(Circulation. 2001;103:125.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Local Delivery of Human Tissue Kallikrein Gene Accelerates Spontaneous Angiogenesis in Mouse Model of Hindlimb Ischemia
From the Laboratorio di Patologia Vascolare (C.E., A.M., A.Z., S.S., M.C.C.) and Third Vascular Surgery Division (G.B., F.S.), Istituto Dermopatico dell’Immacolata, Rome, Italy; National Laboratory of the National Institute of Biostructures and Biosystems (C.E., M.B.S., L.G., P.M.), Osilo, Italy; the Institute of Internal Medicine (P.M.) and Department of Pharmaceutical Sciences (M.G.T.), University of Sassari, Sassari, Italy; and the Department of Biochemistry and Molecular Biology (J.C., L.C., R.S.), Medical University of South Carolina, Charleston.
Correspondence to Paolo Madeddu, MD, National Laboratory I.N.B.B., via Brigata Sassari 13, 07033 Osilo (Sassari), Italy. E-mail madeddu{at}yahoo.com
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.
Key Words: gene therapy • angiogenesis • bradykinin • ischemia • muscles
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