TY - JOUR
T1 - Critical role of tissue kallikrein in vessel formation and maturation
T2 - Implications for therapeutic revascularization
AU - Stone, Oliver A.
AU - Richer, Christine
AU - Emanueli, Costanza
AU - Van Weel, Vincent
AU - Quax, Paul H.A.
AU - Katare, Rajesh
AU - Kraenkel, Nicolle
AU - Campagnolo, Paola
AU - Barcelos, Luciola S.
AU - Siragusa, Mauro
AU - Sala-Newby, Graciela B.
AU - Baldessari, Danila
AU - Mione, Marina
AU - Vincent, Marie P.
AU - Benest, Andrew V.
AU - Al Haj Zen, Ayman
AU - Gonzalez, Julien
AU - Bates, David O.
AU - Alhenc-Gelas, Francois
AU - Madeddu, Paolo
PY - 2009/5
Y1 - 2009/5
N2 - 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.
AB - 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.
KW - Angiogenesis
KW - Gene mutations
KW - Gene therapy
KW - Metalloproteinases
KW - Tissue kallikrein
UR - http://www.scopus.com/inward/record.url?scp=65549102213&partnerID=8YFLogxK
U2 - 10.1161/ATVBAHA.108.182139
DO - 10.1161/ATVBAHA.108.182139
M3 - Article
C2 - 19164804
AN - SCOPUS:65549102213
SN - 1079-5642
VL - 29
SP - 657
EP - 664
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 5
ER -