Print Email Facebook Twitter Critical role of tissue kallikrein in vessel formation and maturation: Implications for therapeutic revascularization Title Critical role of tissue kallikrein in vessel formation and maturation: Implications for therapeutic revascularization Author Stone, O.A. Richer, C. Emanueli, C. van Weel, V. Quax, P.H.A. Katare, R. Kraenkel, N. Campagnolo, P. Barcelos, L.S. Siragusa, M. Sala-Newby, G.B. Baldessari, D. Mione, M. Vincent, M.P. Benest, A.V. Al Haj Zen, A. Gonzalez, J. Bates, D.O. Alhenc-Gelas, F. Madeddu, P. TNO Kwaliteit van Leven Publication year 2009 Abstract 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. © 2009 American Heart Association, Inc. Subject BiologyBiomedical ResearchAngiogenesisGene mutationsGene therapyMetalloproteinasesAnimalsHindlimbHumansIschemiaKallikrein-Kinin SystemMaleMatrix Metalloproteinase 9MiceMice, KnockoutNeovascularization, PhysiologicRatsSplanchnic CirculationTissue KallikreinsWound HealingZebrafish To reference this document use: http://resolver.tudelft.nl/uuid:d3b76c74-76bd-4b53-a002-115756dbe4bf DOI https://doi.org/10.1161/atvbaha.108.182139 TNO identifier 241518 ISSN 1079-5642 Source Arteriosclerosis, Thrombosis, and Vascular Biology, 29 (5), 657-664 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.