Novel GPCR Mechanisms of Phenotypic Control in Vascular Smooth Muscle

Abstract

Cardiovascular disease (CVD) is a significant global health concern and the number one cause of morbidity and mortality in the US and worldwide. Ischemia and resulting tissue hypoxia and acidosis are important contributors to CVD development and progression. G protein-coupled receptors (GPCRs) are seven transmembrane receptors with established functions in cardiovascular (patho)physiology. Phenotypic switching of vascular smooth muscle (VSM) from a contractile, quiescent state to a noncontractile, proliferative state is a common feature of CVD. Two GPCRs, protease-activated receptor 2 (PAR2) and GPR68, have capacity to control cell proliferation in various tissues, but their role(s) in VSM cell proliferation and phenotypic control remain unclear. The purpose of this project was to determine how PAR2 and GPR68 independently control VSM cell growth and phenotype. Findings revealed that PAR2 controls VSM cell growth in a PKA/MEK1/2 and phenotype-dependent manner, while GPR68 inhibits VSM cell growth through Rap1A. Proteomics analysis revealed wide-ranging effects of GPR68 on VSM phenotype including modulation of extracellular matrix, actin-binding, and contractile proteins. Our findings highlight novel mechanisms of PAR2 and GPR68 in VSM cell growth and phenotypic control and offer evidence that they might be important targets for treatment of deleterious phenotypic switching of VSM in CVD.