Constitutively active HIF-1α improves perfusion and arterial remodeling in an endovascular model of limb ischemia

Abstract

Hypoxia-inducible factor 1 (HIF-1) regulates the expression of angiogenic growth factors. We analyzed the effect of intramuscular (i.m.) delivery of AdCA5, an adenovirus encoding a constitutively active form of the HIF-1alpha subunit, in a novel model of limb ischemia. AdCa5 or AdLacZ (6 x 10(8) pfu) was injected into male New Zealand White rabbits that were untreated or subjected to occlusion of the left superficial femoral artery by endovascular coils. Expression of mRNAs was quantified 1, 3, and 7 days after adenovirus injection into rabbits without occlusion. Calf blood pressure (BP), angiography, and immunohistochemical analyses were performed 14 days after arterial occlusion and adenovirus injection. AdCA5 increased the expression of HIF-1alpha, monocyte chemotactic protein-1, placental growth factor, platelet-derived growth factor B, stromal-derived factor 1alpha, and vascular endothelial growth factor (VEGF) mRNA as well as HIF-1alpha and VEGF protein. On day 14, AdCA5-injected limbs showed improved calf BP ratios (0.89+/-0.13 vs. 0.51+/-0.05, p=0.02), angiographic perfusion scores (3.50+/-0.56 vs. 8.33+/-1.31, p=0.007), and distal deep femoral artery diameter ratio (1.84+/-0.25 vs. 0.93+/-0.22, p=0.02) relative to those receiving AdLacZ. The capillary/myocyte ratio (0.93+/-0.03 vs. 0.78+/-0.06, p=0.04) and arterial luminal area (0.32+/-0.05 mm2 vs. 0.21+/-0.03 mm2, p=0.04) were significantly increased in the AdCA5 group. In a model that resembles atherosclerotic obstruction of peripheral arteries in patients, the i.m. administration of AdCA5 promoted arteriogenic and angiogenic responses.