title: Critical role of tissue kallikrein in vessel formation and maturation: implications for therapeutic revascularization.
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.
  
  
  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.
authors.affiliation: Microvascular Research Laboratories, Bristol Heart Institute, Department of Physiology and Pharmacology, University of Bristol, UK.
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Stone
authors.forename: Christine
authors.initials: C
authors.lastname: Richer
authors.forename: Costanza
authors.initials: C
authors.lastname: Emanueli
authors.forename: Vincent
authors.initials: V
authors.lastname: van Weel
authors.forename: Paul H A
authors.initials: PH
authors.lastname: Quax
authors.forename: Rajesh
authors.initials: R
authors.lastname: Katare
authors.forename: Nicolle
authors.initials: N
authors.lastname: Kraenkel
authors.forename: Paola
authors.initials: P
authors.lastname: Campagnolo
authors.forename: Luciola S
authors.initials: LS
authors.lastname: Barcelos
authors.forename: Mauro
authors.initials: M
authors.lastname: Siragusa
authors.forename: Graciela B
authors.initials: GB
authors.lastname: Sala-Newby
authors.forename: Danila
authors.initials: D
authors.lastname: Baldessari
authors.forename: Marina
authors.initials: M
authors.lastname: Mione
authors.forename: Marie P
authors.initials: MP
authors.lastname: Vincent
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Benest
authors.forename: Ayman
authors.initials: A
authors.lastname: Al Haj Zen
authors.forename: Julien
authors.initials: J
authors.lastname: Gonzalez
authors.forename: David O
authors.initials: DO
authors.lastname: Bates
authors.forename: Francois
authors.initials: F
authors.lastname: Alhenc-Gelas
authors.forename: Paolo
authors.initials: P
authors.lastname: Madeddu
mesh_terms: D000818:Animals; D006614:Hindlimb / Q000098:blood supply*; D006801:Humans; D007511:Ischemia / Q000503:physiopathology; D016234:Kallikrein-Kinin System / Q000502:physiology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D051381:Rats; D013152:Splanchnic Circulation / Q000502:physiology*; D020840:Tissue Kallikreins / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology; D015027:Zebrafish
chemical_list: D020840:Tissue Kallikreins; D020780:Matrix Metalloproteinase 9