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.

Introduction Mechanisms that regulate LC20 phosphorylation Mechanisms that regulate the access of myosin to actin Mechanisms that regulate cytoskeletal remodelling Conclusions Smooth muscle contractile activity is a major regulator of function of the vascular system, respiratory system, gastrointestinal system and the genitourinary systems. Malfunction of contractility in these systems leads to a host of clinical disorders, and yet, we still have major gaps in our understanding of the molecular mechanisms by which contractility of the differentiated smooth muscle cell is regulated. This review will summarize recent advances in the molecular understanding of the regulation of smooth muscle myosin activity via phosphorylation/dephosphorylation of myosin, the regulation of the accessibility of actin to myosin via the actin‐binding proteins calponin and caldesmon, and the remodelling of the actin cytoskeleton. Understanding of the molecular ‘players’ should identify target molecules that could point the way to novel drug discovery programs for the treatment of smooth muscle disorders such as cardiovascular disease, asthma, functional bowel disease and pre‐term labour.

This minireview will cover current concepts on the identity and mechanistic function of smooth muscle actin binding proteins that may regulate actin-myosin interactions. The potential roles of tropomyosin, caldesmon, calponin, and SM22 will be discussed. The review, for purposes of brevity, will be nonexhaustive but will give an overview of available information on the in vitro biochemistry and potential in vivo function of these proteins. Preterm labor is discussed as a possible example of where thin filament regulation may be relevant. Considerable controversy surrounds the putative physiological significance of these proteins, and emphasis will be placed on the need for more experimental work to determine the degree to which tissue- and species-specific effects have clouded the interpretation of functional data.

Dynamic remodeling of the actin cytoskeleton plays an essential role in the migration and proliferation of vascular smooth muscle cells. It has been suggested that actin remodeling may also play an important functional role in nonmigrating, nonproliferating differentiated vascular smooth muscle (dVSM). In the present study, we show that contractile agonists increase the net polymerization of actin in dVSM, as measured by the differential ultracentrifugation of vascular smooth muscle tissue and the costaining of single freshly dissociated cells with fluorescent probes specific for globular and filamentous actin. Furthermore, induced alterations of the actin polymerization state, as well as actin decoy peptides, inhibit contractility in a stimulus-dependent manner. Latrunculin pretreatment or actin decoy peptides significantly inhibit contractility induced by a phorbol ester or an α-agonist, but these procedures have no effect on contractions induced by KCl. Aorta dVSM expresses α-smooth muscle actin, β-actin, nonmuscle γ-actin, and smooth muscle γ-actin. The incorporation of isoform-specific cell-permeant synthetic actin decoy peptides, as well as isoform-specific probing of cell fractions and two-dimensional gels, demonstrates that actin remodeling during α-agonist contractions involves the remodeling of primarily γ-actin and, to a lesser extent, β-actin. Taken together, these results show that net isoform- and agonist-dependent increases in actin polymerization regulate vascular contractility.

Abstract  This review focuses on the vascular smooth muscle cells present in the medial layer of the blood vessels wall in the fully differentiated state (dVSMCs). The dVSMC contractile phenotype enables these cells to respond in a highly regulated manner to changes in extracellular stimuli. Through modulation of vascular contractile force and vascular compliance dVSMCs regulate blood pressure and blood flow. The cellular and molecular mechanisms by which vascular smooth muscle contractile functions are regulated are not completely elucidated. Recent studies have documented a critical role for actin polymerization and cytoskeletal dynamics in the regulation of contractile function. Here we will review the current understanding of actin cytoskeletal dynamics and focal adhesion function in dVSMCs in order to better understand actin cytoskeleton connections to the extracellular matrix and the effects of cytoskeletal remodelling on vascular contractility and vascular stiffness in health and disease.