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(American Journal of Pathology. 2006;169:1855-1862.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060260

Essential Role of Bone Marrow Fibroblast Growth Factor-2 in the Effect of Estradiol on Reendothelialization and Endothelial Progenitor Cell Mobilization

Vincent Fontaine^*, Cédric Filipe^*, Nikos Werner, Pierre Gourdy^*, Audrey Billon^*, Barbara Garmy-Susini^*, Laurent Brouchet^*, Francis Bayard^*, Hervé Prats^*, Thomas Doetschman, Georg Nickenig^* and Jean-François Arnal^*

From INSERM U589,^* Institut L. Bugnard, Centre Hospitalier Universitaire Rangueil, Toulouse Cedex, France; Department of Internal Medicine III, University Hospital of the Saarland, Homburg/Saar, Germany; and Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio

17ß-Estradiol (E₂) accelerates reendothelialization and increases the number of circulating endothelial progenitor cells (EPCs), but whether fibroblast growth factor-2 (FGF2) is involved in these processes remains unknown. Here we explored the role of FGF2 in the effect of E₂ on reendothelialization and EPC levels in a mouse model. As previously reported, E₂ increased both the velocity of reendothelialization and the number of circulating EPCs in ovariectomized wild-type (Fgf2^+/+) mice. In contrast, the effect of E₂ on both parameters was abolished in FGF2-deficient mice (Fgf2^–/–), demonstrating that FGF2 is absolutely required for these effects of E₂. To test the implication of medullary and extramedullary FGF2, we developed chimeric mice by grafting Fgf2^–/– bone marrow to Fgf2^+/+ [Fgf2^–/– bone marrow (BM) = >Fgf2^+/+] mice and observed that the effect of E₂ on both reendothelialization and EPC levels was abolished. In contrast, both effects of E₂ in Fgf2^+/+BM = >Fgf2^–/– mice were similar to those observed in Fgf2^+/+ mice, demonstrating that only BM-derived, but not extramedullary, FGF2 is required for both effects. Interestingly, E₂ was found to markedly increase both FGF2^lmw and FGF2^hmw in bone marrow. In conclusion, FGF2, specifically medullary FGF2, is necessary and sufficient to mediate the accelerative effect of E₂ on both reendothelialization and EPC mobilization.

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