Epicardial HIF1 regulates vascular precursor cell invasion into the myocardium through the VEGF signaling pathway

Abstract

During cardiogenesis, a subset of epicardial cells undergoes epithelial‐mesenchymal‐transition (EMT) and the resulting epicardial derived cells (EPDC) migrate into the sub‐epicardium and myocardium and differentiate into several cell types of the coronary vasculature. Our previous data suggested a link between HIF and epicardial EMT and further coronary vasculogenesis. To better understand the autocrine role of HIF in the epicardium, we used an adenoviral system to constitutively express active HIF1a in the embryonic quail epicardium. We observed that over‐expression of HIF1a in the epicardium prevented EPDC from proper migration into the myocardium. In vitro collagen gel assays confirmed that infection with AdcaHIF1a impaired the invasiveness of epicardial cells. Results from immunostaining and real‐time PCR revealed that epicardial EMT and differentiation of EPDC into endothelial cells and smooth muscle cells were not disrupted. Further investigation suggests that the increase in VEGFR1 expression caused the inhibition of EPDC invasion. In conclusion, our studies support the hypothesis that epicardial HIF is required for regulating epicardially derived mesenchyme invasion into the myocardium, a critical step in the vascularization of the myocardium. This role of HIF suggests that the differentially hypoxic microenvironment may inform epicardial cells when to stop or start migration.Grant Funding Source: American Recovery and Reinvestment Act (ARRA) R01HL091171