Rap1-and R-Ras-regulated vascular endothelial cell-cell adhesion

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While vascular integrity is maintained to prevent the leakage of fluid from the lumen to the tissues, angiogenis sprouting and branching is required for angiogenesis. Thus, balance between vascular endothelial cell-cell adhesion and deadheison control vascular quiescence and angiogenesis. However, it remains elusive how vascular endothelial cell-cell adhesion is regulated by small GTPases, Rap1 and R-Ras. We here identified two novel signaling pathways which tighten the endothelial cell-cell adhesion and inhibit the vascular permeability ; (1) cAMP-Epac-Rap1 and (2) Vascular endothelial cadherin(VE- cadherin) -MAGI-1-PDZ-GEF1-Rap1. cAMP has been proven to stabilize the cell-cell contacts and reduce the permeability.In vascular endothelial cells, cAMP activates. Epac, a guanine nucleotide exchange factor for Rap1, thereby increase GTP-bound Rap1. We found that increased GTP-Rap1 leads to tightening of intercellular adhesion and to reduced vascular permeability. Furthermore, Rap1 activat … More ion induces the rearrangement of actin cytoskeleton that support the VE-cadherin- mediated cell-cell adhesion via alph- and beta- catenins. In animal model, cAMP-increasing reagents indeed reduced the leakage of dye from vasculature, indicating the important role of Rap1 for vascular stability.Homophilic association of VE-cadherin is essential for formation of endothelial adherens junction that constitute an essential intercellular adhesion. Ve-cadherin is linked to actin cytoskeleton via beta-catenin and alpha-cateni. n. We found that the trans-association of VE-cadherin recruits MAGI-1/PDZ-GEF1 complex to the cell-cell contacts. Since PDZ-GEF1 functions a GEF for Rap1, the association of VE-cadherin results in the activation of Rap1 at the cell-cell contacts, thereby stabilizing the intercellular adhesion.The two sigmalign pathways we identified in this research provide the evidence that the activation of Rap1 in endothelial cells results in the stabilization of cell-cell contacts and the possibility that Rap1-activating reagent can be used for the reduction of permeability such as edema. We have not yet identified the downstream of Rap1 in detail. Therefore, further research focusing on the Rap1 signaling in endothelial cells will contribute to understanding the regulation of vascular quiescence and angiogenesis. Less