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


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.
Lee
Seung-Pyo
SP
Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongro-gu, Seoul 110-744, South Korea.
Youn
Seock-Won
SW
Cho
Hyun-Jai
HJ
Li
Lian
L
Kim
Tae-Youn
TY
Yook
Hyung-Seon
HS
Chung
Jae-Woong
JW
Hur
Jin
J
Yoon
Chang-Hwan
CH
Park
Kyung-Woo
KW
Oh
Byung-Hee
BH
Park
Young-Bae
YB
Kim
Hyo-Soo
HS
D002448:Cell Adhesion; D004730:Endothelium, Vascular / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D000860:Hypoxia; D007511:Ischemia / Q000503:physiopathology*; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013234:Stem Cells / Q000502:physiology*; D000099200:Scaffold Protein ILK
D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK