Monoclonal antibodies directed to different regions of vascular endothelial cadherin extracellular domain affect adhesion and clustering of the protein and modulate endothelial permeability
Monoclonal antibodies directed to different regions of vascular endothelial cadherin extracellular domain affect adhesion and clustering of the protein and modulate endothelial permeability
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DOI：
10.1182/blood.v97.6.1679
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发表时间：
2001-03-15
期刊：
影响因子：
20.3
通讯作者：
Dejana, E
中科院分区：
文献类型：
--
作者：
Corada, M;Liao, F;Dejana, E
血管内皮钙粘蛋白（Vascular endothelial cadherin，VE-cadherin）是一种内皮细胞特异性的钙粘蛋白，在血管组织的调控中起重要作用。阻断VE-钙粘蛋白抗体强烈抑制血管生成，并且由于缺乏正确的组织和血管重塑，VE-钙粘蛋白基因的失活导致胚胎死亡。因此，VE-钙粘蛋白粘附特性的抑制剂可能构成防止肿瘤新生血管形成的工具。在本文中，我们测试了针对人VE-钙粘蛋白胞外域的不同单克隆抗体（mAb）的功能活性。这些mAb在体外也能诱导内皮细胞凋亡。在这些试验中，另外两种mAb TEA 1.31和Hec 1.2分别具有中等或不可检测的活性。表位作图研究表明，BV 6，BV 9，TEA 1.31，和Hec 1.2绑定到一个重组片段跨越细胞外质膜结构域EC 3至EC 4。通过肽段扫描分析和竞争实验，我们确定位于EC 3上的TIDLRY和EC 1上的KVFRVDAETGDVFAI序列分别为BV 6和Cad 5的结合域。总体而言，这些结果支持VE-钙粘蛋白对人内皮细胞特性起相关作用的概念。针对胞外结构域EC 1以及EC 3-EC 4的抗体影响VE-钙粘蛋白粘附和聚集，并改变内皮细胞通透性、凋亡和血管结构形成。（血。2001;97：1679-1684）（C）2001年由美国血液学会。
Vascular endothelial cadherin (VE-cadherin) is an endothelial cell-specific cadherin that plays an important role in the control of vascular organization. Blocking VE-cadherin antibodies strongly inhibit angiogenesis, and inactivation of VE-cadherin gene causes embryonic lethality due to a lack of correct organization and remodeling of the vasculature. Hence, inhibitors of VE-cadherin adhesive properties may constitute a tool to prevent tumor neovascularization, In this paper, we tested different monoclonal antibodies (mAbs) directed to human VE-cadherin ectodomain for their functional activity Three mAbs (Cad 5, BV6, BV9) were able to increase paracellular permeability, inhibit VE-cadherin reorganization, and block angiogenesis in vitro. These mAbs could also induce endothelial cell apoptosis in vitro. Two additional mAbs, TEA 1.31 and Hec 1.2, had an intermediate or undetectable activity, respectively, in these assays. Epitope mapping studies show that BV6, BV9, TEA 1.31, and Hec 1.2 bound to a recombinant fragment spanning the extracellular juxtamembrane domains EC3 through EC4. In contrast, Cad 5 bound to the aminoterminal domain EC1, By peptide scanning analysis and competition experiments, we defined the sequences TIDLRY located on EC3 and KVFRVDAETGDVFAI on EC1 as the binding domain of BV6 and Cad 5, respectively. Overall, these results support the concept that VE-cadherin plays a relevant role on human endothelial cell properties. Antibodies directed to the extracellular domains EC1 but also EC3-EC4 affect VE-cadherin adhesion and clustering and alter endothelial cell permeability, apoptosis, and vascular structure formation. (Blood. 2001;97:1679-1684) (C) 2001 by The American Society of Hematology.