Crucial role of inhibitor of DNA binding/differentiation in the vascular endothelial growth factor-induced activation and angiogenic processes of human endothelial cells
Crucial role of inhibitor of DNA binding/differentiation in the vascular endothelial growth factor-induced activation and angiogenic processes of human endothelial cells
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DOI：
10.4049/jimmunol.173.9.5801
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发表时间：
2004-11-01
影响因子：
4.4
通讯作者：
Tokunaga, K
中科院分区：
文献类型：
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作者：
Sakurai, D;Tsuchiya, N;Tokunaga, K
血管生成在类风湿关节炎滑膜细胞的侵袭性增殖中起着关键作用。我们以前曾报道过的DNA结合/分化抑制剂（Id）在类风湿关节炎的滑膜组织内的内皮细胞的过度表达。在这项研究中，我们研究了Id在炎症和血管生成中的作用，在体外模型中使用HUVECs。血管内皮生长因子（VEGF）和TGF β诱导了Id 1和Id 3在HUVECs中的表达。Id的强制表达诱导HUVECs的增殖活性，伴随着p16（INK 4a）的下调。Id的过表达增强ICAM-1和E-选择素的表达，并诱导血管生成过程，如迁移，基质金属蛋白酶-2和-9的表达，和管形成。与此相反，敲低Id 1和Id 3的RNA干扰废除增殖，激活，血管生成过程中的血管内皮细胞诱导的VEGF。这些结果表明Id通过引起血管生成过程的激活和增强在VEGF诱导的内皮细胞信号中起关键作用。基于这些发现，提出抑制Id 1和Id 3的表达和/或功能可能对与病理性血管生成相关的病症具有潜在的治疗价值。
Angiogenesis plays a pivotal role in the aggressive proliferation of synovial cells in rheumatoid arthritis. We have previously reported the overexpression of inhibitor of DNA binding/differentiation (Id) in the endothelial cells within the synovial tissues of rheumatoid arthritis. In this study, we investigated the role of Id in inflammation and angiogenesis in an in vitro model using HUVECs. Vascular endothelial growth factor (VEGF) and TGFbeta induced the expression of Id1 and Id3 in HUVECs. Forced expression of Id induced proliferative activity in HUVECs accompanied by down-regulation of p16(INK4a). Overexpression of Id enhanced expression of ICAM-1 and E-selectin, and induced angiogenic processes such as transmigration, matrix metalloproteinase-2 and -9 expression, and tube formation. In contrast, knockdown of Id1 and Id3 with RNA interference abolished proliferation, activation, and angiogenic processes of HUVECs induced by VEGF. These results indicated that Id plays a crucial role in VEGF-induced signals of endothelial cells by causing activation and potentiation of angiogenic processes. Based on these findings, it was proposed that inhibition of expression and/or function of Id1 and Id3 may potentially be of therapeutic value for conditions associated with pathological angiogenesis.