The Journal of Experimental Medicine
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Published online March 5, 2007
doi:10.1084/jem.20061609
The Journal of Experimental Medicine, Vol. 204, No. 3, 605-618
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Deshane et al.
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ARTICLE

 Stromal cell–derived factor 1 promotes angiogenesis via a heme oxygenase 1–dependent mechanism

Jessy Deshane1,2, Sifeng Chen1, Sergio Caballero6, Anna Grochot-Przeczek7, Halina Was7, Sergio Li Calzi6, Radoslaw Lach7, Thomas D. Hock1,2, Bo Chen1, Nathalie Hill-Kapturczak1, Gene P. Siegal3,4,5, Jozef Dulak7, Alicja Jozkowicz7, Maria B. Grant6, and Anupam Agarwal1,2

1 Department of Medicine, Nephrology Research and Training Center and Center for Free Radical Biology, 2 Department of Biochemistry and Molecular Genetics, 3 Department of Pathology, 4 Department of Cell Biology, and 5 Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294
6 Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, 32610
7 Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 31-007 Krakow, Poland

CORRESPONDENCE Anupam Agarwal: agarwal{at}uab.edu

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 endothelial 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.

Abbreviations used: CORM, CO-releasing molecule; DiI-Ac-LDL, 1,1'-dioctadecyl 3,3,3',3'-tetramethylindocarbocyanine perchlorate; CXCR, CXC chemokine receptor; EPC, endothelial progenitor cell; HAEC and MAEC, human and mouse aortic endothelial cell, respectively; HO-1, heme oxygenase 1; PKC, protein kinase C; SDF-1, stromal cell–derived factor 1; VASP, vasodilator-stimulated phosphoprotein; VEGF, vascular endothelial growth factor; ZnPP, zinc protoporphyrin.


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