VE-Cadherin facilitates BMP-induced endothelial cell permeability and signaling

Abstract

Several vascular disorders such as aberrant angiogenesis, atherosclerosis and pulmonary hypertension have been linked to dysfunctional BMP signaling. As vascular hyperpermeability via distortion of endothelial cell adherens junctions is a common feature of these diseases, the role of BMPs in this process has not been investigated yet. BMP signaling is initiated by binding of ligand to and activation of BMP type I (BMPRI) and BMP type II (BMPRII) receptors. Internalization of VE-Cadherin as well as Src-kinase-dependent phosphorylation have been implicated to loosen cell-cell contacts, thereby modulating vascular permeability. Here we demonstrate that BMP6 induces hyperpermeabilization of endothelial cells by inducing internalization and Src-dependent phosphorylation of VE-Cadherin. Furthermore we show BMP-dependent physical interaction of VE-Cadherin with BMP-receptor ALK2 (BMPRI) and BMPRII resulting in stabilization of the BMP-receptor complex and thereby support of BMP6-Smad signaling. Our results give first insights into the molecular mechanism of BMP-induced vascular permeability, a hallmark in different vascular diseases, and provide the base for further investigations on BMPs as regulators of vascular integrity, both under physiological and patho-physiological conditions.