Osteoprotegerin, a new actor in vasculogenesis, stimulates endothelial colony-forming cells properties

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.

Keyword(s)

endothelial colony-forming cells, osteoprotegerin, receptor activator of nuclear factor-kappa B ligand, vasculogenesis

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Benslimane-Ahmim Z., Heymann D., Dizier B., Lokajczyk A., Brion R., Laurendeau I., Bieche I., Smadja D. M., Galy-Fauroux I., Colliec-Jouault Sylvia, Fischer Anne-Marie, Boisson-Vidal Catherine (2011). Osteoprotegerin, a new actor in vasculogenesis, stimulates endothelial colony-forming cells properties. Journal Of Thrombosis And Haemostasis. 9 (4). 834-843. https://doi.org/10.1111/j.1538-7836.2011.04207.x, https://archimer.ifremer.fr/doc/00033/14462/

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