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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:657.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Critical Role of Tissue Kallikrein in Vessel Formation and Maturation

Implications for Therapeutic Revascularization

Oliver A. Stone; Christine Richer; Costanza Emanueli; Vincent van Weel; Paul H.A. Quax; Rajesh Katare; Nicolle Kraenkel; Paola Campagnolo; Luciola S. Barcelos; Mauro Siragusa; Graciela B. Sala-Newby; Danila Baldessari; Marina Mione; Marie P. Vincent; Andrew V. Benest; Ayman Al Haj Zen; Julien Gonzalez; David O. Bates; Francois Alhenc-Gelas; Paolo Madeddu

From the Microvascular Research Laboratories, Bristol Heart Institute, Department of Physiology and Pharmacology (O.A.S., A.V.B., D.O.B.), University of Bristol, UK; INSERM U652/U872, Centre de Recherche des Cordeliers (C.R., M.P.V., F.A.-G), Paris, France; Experimental Cardiovascular Medicine (C.E., R.K., N.K., P.C., L.S.B., M.S., A.A.H.Z., P.M.) and Vascular Biology Division (G.B.S.-N), Bristol Heart Institute, University of Bristol, UK; The Gaubius Laboratory TNO Quality of Life (V.v.W., P.H.A.Q.), Leiden, the Netherlands; Department of Surgery (V.v.W., P.H.A.Q.), Leiden University Medical Center, Leiden, the Netherlands; IFOM, Fondazione Istituto FIRC di Oncologia Molecolare (D.B., M.M.), Milan, Italy; and I2MR INSERM U858 (J.G.), Toulouse, France.

Correspondence to Prof Paolo Madeddu, Experimental Cardiovascular Medicine, Bristol Heart Institute, Level 7, Bristol Royal Infirmary, Upper Maudlin Street, University of Bristol, Bristol, BS2 8HW, United Kingdom. E-mail madeddu{at}yahoo.com

Objective— Human Tissue Kallikrein (hKLK1) overexpression promotes an enduring neovascularization of ischemic tissue, yet the cellular mechanisms of hKLK1-induced arteriogenesis remain unknown. Furthermore, no previous study has compared the angiogenic potency of hKLK1, with its loss of function polymorphic variant, rs5515 (R53H), which possesses reduced kinin-forming activity.

Methods and Results— Here, we demonstrate that tissue kallikrein knockout mice (KLK1^–/–) show impaired muscle neovascularization in response to hindlimb ischemia. Gene-transfer of wild-type Ad.hKLK1 but not Ad.R53H-hKLK1 was able to rescue this defect. Similarly, in the rat mesenteric assay, Ad.hKLK1 induced a mature neovasculature with increased vessel diameter through kinin-B₂ receptor-mediated recruitment of pericytes and vascular smooth muscle cells, whereas Ad.R53H-hKLK1 was ineffective. Moreover, hKLK1 but not R53H-hKLK1 overexpression in the zebrafish induced endothelial precursor cell migration and vascular remodeling. Furthermore, Ad.hKLK1 activates metalloproteinase (MMP) activity in normoperfused muscle and fails to promote reparative neovascularization in ischemic MMP9^–/– mice, whereas its proarteriogenic action was preserved in ApoE^–/– mice, an atherosclerotic model of impaired angiogenesis.

Conclusions— These results demonstrate the fundamental role of endogenous Tissue Kallikrein in vascular repair and provide novel information on the cellular and molecular mechanisms responsible for the robust arterialization induced by hKLK1 overexpression.

Key Words: angiogenesis • gene therapy • gene mutations • metalloproteinases • tissue kallikrein

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