ICAM-1 governs angiogenesis and endothelial redox status

描述（由申请方提供）：血管生成的刺激涉及内皮细胞从静止向促有丝分裂和促迁移表型的转变。内皮细胞运动的协调调节是这一现象中的一个完整过程。然而，负责定向迁移的内皮细胞的具体分子机制仍然很差的特点。VEGF（164）是通过激活包括PI 3 K、Akt和eNOS的各种细胞途径的内皮细胞迁移的有效介质。最近的研究表明，VEGF（164）刺激增加粘附分子表达，例如细胞间粘附分子-1（ICAM-1）表达，其可能参与VEGF介导的内皮细胞迁移。然而，有一个信息缺乏详细的机制，粘附分子调节血管生成。因此，本研究将探讨ICAM-1通过负调节谷氨酸半胱氨酸连接酶（GCL-C）和随后的谷胱甘肽（GSH）对PTEN磷酸酶的氧化还原调节来调控VEGF（164）血管生成活性，并调节内皮NOS活性和细胞内定位的假设。这一假设将通过以下具体目的进行检验：1）确定ICAM-1如何调节GCL-C功能并检查GSH如何影响VEGF（164）ROS产生，2）确定ICAM-1如何控制eNOS细胞定位和活性以响应VEGF（164）刺激，和3）确定GSH的细胞内水平的增加如何影响VEGF（164）信号的PTEN调节。从这些目标积累的数据将提供独特的见解ICAM-1在控制内皮谷胱甘肽代谢，eNOS活性和生物利用度，和PTEN活性在VEGF（164）介导的血管生成和内皮细胞趋化性的作用。该项目的完成将显著推进我们对炎症粘附分子调节血管生成的特定机制的理解，并确定治疗性血管生成干预的新靶点。

DESCRIPTION (provided by applicant): Stimulation of angiogenesis involves the transition of endothelial cells from a quiescent to mitogenic and pro-migratory phenotype. Coordinate regulation of endothelial cell motility is an integral process in this phenomenon. However, specific molecular mechanisms responsible for directional migration of endothelial cells remain poorly characterized. VEGF(164) is a potent mediator of endothelial cell migration through activation of various cellular pathways including PI3K, Akt, and eNOS. Recent studies demonstrate that VEGF(164) stimulation increases adhesion molecule expression, such as intercellular adhesion molecule-1 (ICAM-1) expression, which may participate in VEGF mediated endothelial cell migration. However, there is a paucity of information detailing mechanisms of adhesion molecule regulation of angiogenesis. Therefore, this proposal will investigate the hypothesis that ICAM-1 governs VEGF(164) angiogenic activity by negatively regulating glutamate cysteine ligase (GCL-C) and subsequent glutathione (GSH) redox regulation of PTEN phosphatase, and modulates endothelial NOS activity and intracellular localization. This hypothesis will be examined by the following specific aims: 1) determine how ICAM-1 modulates GCL-C function and examine how GSH affects VEGF(164) ROS production, 2) determine how ICAM-1 governs eNOS cellular localization and activity in response to VEGF(164) stimulation, and 3) determine how increased intracellular levels of GSH affect PTEN regulation of VEGF(164) signaling. Data accumulated from these aims will provide unique insight into the role of ICAM-1 in controlling endothelial glutathione metabolism, eNOS activity and bioavailability, and PTEN activity during VEGF(164) mediated angiogenesis and endothelial cell chemotaxis. Completion of this project will significantly advance our understanding of specific mechanisms by which inflammatory adhesion molecules regulate angiogenesis and identify new targets for therapeutic angiogenic intervention.