Journal
FASEB JOURNAL
Volume 37, Issue 4, Pages -Publisher
WILEY
DOI: 10.1096/fj.202201623RR
Keywords
blood-brain barrier; CD93; endothelial junctions; RhoGTPases; vascular permeability; VE-cadherin
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CD93 regulates the stability of VE-cadherin at endothelial junctions by interacting with VE-cadherin and limiting its phosphorylation and turnover. CD93 deficiency leads to increased phosphorylation of VE-cadherin, displacing it from endothelial cell-cell contacts and disrupting endothelial junctions, resulting in enhanced blood-brain barrier permeability. This mechanism is regulated through the Rho/Rho kinase-dependent pathway.
Regulation of vascular permeability to plasma is essential for tissue and organ homeostasis and is mediated by endothelial cell-to-cell junctions that tightly regulate the trafficking of molecules between blood and tissue. The single-pass transmembrane glycoprotein CD93 is upregulated in endothelial cells during angiogenesis and controls cytoskeletal dynamics. However, its role in maintaining homeostasis by regulating endothelial barrier function has not been elucidated yet. Here, we demonstrate that CD93 interacts with vascular endothelial (VE)-cadherin and limits its phosphorylation and turnover. CD93 deficiency in vitro and in vivo induces phosphorylation of VE-cadherin under basal conditions, displacing it from endothelial cell-cell contacts. Consistent with this, endothelial junctions are defective in CD93(-/-) mice, and the blood-brain barrier permeability is enhanced. Mechanistically, CD93 regulates VE-cadherin phosphorylation and turnover at endothelial junctions through the Rho/Rho kinase-dependent pathway. In conclusion, our results identify CD93 as a key regulator of VE-cadherin stability at endothelial junctions, opening up possibilities for therapeutic strategies directed to control vascular permeability.
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