Published Online
on November 26, 2007

A more recent version of this article appeared on December 11, 2007

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Submitted on May 16, 2007
Accepted on September 28, 2007

Age Decreases Endothelial Progenitor Cell Recruitment Through Decreases in Hypoxia-Inducible Factor 1 Stabilization During Ischemia

Eric I. Chang MD, Shang A. Loh MD, Daniel J. Ceradini MD, Edward I. Chang MD, Shin-e Lin MD, Nicholas Bastidas MD, Shahram Aarabi MD, Denise A. Chan PhD, Michael L. Freedman MD, Amato J. Giaccia PhD, and Geoffrey C. Gurtner MD^*

From the Department of Surgery (Eric I. Chang, S.A.L., D.J.C., Edward I. Chang, S.L., N.B., S.A., G.C.G.) and Department of Radiation Biology (D.A.C., A.J.G.), Stanford University, Stanford, Calif; and Department of Medicine (M.L.F.), New York University, New York, NY.

^* To whom correspondence should be addressed. E-mail: ggurtner{at}stanford.edu.

Background—Advanced age is known to impair neovascularization. Because endothelial progenitor cells (EPCs) participate in this process, we examined the effects of aging on EPC recruitment and vascular incorporation.

Methods and Results—Murine neovascularization was examined by use of an ischemic flap model, which demonstrated aged mice (19 to 24 months) had decreased EPC mobilization (percent mobilized 1.4±0.2% versus 0.4±0.1%, P<0.005) that resulted in impaired gross tissue survival compared with young mice (2 to 6 months). This decrease correlated with diminished tissue perfusion (P<0.005) and decreased CD31⁺ vascular density (P<0.005). Gender-mismatched bone marrow transplantation demonstrated significantly fewer chimeric vessels in aged mice (P<0.05), which confirmed a deficit in bone marrow–mediated vasculogenesis. Age had no effect on total EPC number in mice or humans. Reciprocal bone marrow transplantations confirmed that impaired neovascularization resulted from defects in the response of aged tissue to hypoxia and not from intrinsic defects in EPC function. We demonstrate that aging decreased hypoxia-inducible factor 1 stabilization in ischemic tissues because of increased prolyl hydroxylase–mediated hydroxylation (P<0.05) and proteasomal degradation. This resulted in a diminished hypoxia response, including decreased stromal cell–derived factor 1 (P<0.005) and vascular endothelial growth factor (P<0.0004). This effect can be reversed with the iron chelator deferoxamine, which results in hypoxia-inducible factor 1 stabilization and increased tissue survival.

Conclusions—Aging impairs EPC trafficking to sites of ischemia through a failure of aged tissues to normally activate the hypoxia-inducible factor 1–mediated hypoxia response.

Key words: aging • vasculogenesis • hypoxia • ischemia

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