Local delivery of human tissue kallikrein gene accelerates spontaneous angiogenesis in mouse model of hindlimb ischemia

Background-Human tissue kallikrein (HK) releases kinins from kininogen. We investigated whether adenovirus-mediated HK gene delivery is angiogenic in the context of ischemia. Methods and Results-Hindlimb ischemia, caused by femoral artery excision, increased muscular capillary density (P<0.001) and induced the expression of kinin B-1 receptor gene (P<0.05). Pharmacological blockade of B-1 receptors blunted ischemia-induced angiogenesis (P<0.01), whereas kinin B-1 receptor antagonism was ineffective. Intramuscular delivery of adenovirus containing the HK gene (Ad.CMV-cHK) enhanced the increase in capillary density caused by ischemia (969+/-32 versus 541+/-18 capillaries/mm(2) for control, P<0.001), accelerated blood flow recovery (P<0.01), and preserved energetic charge of ischemic muscle (P<0.01), Chronic blockade of kinin B-1 or B-2 receptors prevented HK-induced angiogenesis. Conclusions-HK gene delivery enhances the native angiogenic response to ischemia, Angiogenesis gene therapy with HK might be applicable to peripheral occlusive vascular disease.