Bone morphogenetic protein endothelial cell precursor-derived regulator regulates retinal angiogenesis in vivo in a mouse model of oxygen-induced retinopathy.

ABSTRACT

OBJECTIVE: Bone morphogenetic proteins (BMPs) are potently proangiogenic; however, the mechanisms underlying the regulation of vessel development by BMPs are not fully understood. To assess the significance of BMP endothelial cell precursor-derived regulator (BMPER) in blood vessel formation in vivo, we investigated its role in retinal angiogenesis. METHODS AND RESULTS: In a model of oxygen-induced retinopathy, Bmper mRNA expression and protein levels are downregulated, correlating with the initiation of Sma and Mad related protein phosphorylation in endothelial cells. Moreover, Bmper haploinsufficiency results in an increased rate of retinal revascularization, with retinas from Bmper+/- mice displaying increased numbers of branching points and angiogenic sprouts at the leading edge of the newly formed vasculature. Furthermore, although Bmper haploinsufficiency does not alter Bmp expression, it does lead to an increase in BMP signaling, as evidenced by increased phosphorylated Sma and Mad related protein levels in endothelial cells and increased expression of known BMP target genes. CONCLUSIONS: These observations provide compelling evidence that BMPER is important in the regulation of BMP signaling and revascularization in the hypoxic retina. These bring forth the possibility of novel therapeutic approaches for pathological angiogenesis based on manipulation of BMP signaling.