Vascular Smooth Muscle Function Contraction of vascular smooth muscle cells reduces vessel diameter, increases vascular tone, and regulates blood flow by shortening the cells This contractile phenotype is modified by the expression of genes that encode contractile proteins, ion channels, and other molecules involved in contraction.66,67 Smooth muscle contraction is regulated in vivo primarily by pharmacomechanical and electromechanical activation of the contractile proteins myosin and actin.68 Pharmacomechanical coupling refers to the activation of contraction by ligands of cell surface receptors without an obligatory change in the plasma membrane potential The phosphoinositide signaling cascade is the common secondmessenger system utilized by the surface receptors Electromechanical coupling, on the other hand, involves alterations in the plasma membrane potential Receptor activation may induce an activation of receptor-operated or voltagedependent channels and lead to the passive influx of calcium down its concentration gradient The balance between force generation and release is responsible for the maintenance of vascular tone.69 The vascular tone is influenced by local metabolic substances, humoral factors, and activity of the autonomic nervous system A detailed discussion of the molecular mechanisms of smooth muscle contraction is beyond the scope of this chapter; however, interested readers are referred to recent published reviews.70,71 Apart from a contractile phenotype, vascular smooth muscle cells exhibit other phenotypes This phenotypic diversity plays an important role in the normal development, repair of vascular injury and in vascular disease process.67,72 After vascular injury, phenotypic modulation of vascular smooth muscle cells causes the upregulation of genes required for their proliferation and the production of extracellular matrix and suppression of genes that characterize the contractile phenotype On the other hand, inappropriate pathologic differentiation into other mesenchymal lineages—such as osteoblastic, chondrocytic, and adipocytic ones—may contribute to vessel calcification, altered matrix production, and abnormal lipid accumulation, respectively.73–77 Studies have focused on the understanding of mechanisms that underlie the physiologic control and pathologic alterations of phenotypic switching of vascular smooth muscle cells.67,72,78 Control of Circulation The regulation of circulation aims to adjust the blood flow precisely to meet the needs of tissue and to maintain an adequate driving pressure to perfuse the various body tissues Such control is achieved through local mechanisms, humoral factors, and neural regulation Local Control Autoregulation refers to the ability to maintain a relatively constant blood flow in response to acute changes in perfusion pressure The coronary, renal, and cerebral circulations exhibit autoregulation Two theories have been proposed for this autoregulatory mechanism The metabolic theory79 suggests that elevated perfusion pressure increases blood flow, and hence oxygen delivery and removal of vasodilators, thereby leading to vasoconstriction and reduction of blood flow and vice versa The myogenic theory80 proposes that stretching of vascular smooth muscle cells by the elevated perfusion pressure increases their tension, which in turn causes vasoconstriction to reduce blood flow Conversely, less stretching at lower perfusion pressure causes smooth muscle relaxation and increases blood flow However, the exact mechanisms that link intraluminal pressure generation to myogenic constriction remain uncertain.81 Metabolic mechanisms also contribute to the control of local blood flow Two theories have likewise been proposed The vasodilator theory proposes that vasodilator substances are formed and released from tissues when metabolic rate increases or oxygen and other nutrient supplies decrease Possible vasodilator substances include adenosine, carbon dioxide, potassium ion, hydrogen ion, lactic acid, histamine, and adenosine phosphate The nutrient theory suggests that blood vessels dilate naturally when oxygen or other nutrients are deficient Hence increased utilization of oxygen and nutrients increases metabolism to cause local vasodilation, a phenomenon referred to as active hyperemia Reactive hyperemia is another phenomenon related to the local metabolic flowcontrol mechanism In reactive hyperemia, a brief interruption of arterial blood flow results in a transient increase in blood flow that exceeds the baseline, after which the flow returns to baseline level Both the deprivation of tissue oxygen and accumulation of vasodilating substances probably account for this phenomenon The duration of reactive hyperemia depends on the duration of flow cessation and usually lasts long enough to repay the oxygen debt Autoregulation and metabolic mechanisms control blood flow by dilation of the microvasculature The consequent increase in blood flow dilates the larger arteries upstream via the mechanism of flow-mediated dilation The pivotal role of endothelial cells in the transduction of shear stress secondary to increased blood flow and the release of the vasodilators has been alluded to earlier Flowmediated dilation occurs predominantly as a result of local endothelial release of nitric oxide.82 The mechanisms of shear stress detection and subsequent signal transduction are unclear but probably involve opening of calcium-activated potassium channels83–85 that hyperpolarizes endothelial cells and calcium activation of endothelial nitric oxide synthase.82,86 Flow-mediated dilation increases flow with a negligible increase in pressure gradient, thus optimizing energy losses within the circulation.87 The phenomenon of flow-mediated dilation as induced by reactive hyperemia has commonly been used as an assessment of endothelial function in vivo All of the aforementioned mechanisms represent relatively acute responses to regulate local blood flow Long-term local mechanisms involve changes in tissue vascularity, the release of angiogenic factors, and the development of collateral circulations Humoral Control Humoral control refers to regulation by hormones or locally produced vasoactive substances that act in an autocrine or a paracrine fashion These humoral substances act either directly via receptors on vascular smooth muscle cells or indirectly by stimulating the endothelium to release vasoactive substances Circulating catecholamines, noradrenaline and adrenaline, are secreted by the adrenal medulla, which is innervated by preganglionic sympathetic fibers Sympathetic activation stimulates the release of catecholamines, about 80% being noradrenaline, from the adrenal gland The adrenal gland and the noradrenergic sympathetic vasoconstrictor fibers provide dual control of the circulation by catecholamines The adrenergic receptors in the blood vessels are α1, α2, and β2 receptors Noradrenaline causes vasoconstriction by acting on αreceptors, while adrenaline causes vasodilation at physiologic concentrations through its β-agonist effect At higher concentrations, adrenaline also causes vasoconstriction by activating α-receptors The regulatory role of the renin-angiotensin system in the circulation is well known The final effector of the system, angiotensin II, mediates its effects classically in an endocrine fashion In response to decreased renal perfusion pressure or extracellular fluid volume, renin is secreted from the juxtaglomerular apparatus of the kidney and cleaves angiotensinogen, released from the liver, to