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(Circulation Research. 2007;101:1310.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Effects of Aging and Hypoxia-Inducible Factor-1 Activity on Angiogenic Cell Mobilization and Recovery of Perfusion After Limb Ischemia

Marta Bosch-Marce, Hiroaki Okuyama, Jacob B. Wesley, Kakali Sarkar, Hideo Kimura, Ye V. Liu, Huafeng Zhang, Marianne Strazza, Sergio Rey, Lindsey Savino, Yi Fu Zhou, Karin R. McDonald, Youn Na, Scott Vandiver, Alireza Rabi, Yuval Shaked, Robert Kerbel, Theresa LaVallee, Gregg L. Semenza

From the Vascular Biology Program, Institute for Cell Engineering (M.B.-M., H.O., J.B.W., K.S., H.K., Y.V.L., H.Z., M.S., S.R., L.S., Y.F.Z., K.R.M., Y.N., S.V., A.R., G.L.S.); Departments of Pediatrics (G.L.S.), Medicine (K.S., G.L.S.), Oncology (G.L.S.), and Radiation Oncology (G.L.S.); and McKusick-Nathans Institute for Genetic Medicine (Y.F.Z., G.L.S.), The Johns Hopkins University School of Medicine, Baltimore, Md; Department of Molecular and Cellular Biology Research (Y.S., R.K.), Sunnybrook Health Sciences Centre, Toronto, Canada; and EntreMed Inc (T.L.), Rockville, Md.

Correspondence to Gregg L. Semenza, MD, PhD, Broadway Research Building, Suite 671, 733 North Broadway, Baltimore, MD 21205. E-mail gsemenza{at}jhmi.edu

Ischemia is a stimulus for production of angiogenic cytokines that activate local vascular cells and mobilize angiogenic cells to the circulation. These responses are impaired in elderly patients with peripheral arterial disease. Hypoxia-inducible factor (HIF)-1 mediates adaptive responses to ischemia, including production of angiogenic cytokines. In this study, we demonstrate that aging and HIF-1 loss-of-function impair the expression of multiple angiogenic cytokines, mobilization of angiogenic cells, maintenance of tissue viability, and recovery of limb perfusion following femoral artery ligation. We show that HIF-1 directly activates transcription of the gene encoding stem cell factor and that mice lacking the cognate receptor C-KIT have impaired recovery from ischemia. Administration of AdCA5, an adenovirus encoding a constitutively active form of HIF-1, improved the recovery of perfusion in older mice to levels similar to those in young mice. Injection of AdCA5 into nonischemic limb was sufficient to increase the number of circulating angiogenic cells. These results indicate that HIF-1 activity is necessary and sufficient for the mobilization of angiogenic cells and that HIF-1 gene therapy can counteract the pathological effects of aging in a mouse model of limb ischemia.

Key Words: angiogenesis • hypoxia • vascularization