VE-cadherin is a critical endothelial regulator of TGF-β signalling

Abstract

VE‐cadherin is an endothelial‐specific transmembrane protein concentrated at cell‐to‐cell adherens junctions. Besides promoting cell adhesion and controlling vascular permeability, VE‐cadherin transfers intracellular signals that contribute to vascular stabilization. However, the molecular mechanism by which VE‐cadherin regulates vascular homoeostasis is still poorly understood. Here, we report that VE‐cadherin expression and junctional clustering are required for optimal transforming growth factor‐β (TGF‐β) signalling in endothelial cells (ECs). TGF‐β antiproliferative and antimigratory responses are increased in the presence of VE‐cadherin. ECs lacking VE‐cadherin are less responsive to TGF‐β/ALK1‐ and TGF‐β/ALK5‐induced Smad phosphorylation and target gene transcription. VE‐cadherin coimmunoprecipitates with all the components of the TGF‐β receptor complex, TβRII, ALK1, ALK5 and endoglin. Clustered VE‐cadherin recruits TβRII and may promote TGF‐β signalling by enhancing TβRII/TβRI assembly into an active receptor complex. Taken together, our data indicate that VE‐cadherin is a positive and EC‐specific regulator of TGF‐β signalling. This suggests that reduction or inactivation of VE‐cadherin may contribute to progression of diseases where TGF‐β signalling is impaired.