PUBLICATION
Critical Role of Tissue Kallikrein in Vessel Formation and Maturation: Implications for Therapeutic Revascularization
- Authors
- Stone, O.A., Richer, C., Emanueli, C., van Weel, V., Quax, P.H., Katare, R., Kraenkel, N., Campagnolo, P., Barcelos, L.S., Siragusa, M., Sala-Newby, G.B., Baldessari, D., Mione, M., Vincent, M.P., Benest, A.V., Al Haj Zen, A., Gonzalez, J., Bates, D.O., Alhenc-Gelas, F., and Madeddu, P.
- ID
- ZDB-PUB-090204-9
- Date
- 2009
- Source
- Arterioscler. Thromb. Vasc. Biol. 29(5): 657-664 (Journal)
- Registered Authors
- Baldessari, Danila, Mione, Marina
- Keywords
- angiogenesis, gene therapy, gene mutations, metalloproteinases, tissue kallikrein
- MeSH Terms
-
- Animals
- Hindlimb/blood supply*
- Humans
- Ischemia/physiopathology
- Kallikrein-Kinin System/physiology
- Male
- Matrix Metalloproteinase 9/physiology
- Mice
- Mice, Knockout
- Neovascularization, Physiologic/physiology*
- Rats
- Splanchnic Circulation/physiology*
- Tissue Kallikreins/physiology*
- Wound Healing/physiology
- Zebrafish
- PubMed
- 19164804 Full text @ Arterioscler. Thromb. Vasc. Biol.
Citation
Stone, O.A., Richer, C., Emanueli, C., van Weel, V., Quax, P.H., Katare, R., Kraenkel, N., Campagnolo, P., Barcelos, L.S., Siragusa, M., Sala-Newby, G.B., Baldessari, D., Mione, M., Vincent, M.P., Benest, A.V., Al Haj Zen, A., Gonzalez, J., Bates, D.O., Alhenc-Gelas, F., and Madeddu, P. (2009) Critical Role of Tissue Kallikrein in Vessel Formation and Maturation: Implications for Therapeutic Revascularization. Arterioscler. Thromb. Vasc. Biol.. 29(5):657-664.
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. 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping