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Integrin-linked kinase, a hypoxia-responsive molecule, controls postnatal vasculogenesis by recruitment of endothelial progenitor cells to ischemic tissue

Cited 81 time in Web of Science Cited 86 time in Scopus
Authors
Lee, Seung-Pyo; Youn, Seock-Won; Cho, Hyun-Jai; Li, Lian; Kim, Tae-Youn; Yook, Hyung-Seon; Chung, Jae-Woong; Hur, Jin; Yoon, Chang-Hwan; Park, Kyung-Woo; Oh, Byung-Hee; Park, Young-Bae; Kim, Hyo-Soo
Issue Date
2006-07-05
Publisher
American Heart Association
Citation
Circulation. 2006 Jul 11;114(2):150-9. Epub 2006 Jul 3.
Keywords
AnoxiaCell AdhesionEndothelium, Vascular/*physiologyHomeostasisHumansIschemia/*physiopathologyNF-kappa B/metabolismProtein-Serine-Threonine Kinases/*metabolismStem Cells/*physiology
Abstract
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-kappaB and hypoxia-inducible factor-1alpha 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-kappaB and hypoxia-inducible factor-1alpha. 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.
ISSN
1524-4539 (Electronic)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16818815

http://hdl.handle.net/10371/29377
DOI
https://doi.org/10.1161/CIRCULATIONAHA.105.595918
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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