Abstract 254: Platelet Derived Growth Factor Receptor Beta Activation Promotes Atheroprotective Changes in Smooth Muscle Cell Phenotype

Despite decades of research, little is known about mechanisms and factors driving atherosclerotic progression leading to plaque rupture, thrombosis and myocardial infarction or stroke. The widely accepted dogma is a thin fibrous cap and a paucity of Acta2+ smooth muscle cells (SMC) relative to macrophages increases risk of plaque rupture. However, our recent rigorous lineage tracing studies in advanced lesions showed a subset of cells that express macrophage markers are SMC-derived and SMC specific conditional knockout of stem pluripotency gene Klf4 resulted in increased fibrous cap thickness and decreased lesion size and abundance of SMC-derived macrophage-like cells. Results indicate that SMC play a critical role in lesion pathogenesis but paradoxically can transition to a beneficial or detrimental state, presumably as a function of the local environmental milieu within lesions. Studies highlight the critical need to identify factors and mechanisms that direct SMC to form a stable fibrous cap. Various in vitro data show that SMC treated with platelet derived growth factor receptor beta (PDGFR beta) ligands dedifferentiate, proliferate, and synthesize extracellular matrix (ECM) molecules, including collagens known to be enriched within the fibrous cap. We hypothesize that PDGFR beta activation in SMC is necessary for fibrous cap stabilization through EMC protein synthesis. Herein we employ Myh11-ER T2 -cre eYFP SMC lineage tracing ApoE-/- Western diet fed mice to show that a subset of SMC in advanced lesions express PDGFR beta and are localized to the fibrous cap. Moreover we demonstrate that SMC specific conditional KO of the PDGFR beta in these lineage tracing mice resulted in dramatic reductions in the numbers of YFP+ (SMC-derived) cells within lesions but an increase in YFP- (not SMC-derived) macrophages, as well as a decrease in Acta2+ cells in the fibrous cap. Results indicate that PDGFR beta activation in SMC is a critical determinant of the cellular composition of lesions and is essential for investment of SMC within the fibrous cap. Supported by NIH R01 grants HL121008 and HL087867 to GKO.