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
Biology
Biomedical Research
Angiogenesis
Gene mutations
Gene therapy
Metalloproteinases
Animals
Hindlimb
Humans
Ischemia
Kallikrein-Kinin System
Male
Matrix Metalloproteinase 9
Mice
Mice, Knockout
Neovascularization, Physiologic
Rats
Splanchnic Circulation
Tissue Kallikreins
Wound Healing
Zebrafish
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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