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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:2379.)
© 2000 American Heart Association, Inc.

Vascular Biology

Adenovirus-Mediated Human Tissue Kallikrein Gene Delivery Induces Angiogenesis in Normoperfused Skeletal Muscle

Costanza Emanueli; Antonella Zacheo; Alessandra Minasi; Julie Chao; Lee Chao; Maria Bonaria Salis; Tiziana Stacca; Stefania Straino; Maurizio C. Capogrossi; Paolo Madeddu

From the Laboratorio di Patologia Vascolare (C.E., A.Z., A.M., M.B.S., S.S., M.C.C., P.M.), Istituto Dermopatico dell’ Immacolata (IDI-IRCCS), Rome; the National Laboratory of the National Institute of Biostructures and Biosystems (C.E., M.B.S., T.S., P.M.), Osilo; and the Institute of Internal Medicine (P.M.), Medical University of Sassari, Sassari, Italy; and the Department of Biochemistry and Molecular Biology (J.C., L.C.), Medical University of South Carolina, Charleston.

Correspondence to Paolo Madeddu, MD, National Laboratory of the National Institute of Biostructures and Biosystems (INBB), Via Brigata Sassari, 13 07033 Osilo, Sassari, Italy. E-mail madeddu{at}yahoo.com

Abstract—We investigated whether local delivery of the tissue kallikrein gene induces angiogenesis in normoperfused mouse hindlimb muscles. Intramuscular injection of adenovirus containing the human tissue kallikrein gene under the control of a cytomegalovirus enhancer/promoter sequence resulted in local production and release of recombinant human tissue kallikrein, whereas transgene expression was absent in muscles of the contralateral hindlimb. Angiogenesis in infected muscles was documented by histological evidence of increased capillary density. In contrast, no angiogenic effect was seen either in the ipsilateral gastrocnemius or contralateral hindlimb muscles. Neovascularization was associated with a transient increase in muscular blood flow as determined by laser Doppler flowmetry. We also investigated the mechanisms of kallikrein-induced angiogenesis. We found that the angiogenic response to kallikrein was abolished by chronic blockade of the kinin B₁ or B₂ receptor or by inhibition of nitric oxide synthase. In addition, inhibition of cyclooxygenase-2 by nimesulide significantly reduced kallikrein-induced effects. These results indicate that (1) human tissue kallikrein acts as an angiogenic factor in normoperfused skeletal muscle and (2) nitric oxide and prostacyclin are essential mediators of kallikrein-induced angiogenesis. Our findings provide new insights into the role of the tissue kallikrein-kinin system in vascular biology.

Key Words: gene delivery • angiogenesis • kallikrein • kinins • nitric oxide

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