, or perhaps worse, had answers but that were incorrect. He is credited with numerous cardiovascular advancements including both ventricles beating simultaneously (not asynchronously), systole forcing blood through the vascular bed (not by vascular contraction), one way circular flow (veins do not carry blood to the tissue), blood recirculation (it is not made in the liver and consumed by the tissue), and valves preventing backflow of blood in the veins (not necessary when the blood is traveling to the tissues via the veins) to list a few.¹ Significant technological advances since Harvey, especially in the past century, have allowed cellular and subcellular anatomy to continue to add to our understanding of function at these levels. Not least of these advances are a host of new and/or refined crystallization methods and microscopic techniques that allow us to “see” things that were never possible before. Thus while much of what we know about the vascular system ...

Table of contents

• Cover Page
• Title
• Copyright
• Dedication
• Contents
• 1. Introduction
• 2. Structure of Differentiated/Contractile Vascular Smooth Muscle Cells
• 3. Vascular Structure and Function
• 4. Actin Filament Dynamics During Vascular Smooth Muscle Contraction
• 5. Developmental Basis of Vascular Smooth Muscle Cell Phenotypes
• 6. Regulation of Podosomes in Vascular Smooth Muscle Cell Invasion of the Extracellular Matrix
• 7. Vascular Smooth Muscle Cell Proliferation and Invasion in Atherosclerosis
• 8. The Role of Non-coding RNA in the Control of Vascular Contractility and Disease
• 9. Vascular Smooth Muscle Cells as Therapeutic Target for the Treatment of Circulatory Shock