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

当维持血管完整性以防止流体从管腔泄漏到组织时，血管生成素发芽和分支是血管生成所需的。因此，血管内皮细胞-细胞粘附和去粘附之间的平衡控制血管静止和血管生成。然而，它仍然是难以捉摸的血管内皮细胞-细胞粘附是如何调节小GTP酶，Rap 1和R-Ras。我们在此鉴定了两种收紧内皮细胞-细胞粘附并抑制血管渗透性的新信号传导途径：（1）cAMP-Epac-Rap 1和（2）血管内皮钙粘蛋白（VE-钙粘蛋白）-MAGI-1-PDZ-GEF 1-Rap 1。cAMP已被证明可以稳定细胞间的接触，降低通透性。Epac，Rap 1的鸟嘌呤核苷酸交换因子，从而增加GTP结合的Rap 1。我们发现，增加GTP-Rap 1导致收紧细胞间粘附和降低血管通透性。此外，Rap 1激活 ...更多信息 离子诱导肌动蛋白细胞骨架的重排，所述肌动蛋白细胞骨架通过α-和β-连环蛋白支持VE-钙粘蛋白介导的细胞-细胞粘附。在动物模型中，cAMP增加剂确实减少了染料从血管的渗漏，表明Rap 1对血管稳定性的重要作用。VE-钙粘蛋白的嗜同性缔合是形成内皮粘附连接所必需的，而内皮粘附连接构成了必要的细胞间粘附。Ve-钙粘蛋白通过β-连环蛋白和α-连环蛋白与肌动蛋白细胞骨架连接。n.我们发现VE-cadherin的反式缔合将MAGI-1/PDZ-GEF 1复合物募集到细胞-细胞接触。由于PDZ-GEF 1作为Rap 1的GEF发挥作用，因此VE-钙粘蛋白的结合导致Rap 1在细胞-细胞接触处活化，我们在这项研究中鉴定的两条sigmalign通路提供了证据，即内皮细胞中Rap 1的激活导致细胞-细胞接触的稳定，以及Rap 1-细胞粘附的可能性。活化剂可用于降低渗透性如水肿。我们还没有详细确定Rap 1的下游。因此，对内皮细胞Rap 1信号通路的深入研究将有助于理解血管静止和血管生成的调控。少

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