Abstract 1001: Platelet Derived Growth Factor Receptor beta Function in Epithelial to Mesenchymal Transition of the Epicardium
Platelet derived growth factor receptor beta (PDGFRbeta) is known to promote vascular smooth muscle cell (VSMC) proliferation and migration. Contrary to this dogma, our current studies demonstrate that the PDGFRbeta is essential for the initiation of coronary vascular smooth muscle cell (CVSMC) development and the remodeling of endothelial vessels. The objective of this study is to characterize the mechanism through which PDGFRbeta exerts its early effect on CVSMC. CVSMCs and cardiac fibroblasts arise from a unique precursor population termed the proepicardial organ (PEO). Our data shows that the PDGFRbeta is expressed in this precursor population, but it does not affect the ability of these cells to form nor their ability to migrate over the heart. However, the loss of the PDGFRbeta does impact the development of the epicardium, subepicardial mesenchyme, and CVSMCs. Histological and transmission electron microscopic examination of the newly formed epicardium reveals a failure of epicardial cells to establish a uniform monolayer. We observe a decrease in cells emerging from the epicardium in the PDGFRbeta deficient mice using known markers of epicardial derivatives: WT1, capsulin, and vimentin. Finally, we observe a severe reduction in CVSMCs using three independent markers of VSMCs. Moreover, there does not appear to be an overt change in apoptosis or proliferation. These data suggest that the PDGFRbeta is important for either epicardial maintenance or progression of the epithelial to mesenchymal transition (EMT). As we further characterize the specific mechanism of EMT disruption we will also determine the PDGFRbeta signaling pathway that is responsible in vivo utilizing a series of signaling point mutations. In addition, we will determine if the PDGFRbeta is required for cardiac fibroblast formation in this same system. All of our evidence supports a novel in vivo role for the PDGFRbeta in the EMT of the epicardium.