Effects of aging and hypoxia-inducible factor-1 activity on angiogenic cell mobilization and recovery of perfusion after limb ischemia.
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-1alpha, 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-1alpha gene therapy can counteract the pathological effects of aging in a mouse model of limb ischemia.
Bosch-Marce
Marta
M
Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Okuyama
Hiroaki
H
Wesley
Jacob B
JB
Sarkar
Kakali
K
Kimura
Hideo
H
Liu
Ye V
YV
Zhang
Huafeng
H
Strazza
Marianne
M
Rey
Sergio
S
Savino
Lindsey
L
Zhou
Yi Fu
YF
McDonald
Karin R
KR
Na
Youn
Y
Vandiver
Scott
S
Rabi
Alireza
A
Shaked
Yuval
Y
Kerbel
Robert
R
Lavallee
Theresa
T
Semenza
Gregg L
GL
D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D007511:Ischemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D035002:Lower Extremity / Q000098:blood supply* / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D015424:Reperfusion / Q000379:methods
D051793:Hypoxia-Inducible Factor 1