Age decreases endothelial progenitor cell recruitment through decreases in hypoxia-inducible factor 1alpha stabilization during ischemia.
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.


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 1alpha 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 1alpha 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 1alpha-mediated hypoxia response.
Department of Surgery, Stanford University, Stanford, CA 94305, USA.
Eric I
EI
Chang
Shang A
SA
Loh
Daniel J
DJ
Ceradini
Edward I
EI
Chang
Shin-e
SE
Lin
Nicholas
N
Bastidas
Shahram
S
Aarabi
Denise A
DA
Chan
Michael L
ML
Freedman
Amato J
AJ
Giaccia
Geoffrey C
GC
Gurtner
D000375:Aging / Q000502:physiology; D000818:Animals; D016026:Bone Marrow Transplantation; D004730:Endothelium, Vascular / Q000254:growth & development / Q000502:physiology*; D019650:Hematopoietic Stem Cell Mobilization; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D051379:Mice; D023421:Models, Animal; D017202:Myocardial Ischemia / Q000601:surgery; D016038:Skin Transplantation; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D013524:Surgical Flaps
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit