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 B 1 receptor gene ( P <0.05). Pharmacological blockade of B 1 receptors blunted ischemia-induced angiogenesis ( P <0.01), whereas kinin B 2 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.