Published Online
on July 3, 2006

A more recent version of this article appeared on July 11, 2006

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Submitted on October 17, 2005
Revised on May 10, 2006
Accepted on May 12, 2006

Integrin-Linked Kinase, a Hypoxia-Responsive Molecule, Controls Postnatal Vasculogenesis by Recruitment of Endothelial Progenitor Cells to Ischemic Tissue

Seung-Pyo Lee MD, Seock-Won Youn MS, Hyun-Jai Cho MD, Lian Li BA, Tae-Youn Kim BA, Hyung-Seon Yook BA, Jae-Woong Chung MS, Jin Hur MS, Chang-Hwan Yoon MD, Kyung-Woo Park MD, Byung-Hee Oh MD, Young-Bae Park MD, and Hyo-Soo Kim MD^*

From the Department of Internal Medicine (S.-P.L., H.-J.C., C.-H.Y., K.-W.P., B.-H.O., Y.-B.P., H.-S.K.), Seoul National University College of Medicine, and Cardiovascular Laboratory (S.-P.L., S.-W.Y., H.-J.C., L.L., T.-Y.K., H.-S.Y., J.-W.C., J.H., C.-H.Y., K.-W.P., B.-H.O., Y.-B.P., H.-S.K.), Clinical Research Institute, Seoul National University Hospital, Seoul, Korea.

^* To whom correspondence should be addressed. E-mail: hyosoo{at}snu.ac.kr.

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-B and hypoxia-inducible factor-1 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-B and hypoxia-inducible factor-1. 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.

Key words: angiogenesis • hypoxia • ischemia • endothelial cell • endothelial progenitor cell

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