Adenoviral transfer of HIF-1alpha enhances vascular responses to critical limb ischemia in diabetic mice.
Diabetes is a major risk factor for ischemic disease. Treatment options for diabetic patients with peripheral arterial disease when revascularization is not possible are limited, resulting in a high incidence of limb amputation. We evaluated the therapeutic potential of AdCA5, an adenovirus encoding a constitutively active form of HIF-1alpha, in a diabetic model of critical limb ischemia. Diabetic db/db and nondiabetic db/+ mice were subjected to unilateral femoral artery ligation. Limb perfusion, tissue viability, and motor function were more severely impaired in db/db mice. Intramuscular injection of AdCA5 into the ischemic limb of db/db mice increased the recovery of limb perfusion and function, reduced tissue necrosis, rescued the diabetes-associated impairment of circulating angiogenic cells, enhanced endothelial nitric oxide synthase activation, and increased vessel density and luminal area in the ischemic limb.
Department of Medicine, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Suite 671, 733 North Broadway, Baltimore, MD 21205, USA.
Kakali
K
Sarkar
Karen
K
Fox-Talbot
Charles
C
Steenbergen
Marta
M
Bosch-Marcé
Gregg L
GL
Semenza
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D005121:Extremities / Q000098:blood supply* / Q000473:pathology; D005263:Femoral Artery / Q000601:surgery; D015316:Genetic Therapy; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007511:Ischemia / Q000150:complications / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D008026:Ligation; D051379:Mice; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D015398:Signal Transduction
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D052250:Nitric Oxide Synthase Type III