Mechanisms of the inward remodeling process in resistance vessels: is the actin cytoskeleton involved?

Abstract

The resistance arteries and arterioles are the vascular components of the circulatory system where the greatest drop in blood pressure takes place. Consequently, these vessels play a preponderant role in the regulation of blood flow and the modulation of blood pressure. For this reason, the inward remodeling process of the resistance vasculature, as it occurs in hypertension, has profound consequences on the incidence of life-threatening cardiovascular events. In this manuscript, we review some of the most prominent characteristics of inwardly remodeled resistance arteries including their changes in vascular passive diameter, wall thickness, and elastic properties. Then, we explore the known contribution of the different components of the vascular wall to the characteristics of inwardly remodeled vessels, and pay particular attention to the role the vascular smooth muscle actin cytoskeleton may play on the initial stages of the remodeling process. We end by proposing potential ways by which many of the factors and mechanisms known to participate in the inward remodeling process may be associated with cytoskeletal modifications and participate in reducing the passive diameter of resistance vessels.

Keywords: Rac; Rho; actin polymerization; elasticity; hypertension; matrix metalloproteinases; stiffness; strain; stress; transglutaminase.

Figure 1

Structural and mechanical characteristics of an inwardly remodeled resistance artery. A) Diagrammatic representation describing the main changes in inner and outer diameters and cross-sectional area observed in the arteriolar wall of arterioles with inward eutrophic remodeling. B) Diagrammatic representation of the intraluminal pressure to passive diameter relationships of a control and an inwardly remodeled arteriole C) Diagrammatic representation of the strain-stress relationships of the control and inwardly remodeled arterioles presented in panel 1B. D) Diagrammatic representation of the moduli of elasticity obtained from the control and inwardly remodeled arterioles presented in panel 1B.

Figure 2

Vascular smooth muscle intracellular mechanisms for vasoconstriction. Vascular smooth muscle cells (VSMC) located in the medial layer of resistance arteries reduce their length to cause vasoconstriction. This process involves mechanisms associated with the phosphorylation of myosin-light chain (MLC20), and the formation and disruption of actin cytoskeletal structures. The activation of Rho Kinase (ROCK) is an event that potentially links MLC-20 phosphorylation and actin polymerization mechanisms. ROCK inactivates myosin-light chain phosphatase (MLCP) to maintain MLC-20 phosphorylation and constriction. It also deactivates cofilin and its severing action on actin filaments via the activation of LIM kinase (LIMK). Consequently integrin linked actin fibers are able to polymerize and strengthen the cytoskeleton through processes that involve the phosphorylation of paxillin and a number of other focal adhesion proteins with and without kinase activity. GPCRs, G-protein coupled receptors; IEL, internal elastic lamina; PLC, phospholipase C; IP₃, inositol triphosphate; DAG, diacyl glycerol; RhoGEF, Rho guanine exchange factor; MLCK, myosin-light chain kinase; FAK, focal adhesion kinase. Figure adapted from references 28, 47.