Protein Kinase G and VASP in the Control of Vascular Smooth Muscle Cell Migration

Abstract

Uncontrolled migration of vascular smooth muscle cells (VSMCs) is a mechanistic foundation of cardiovascular disease, the number one killer of Americans and individuals worldwide. Unfortunately, current strategies aimed at preventing pathologic VSMC migration are largely inefficient. This study was designed to characterize a potential novel target capable of controlling VSMC migration, and our hypothesis is that protein kinase G (PKG)-stimulated vasodilator-activated serum phosphoprotein (VASP) serves to inhibit VSMC migration through enhanced actin polymerization and increased cytoskeletal stability. In human primary and rat commercial VSMCs, using pharmacologic and mechanical stimulation as well as a newly developed confocal and laser capture microdissection-assisted migration assay, results show that PKG phosphorylates VASP at Ser239, a reported PKG-sensitive site, and that this correlates with reduced globular to filamentous actin (G:F), and inhibited cell migration. In complement, using a rat carotid artery injury model, PKG activation and subsequent VASP activation significantly diminished neointima formation and vascular wall remodeling. These findings suggest that vascular protection can be accomplished through PKG and downstream phosphorylation of the actin binding protein VASP, which may serve to increase cytoskeletal stability and offset the capacity of VSMCs to migrate as an underpinning of abnormal cell migration during cardiovascular disease.