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

Abstract

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 B1 receptor gene (P<0.05). Pharmacological blockade of B1 receptors blunted ischemia-induced angiogenesis (P<0.01), whereas kinin B2 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/mm2 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 B1 or B2 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.