Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 204, Issue 3, Pages 605-618Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20061609
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Funding
- NEI NIH HHS [R01 EY012601, R01 EY007739, R01-EY007739, R01-EY012601] Funding Source: Medline
- NHLBI NIH HHS [R01 HL068157, R01-HL068157] Funding Source: Medline
- NIDDK NIH HHS [R01-DK59600, R01 DK059600, R21-DK071023, P30 DK074038, R01-DK75532, R21 DK071023, R01 DK075532] Funding Source: Medline
- Wellcome Trust [073974] Funding Source: Medline
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Stromal cell-derived factor 1 (SDF-1) plays a major role in the migration, recruitment, and retention of endothelial progenitor cells to sites of ischemic injury and contributes to neovascularization. We provide direct evidence demonstrating an important role for heme oxygenase 1 (HO-1) in mediating the proangiogenic effects of SDF-1. Nanomolar concentrations of SDF-1 induced HO-1 in endothelial cells through a protein kinase C zeta-dependent and vascular endothelial growth factor-independent mechanism. SDF-1-induced endo thelial tube formation and migration was impaired in HO-1-deficient cells. Aortic rings from HO-1(-/-) mice were unable to form capillary sprouts in response to SDF-1, a defect reversed by CO, a byproduct of the HO-1 reaction. Phosphorylation of vasodilator-stimulated phosphoprotein was impaired in HO-1(-/-) cells, an event that was restored by CO. The functional significance of HO-1 in the proangiogenic effects of SDF-1 was confirmed in Matrigel plug, wound healing, and retinal ischemia models in vivo. The absence of HO-1 was associated with impaired wound healing. Intravitreal adoptive transfer of HO-1 deficient endothelial precursors showed defective homing and reendothelialization of the retinal vasculature compared with HO-1 wild-type cells following ischemia. These findings demonstrate a mechanistic role for HO-1 in SDF-1-mediated angiogenesis and provide new avenues for therapeutic approaches in vascular repair.
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