on January 22, 2009
Published online before print January 22, 2009, doi: 10.1161/ATVBAHA.108.182139
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on December 5, 2008
Accepted on January 9, 2009
Critical Role of Tissue Kallikrein in Vessel Formation and Maturation. Implications for Therapeutic Revascularization
Oliver A. Stone ;
From the Microvascular Research Laboratories, Bristol Heart Institute, Department of Physiology and Pharmacology (O.A.S., A.V.B., D.O.B.), University of Bristol, UK; INSERM U652/U872, Centre de Recherche des Cordeliers (C.R., M.P.V., F.A.-G), Paris, France; Experimental Cardiovascular Medicine (C.E., R.K., N.K., P.C., L.S.B., M.S., A.A.H.Z., P.M.) and Vascular Biology Division (G.B.S.-N), Bristol Heart Institute, University of Bristol, UK; The Gaubius Laboratory TNO Quality of Life (V.v.W., P.H.A.Q.), Leiden, the Netherlands; Department of Surgery (V.v.W., P.H.A.Q.), Leiden University Medical Center, Leiden, the Netherlands; IFOM, Fondazione Istituto FIRC di Oncologia Molecolare (D.B., M.M.), Milan, Italy; and I2MR INSERM U858 (J.G.), Toulouse, France.
* To whom correspondence should be addressed. E-mail: madeddu{at}yahoo.com.
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.
Key words: angiogenesis • gene therapy • gene mutations • metalloproteinases • tissue kallikrein
Related Article:
- Kallikrein–Kinin System in Neovascularization
- Michael Bader
Arterioscler Thromb Vasc Biol 2009 29: 617-619.[Extract] [Full Text] [PDF]
This article has been cited by other articles:
 |
|
 |
|
  M. Bader Kallikrein-Kinin System in Neovascularization Arterioscler Thromb Vasc Biol, May 1, 2009; 29(5): 617 - 619. [Full Text] [PDF]
|
|