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

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

Research output: Contribution to journalArticle

83 Citations (Scopus)

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-κB and hypoxia-inducible factor-1α 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-κB and hypoxia-inducible factor-1α. 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.

Original languageEnglish (US)
Pages (from-to)150-159
Number of pages10
JournalCirculation
Volume114
Issue number2
DOIs
StatePublished - Jul 1 2006

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Endothelial Cells
Chemokine CXCL12
Intercellular Adhesion Molecule-1
Hypoxia-Inducible Factor 1
Up-Regulation
Hypoxia
integrin-linked kinase
Endothelial Progenitor Cells
HSP90 Heat-Shock Proteins
Hindlimb
Phosphotransferases
Ischemia
Extremities

Keywords

  • Angiogenesis
  • Endothelial cell
  • Endothelial progenitor cell
  • Hypoxia
  • Ischemia

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

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

In: Circulation, Vol. 114, No. 2, 01.07.2006, p. 150-159.

Research output: Contribution to journalArticle

Lee, SP, Youn, SW, Cho, HJ, Li, L, Kim, TY, Yook, HS, Chung, JW, Hur, J, Yoon, CH, Park, KW, Oh, BH, Park, YB & Kim, HS 2006, 'Integrin-linked kinase, a hypoxia-responsive molecule, controls postnatal vasculogenesis by recruitment of endothelial progenitor cells to ischemic tissue', Circulation, vol. 114, no. 2, pp. 150-159. https://doi.org/10.1161/CIRCULATIONAHA.105.595918
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. / Integrin-linked kinase, a hypoxia-responsive molecule, controls postnatal vasculogenesis by recruitment of endothelial progenitor cells to ischemic tissue. In: Circulation. 2006 ; Vol. 114, No. 2. pp. 150-159.
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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-κB and hypoxia-inducible factor-1α 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-κB and hypoxia-inducible factor-1α. 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.",
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T1 - Integrin-linked kinase, a hypoxia-responsive molecule, controls postnatal vasculogenesis by recruitment of endothelial progenitor cells to ischemic tissue

AU - Lee, Seung Pyo

AU - Youn, Seock Won

AU - Cho, Hyun Jai

AU - Li, Lian

AU - Kim, Tae Youn

AU - Yook, Hyung Seon

AU - Chung, Jae Woong

AU - Hur, Jin

AU - Yoon, Chang Hwan

AU - Park, Kyung Woo

AU - Oh, Byung Hee

AU - Park, Young Bae

AU - Kim, Hyo Soo

PY - 2006/7/1

Y1 - 2006/7/1

N2 - 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-κB and hypoxia-inducible factor-1α 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-κB and hypoxia-inducible factor-1α. 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.

AB - 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-κB and hypoxia-inducible factor-1α 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-κB and hypoxia-inducible factor-1α. 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.

KW - Angiogenesis

KW - Endothelial cell

KW - Endothelial progenitor cell

KW - Hypoxia

KW - Ischemia

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