Abstract
The importance of morphogenetic proteins (BMPs) and their antagonists in vascular development is increasingly being recognized. BMP-4 is essential for angiogenesis and is antagonized by matrix Gla protein (MGP) and crossveinless 2 (CV2), both induced in a staged fashion by the activin-like kinase receptor 1 (ALK1) after stimulation by BMP-9. In this study, however, we show that CV2 preferentially binds and inhibits BMP-9 thereby providing strong feedback inhibition for BMP-9/ALK1 signaling rather than for BMP-4/ALK2 signaling. CV2 disrupts complex formation by ALK2, ALK1, BMP-4 and BMP-9 required for the induction of both BMP antagonists. It also limits VEGF expression and proliferation of ALK1-expressing endothelial cells. In vivo, CV2 deficiency translates into a dysregulation of vascular BMP signaling, resulting in a thickened, abnormal endothelium with increased markers of endothelial differentiation. Thus, mutual regulation by BMP-9 and CV2 is essential in regulating the development of the vascular endothelium.
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