PDGFRβ signaling is required for efficient epicardial cell migration and development of two distinct coronary vascular smooth muscle cell populations

• Published in: Circulation research Vol. 103; no. 12; pp. 1393 - 1401
• Main Authors: Mellgren, Amy M., Smith, Christopher L., Olsen, Gregory S., Eskiocak, Banu, Zhou, Bin, Kazi, Michelle N., Ruiz, Fernanda R., Pu, William T., Tallquist, Michelle D.
• Format: Journal Article
• Language: English
• Published: 23.10.2008
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.108.176768

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 β ( PDGFR β) in development of epicardial-derived vascular smooth muscle cells (VSMC), we examined PDGFR β -/- and PDGFR β epicardial-mutant hearts. We found that PDGFR β -/- hearts failed to form dominant coronary vessels on the ventral heart surface, had a thinned myocardium, and completely lacked coronary VSMC (cVSMC). 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 PDGFRβ that resulted in reduced cVSMC distal to the aorta. The regional absence of cVSMC suggested that cVSMC could arise from two sources, epicardial and non-epicardial, and that both were dependent on PDGFRβ. In the absence of PDGFRβ 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 PDGFRβ-driven phosphoinositide 3' kinase (PI3K) signaling was critical for this process. Our data demonstrate that PDGFRβ is required for the formation of two distinct cVSMC populations and that loss of PDGFRβ-PI3K signaling disrupts epicardial cell migration.