Critical Role of Tissue Kallikrein in Vessel Formation and Maturation: Implications for Therapeutic Revascularization
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.
Arteriosclerosis, thrombosis, and vascular biology