Critical Role of Tissue Kallikrein in Vessel Formation and Maturation

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Abstract
Objective—Human Tissue Kallikrein (hKLK1) overexpression promotes an enduring neovascularization of ischemic tissue, yet the cellular mechanisms ofhKLK1-induced arteriogenesis remain unknown. Furthermore, no previous study has compared the angiogenic potency ofhKLK1, with its loss of function polymorphic variant, rs5515 (R53H), which possesses reduced kinin-forming activity.Methods and Results—Here, we demonstrate thattissue kallikreinknockout mice (KLK1−/−) show impaired muscle neovascularization in response to hindlimb ischemia. Gene-transfer of wild-typeAd.hKLK1but notAd.R53H-hKLK1was able to rescue this defect. Similarly, in the rat mesenteric assay,Ad.hKLK1induced a mature neovasculature with increased vessel diameter through kinin-B2receptor-mediated recruitment of pericytes and vascular smooth muscle cells, whereasAd.R53H-hKLK1was ineffective. Moreover,hKLK1but notR53H-hKLK1overexpression in the zebrafish induced endothelial precursor cell migration and vascular remodeling. Furthermore,Ad.hKLK1activates metalloproteinase (MMP) activity in normoperfused muscle and fails to promote reparative neovascularization in ischemicMMP9−/−mice, whereas its proarteriogenic action was preserved inApoE−/−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 byhKLK1overexpression.