Abstract 92: Platelet Derived Growth Factor Receptor Alpha Signaling is Required for Cardiac Fibroblast Survival and Proliferation

Abstract

Cardiac fibrosis contributes significantly to heart disease and is a hallmark of decreased cardiac function. Currently, there are no treatments that attenuate fibrosis, but identification of signaling pathways required for fibroblast function would provide some potential targets. PDGFRα is a receptor tyrosine kinase that is required for fibroblast formation in the developing heart, and preliminary data indicates that it is also required for maintenance of resident fibroblasts and expansion of activated fibroblasts after injury. Preliminary experiments demonstrate that loss of PDGFRα expression in adult cardiac fibroblasts results in 50% reduction in the number of the resident fibroblasts by 4 days after gene deletion. This was further validated using an independent fibroblast marker, collagen1a1GFP. Based on the low basal level of fibroblast proliferation, we hypothesize that PDGFRα signaling is essential for fibroblast survival and that fibroblasts undergo rapid turnover in the absence of PDGFRα signaling. Future studies will determine the exact mechanism of this loss. We have also begun to elucidate which PDGFRα downstream signals promote fibroblast maintenance. Using a PDGFRα-dependent-PI3K-deficient mouse model, preliminary data indicates that PDGFRα-dependent PI3K signaling is essential for cell survival. We are also investigating the role of PDGFRα signaling after myocardial infarction. Using recently described genetic tools to follow fibroblasts after injury, we have determined that fibroblasts reach their peak of proliferation within a week after permanent left anterior descending artery ligation. This injury-induced proliferation is reduced by 50% after deletion of PDGFRα. Therefore, we have demonstrated that PDGFRα has a role in fibroblast maintenance in the healthy heart, as well as a role in fibroblast proliferation after injury. Our studies will continue to illuminate additional roles for PDGFRα in the fibroblast, as well as the implications of fibroblast loss on other cell types and overall heart function.