Osteoprotegerin, a new actor in vasculogenesis, stimulates endothelial colony-forming cells properties
|Author(s)||Benslimane-Ahmim Z., Heymann D.2, 3, Dizier B., Lokajczyk A.4, Brion R.2, Laurendeau I.5, Bieche I.5, Smadja D. M.4, 6, Galy-Fauroux I.4, Colliec-Jouault Sylvia7, Fischer Anne-Marie4, 6, Boisson-Vidal Catherine1|
|Affiliation(s)||1 : Fac Pharm, INSERM, U765, F-75270 Paris 06, France.
2 : INSERM, UMR S 957, Nantes, France.
3 : Nantes Atlantique Univ, Univ Nantes, Nantes, France.
4 : Univ Paris Cite Paris Descartes, Fac Pharm, Paris, France.
5 : INSERM, U745, Genet Mol Lab, Paris, France.
6 : Hop Europeen Georges Pompidou, AP HP, Dept Haematol, Paris, France.
7 : IFREMER, Nantes, France.
|Source||Journal Of Thrombosis And Haemostasis (1538-7933) (Wiley-blackwell), 2011-04 , Vol. 9 , N. 4 , P. 834-843|
|WOS© Times Cited||36|
|Keyword(s)||endothelial colony-forming cells, osteoprotegerin, receptor activator of nuclear factor-kappa B ligand, vasculogenesis|
|Abstract||Background: Osteoprotegerin (OPG), a soluble receptor of the tumour necrosis factor family, and its ligand, the receptor activator of nuclear factor-kappa B ligand (RANKL), are emerging as important regulators of vascular pathophysiology. Objectives: We evaluated their effects on vasculogenesis induced by endothelial colony-forming cells (ECFC) and on neovessel formation in vivo. Methods: Effects of OPG and RANKL on in vitro angiogenesis were evaluated after ECFC incubation with OPG or RANKL (0-50 ng mL(-1)). Effects on microvessel formation were evaluated with an in vivo murin Matrigel plug assay. Vascularization was evaluated by measuring plug hemoglobin and vascular endothelial growth factor (VEGF)-R2 content 14 days after implantation. Results: We found that ECFC expressed OPG and RANK but not RANKL mRNA. Treatment of ECFC with VEGF or stromal cell-derived factor-1 (SDF-1) upregulated OPG mRNA expression. OPG stimulated ECFC migration (P < 0.05), chemotaxis (P < 0.05) and vascular cord formation on Matrigel (R) (P < 0.01). These effects were correlated with SDF-1 mRNA overexpression, which was 30-fold higher after 4 h of OPG stimulation (P < 0.01). OPG-mediated angiogenesis involved the MAPK signaling pathway as well as Akt or mTOR cascades. RANKL also showed pro-vasculogenic effects in vitro. OPG combined with FGF-2 promoted neovessel formation in vivo, whereas RANKL had no effect. Conclusions: OPG induces ECFC activation and is a positive regulator of microvessel formation in vivo. Our results suggest that the OPG/RANK/RANKL axis may be involved in vasculogenesis and strongly support a modulatory role in tissue revascularization.|