Integrin-linked kinase, a hypoxia-responsive molecule, controls postnatal vasculogenesis by recruitment of endothelial progenitor cells to ischemic tissue
Integrin-linked kinase, a hypoxia-responsive molecule, controls postnatal vasculogenesis by recruitment of endothelial progenitor cells to ischemic tissue
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DOI：
10.1161/circulationaha.105.595918
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发表时间：
2006-07-11
期刊：
影响因子：
37.8
通讯作者：
Kim, Hyo-Soo
中科院分区：
文献类型：
--
作者：
Lee, Seung-Pyo;Youn, Seock-Won;Kim, Hyo-Soo
背景 - 内皮祖细胞 (EPC) 向缺氧内皮细胞 (EC) 的募集和粘附对于缺血组织中的血管生成至关重要；然而，对于缺氧时 EC 表达粘附分子的关键信号或细胞内信号通路以及这与 EPC 募集到缺血组织之间的关系，人们知之甚少。在这里，我们报道内源性整合素连接激酶（ILK）是一种对内皮细胞缺氧做出反应的新型分子，通过核因子-κB和缺氧诱导因子-1α调节基质细胞衍生因子-1（SDF-1）和细胞间粘附分子-1（ICAM-1）的表达，并诱导EPCs募集到缺血区域。 ILK 激酶活性在 EC 中呈时间依赖性上调，这与 ICAM-1 和 SDF-1 的增加有关。 ILK 的这种上调是通过热休克蛋白 90 对 ILK 的稳定作用介导的。常氧 EC 中的 ILK 过表达通过核因子 kappa B 和缺氧诱导因子 1 α 的双重控制导致 ICAM-1 和 SDF-1 上调。在缺氧 EC 中阻断 ILK 显着消除了两种分子的表达，从而导致 EPC 掺入 EC 减少。后肢缺血模型表明，ILK 阻断显着减少 EPC 归巢至缺血肢体，从而导致新血管形成不良。基质胶栓中 ILK 的过表达显着改善体内新生血管形成，而 ILK 的阻断则产生相反的效果。结论 - 内源性 ILK 是参与 EC 缺氧应激的众多细胞内分子的新型生理上游反应物，并可能控制 EPC 向缺血组织的募集。
Background - Recruitment and adhesion of endothelial progenitor cells (EPCs) to hypoxic endothelial cells (ECs) is essential for vasculogenesis in ischemic tissue; little is known, however, about the key signals or intracellular signaling pathways involved in orchestrating the expression of adhesion molecules by ECs in response to hypoxia and how this is related to the recruitment of EPCs to the ischemic tissue. Here, we report that endogenous integrin-linked kinase (ILK) is a novel molecule that responds to hypoxia in ECs that regulates the expression of stromal cell - derived factor-1 (SDF-1) and intercellular adhesion molecule-1 (ICAM-1) through nuclear factor-kappa B and hypoxia-inducible factor-1 alpha and induces recruitment of EPCs to ischemic areas.Methods and Results - Under hypoxia, both the endogenous amount and kinase activity of ILK were time-dependently upregulated in ECs, which was associated with increased ICAM-1 and SDF-1. This upregulation of ILK was mediated by stabilization of ILK by heat shock protein 90. ILK overexpression in normoxic ECs resulted in ICAM-1 and SDF-1 upregulation through dual control by nuclear factor-kappa B and hypoxia-inducible factor-1 alpha. Blockade of ILK in hypoxic ECs significantly abrogated the expression of both molecules, which led to decreased EPC incorporation into ECs. A hindlimb ischemia model showed that ILK blockade significantly reduced EPC homing to ischemic limb and consequently led to poor neovascularization. Overexpression of ILK in the Matrigel plug significantly improved neovascularization in vivo, whereas the blockade of ILK resulted in the opposite effect.Conclusions - Endogenous ILK is a novel and physiological upstream responder of numerous intracellular molecules involved in hypoxic stress in ECs and may control the recruitment of EPCs to ischemic tissue.