RACing up a New Regulatory Mechanism for Vascular Smooth Muscle Cell Migration

Abstract

Pathophysiological vascular smooth muscle cell (VSMC) migration is a critical component of atherosclerosis and contributes substantially to neointimal hyperplasia. Injury to the intimal layer of the vessel promotes the dedifferentiation of VSMCs in the tunica media from a quiescent contractile phenotype to a synthetic phenotype that proliferates and migrates, thus contributing to neointimal thickening. A better understanding of the signaling mechanisms that promote VSMC dedifferentiation, proliferation, and migration may lead to the identification of new pharmacological targets for atherosclerosis and other vascular diseases. See accompanying article on page 702 Several signal transduction pathways regulate actin polymerization and cell contractility, both integral to VSMC migration. The process of cell migration is complex but requires fundamental processes that depend on tight regulation of the GTPases Rac and Rho (Figure).1–3 Migration initiates when a cell is exposed to a chemoattractant gradient and establishes polarity. This triggers the extension of the plasma membrane, called a lamellipodium, in the direction of eventual cell movement and establishes the front/leading edge of the cell.2,4 In vascular injury, a gradient is often established by the release of platelet-derived growth factor (PDGF), such that VSMCs migrate toward the lumen of the vessel.4,5 The formation of lamellipodia requires the polymerization and assembly of actin, which is regulated by the GTPase Rac. …