Building bridges Molecular regulation of endothelial junctions for the vascular barrier

Adherens junctions (AJs) are dynamic structures that bridge neighboring endothelial cells in the vessel wall, balancing mechanical stability in diverse hemodynamic environments with adaptability to homeostatic and inflammatory cues. This thesis investigates how vascular endothelial (VE)-cadherin, the core adhesion receptor of AJs, orchestrates molecular organization, intracellular signaling, and mechanotransduction to control vascular integrity. By uncovering new VE-cadherin-binding partners and their regulatory principles, our work moves beyond the classical view of VE-cadherin as a static adhesive link and instead positions it as a responsive, multifunctional scaffold that shapes endothelial behavior across scales, from protein structure to cellular dynamics and ultimately tissue-level force adaptation. 
At the molecular level, we showed that VE-cadherin forms a functional adhesive interface independent of its conserved extracellular arginine-glycine-aspartate (RGD) integrin binding motifs (chapter 4). Intracellularly, the VE-cadherin complex associates with a versatile set of catenins and regulatory factors, including PKP4 and newly identified partners ARVCF, ARHGAP23, and KEAP1, which modulate junction organization, cytoskeletal tension, and redox balance (chapters 2&3). Mechanistically, we demonstrate that the mechanosensitive α-catenin-vinculin module strengthens the endothelial barrier and prevents vascular leakage in developing vessels (chapter 5). During leukocyte transmigration, AJs function within a broader biomechanical framework in which external stress, receptor mechanics, and cellular compliance collectively determine whether the vascular barrier resists or remodels (chapter 6). Together, the findings presented in this thesis uncover previously unrecognized mechanisms governing endothelial junction stability and remodeling in vascular homeostasis, development and inflammation.