Platelet-Derived Growth Factor Receptor β Signaling Is Required for Efficient Epicardial Cell Migration and Development of Two Distinct Coronary Vascular Smooth Muscle Cell Populations

The epicardium plays an essential role in coronary artery formation and myocardial development, but signals controlling the development and differentiation of this tissue are not well understood. To investigate the role of platelet-derived growth factor receptor (PDGFR)beta in development of epicardial-derived vascular smooth muscle cells (VSMCs), we examined PDGFR(-/-) and PDGFR beta epicardial mutant hearts. We found that PDGFR(-/-) hearts failed to form dominant coronary vessels on the ventral heart surface, had a thinned myocardium, and completely lacked coronary VSMCs (cVSMCs). This constellation of defects was consistent with a primary defect in the epicardium. To verify that these defects were specific to epicardial derivatives, we generated mice with an epicardial deletion of PDGFR beta that resulted in reduced cVSMCs distal to the aorta. The regional absence of cVSMCs suggested that cVSMCs could arise from 2 sources, epicardial and nonepicardial, and that both were dependent on PDGFR beta. In the absence of PDGFR beta signaling, epicardial cells adopted an irregular actin cytoskeleton, leading to aberrant migration of epicardial cells into the myocardium in vivo. In addition, PDGF receptor stimulation promoted epicardial cell migration, and PDGFR beta-driven phosphoinositide 3'-kinase signaling was critical for this process. Our data demonstrate that PDGFR beta is required for the formation of 2 distinct cVSMC populations and that loss of PDGFR beta-PI3K signaling disrupts epicardial cell migration. (Circ Res. 2008;103:1393-1401.)