Quinn S. Lee

Vascular endothelial (VE)–cadherin forms homotypic adherens junctions (AJs) in the endothelium, whereas N-cadherin forms heterotypic adhesion between endothelial cells and surrounding vascular smooth muscle cells and pericytes. Here we addressed the question whether both cadherin adhesion complexes communicate through intracellular signaling and contribute to the integrity of the endothelial barrier. We demonstrated that deletion of N-cadherin (Cdh2) in either endothelial cells or pericytes increases junctional endothelial permeability in lung and brain secondary to reduced accumulation of VE-cadherin at AJs. N-cadherin functions by increasing the rate of VE-cadherin recruitment to AJs and induces the assembly of VE-cadherin junctions. We identified the dual Rac1/RhoA Rho guanine nucleotide exchange factor (GEF) Trio as a critical component of the N-cadherin adhesion complex, which activates both Rac1 and RhoA signaling pathways at AJs. Trio GEF1-mediated Rac1 activation induces the recruitment of VE-cadherin to AJs, whereas Trio GEF2-mediated RhoA activation increases intracellular tension and reinforces Rac1 activation to promote assembly of VE-cadherin junctions and thereby establish the characteristic restrictive endothelial barrier.

The blood brain barrier (BBB) consists of a specialized microvasculature with highly restricted permeability to both low and high molecular weight proteins. The BBB plays a critical role in maintaining tissue‐fluid homeostasis and preventing blood‐to‐brain paracellular diffusion of plasma components that can cause neuronal dysfunction. The BBB is composed of brain endothelial cells (BEC), which physically interact with pericytes at the basement membrane. BECs and pericytes express N‐cadherin, which forms homophilic adhesions to establish cross‐communications between these cell types. The role of N‐cadherin in the BBB is not well understood. We have demonstrated that an endothelial specific deletion of N‐cadherin gene ( Cdh2 ) in mice resulted in increased permeability of the BBB in a size dependent manner, suggesting that N‐cadherin juxtacrine signaling in endothelial cells restricts BBB permeability. These changes in the BBB permeability were not associated with pericyte loss since we observed an increase in capillary coverage by pericytes in the cerebral cortex in these mice. To gain a holistic picture of N‐cadherin juxtacrine signaling in maintenance of the BBB, we utilized N‐cadherin biomimetic surfaces to induce signaling in a cell culture model. We found that Trio, a Rho guanine nucleotide exchange factor consisting of two GEFs, is recruited to N‐cadherin adhesions to induce Rac1 signaling through activation of GEF1. Genetic studies in humans provide a causal link between a deficiency of Trio GEF1 activity and neurodevelopmental diseases such as intellectual disability, suggesting that increased vascular leakage and associated neurotoxicity impairs cognitive function. Therefore, we tested whether N‐cadherin deficient mice exhibited cognitive deficit. Using the Morris water navigation task, we demonstrated that loss of N‐cadherin in endothelial cells results in a deficit in spatial learning and memory. This difference to control mice became indistinguishable with age, suggesting that deficiency of N‐cadherin juxtacrine signaling may be an underlying cause for cognitive dysfunction in the elderly population. Hence, mice lacking Cdh2 gene in endothelial cells may serve as an animal model to study vascular leakage and cognitive function in aging. Support or Funding Information NIH T32 HL027829, NIH R01 HL103922 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .