Atheroprotection by smooth muscle selective RhoGAPs

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1. Summary Atherosclerosis is a leading cause of morbidity and mortality world-wide. It is clear that vascular smooth muscle cells (SMCs) play a critical role in plaque progression and stability, but many questions remain in regard to the source, fate, and function of the phenotypically modulated SMCs within the protective fibrous cap and necrotic core. Defects in SMC function that lead to hypertension (HTN) and increased vascular stiffness also affect plaque formation and progression by altering mechanical signaling within the vessel wall. Although these physiologic parameters are major independent cardiovascular risk factors, we know surprisingly little about their development, their inter-relationship, or the mechanisms by which they promote atherosclerosis. We have previously shown that the SMC-selective Rho-specific GAP, GRAF3, reduces blood pressure in mice and humans by limiting RhoA-dependent SMC contractility in resistance arterioles and went on to identify rs604723 as the causal variant within the BP-associated locus in this gene. Our more recent data indicate that GRAF signaling is atheroprotective and inhibits the expression of the contractile and extracellular matrix genes that drive vascular stiffness, and the pro-inflammatory and pro-calcification gene programs that contribute to atherosclerotic plaque development and rupture. The overall goals of this proposal are to assess the role of GRAF3 genotype on cardiovascular outcomes in a large and diverse cardiovascular disease patient population, to directly measure the contribution of GRAF signaling to atherosclerosis and vascular stiffening, and to use our understanding of GRAF intra-molecular interactions to identify GRAF-activating compounds that could be useful for treating HTN and atherosclerotic disease.