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.


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.
Stone
Oliver A
OA
Microvascular Research Laboratories, Bristol Heart Institute, Department of Physiology and Pharmacology, University of Bristol, UK.
Richer
Christine
C
Emanueli
Costanza
C
van Weel
Vincent
V
Quax
Paul H A
PH
Katare
Rajesh
R
Kraenkel
Nicolle
N
Campagnolo
Paola
P
Barcelos
Luciola S
LS
Siragusa
Mauro
M
Sala-Newby
Graciela B
GB
Baldessari
Danila
D
Mione
Marina
M
Vincent
Marie P
MP
Benest
Andrew V
AV
Al Haj Zen
Ayman
A
Gonzalez
Julien
J
Bates
David O
DO
Alhenc-Gelas
Francois
F
Madeddu
Paolo
P
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
D020840:Tissue Kallikreins; D020780:Matrix Metalloproteinase 9