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.
Sarkar
Kakali
K
Department of Medicine, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Suite 671, 733 North Broadway, Baltimore, MD 21205, USA.
Fox-Talbot
Karen
K
Steenbergen
Charles
C
Bosch-Marcé
Marta
M
Semenza
Gregg L
GL
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