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Osteoprotegerin, a new actor in vasculogenesis, stimulates endothelial colony‐forming cells properties
Author(s) -
BENSLIMANEAHMIM Z.,
HEYMANN D.,
DIZIER B.,
LOKAJCZYK A.,
BRION R.,
LAURENDEAU I.,
BIÈCHE I.,
SMADJA D.M.,
GALYFAUROUX I.,
COLLIECJOUAULT S.,
FISCHER A. M.,
BOISSONVIDAL C.
Publication year - 2011
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2011.04207.x
Subject(s) - vasculogenesis , osteoprotegerin , microbiology and biotechnology , chemistry , medicine , biology , progenitor cell , stem cell , receptor , activator (genetics)
Summary. Background: Osteoprotegerin (OPG), a soluble receptor of the tumour necrosis factor family, and its ligand, the receptor activator of nuclear factor‐κB 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 ® ( 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.