N-Cadherin Juxtacrine Signaling Regulates the Endothelial Barrier

Endothelial cells express Vascular Endothelial (VE)- and Neural (N)-cadherin, which have overlapping functions. VE-cadherin forms homotypic adhesion between endothelial cells whereas N-cadherin forms heterotypic adhesion with the surrounding pericytes in capillary endothelia. Endothelial specific deletions of Cdh2 (N-cadherin) or Cdh5 (VE-cadherin) in mice demonstrated poorly formed leaky capillaries and in utero death at E9.5 due to defective angiogenesis. These findings raise the question of whether N- and VE-cadherin function independently or whether N-cadherin activated signaling regulates the assembly of VE-cadherin and thereby the formation of adherens junctions. I investigated the role of N-cadherin in the formation of VE-cadherin junctions using mouse genetic models and identified N-cadherin a novel signaling pathway in endothelial cells. I show that N-cadherin functions by interacting with the RhoGEF Trio to activate the RhoGTPases Rac1 and RhoA at adherens junctions, inducing the recruitment of VE-cadherin. This N-cadherin activated signaling pathway is essential for maximal VE-cadherin assembly and the formation of the endothelial junctional barrier.