O206	Essential role of medullar high molecular weight FGF2 in the effect of estradiol on reendothelialization - Possible dissociation with EPC mobilization.
1V.Fontaine, 1C.Filipe, 2N.Werner, 1P.Gourdy, 1A.Billon, 1B.Garmy-Susini, 1L.Henrik, 1A.Mugniot, 1F.Bayard, 1H.Prats, 3T.Doetschman, 2G.Nickenig, 1J-F.Arnal
1INSERM U589, Institut L. Bugnard, CHU Rangueil, Toulouse, FR; 2Department of Internal Medicine III, University Hospital of the Saarland, Homburg/Saar, DE; 3Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, US.

17ß-estradiol (E2) accelerates reendothelialization and increases the number of circulating endothelial progenitor cells (EPC), but whether a major growth factor as Fibroblast Growth Factor-2 (FGF2) is involved remains unknown. FGF2 is expressed as both a secreted low MW isoform, and high MW isoforms which are intranuclear, but which respective functions are also unknown. The present study explored the role of FGF2 isoforms in the effect of E2 in a mouse model of reendothelialization, as well as on EPC levels. As previously reported, in ovariectomized wild type (Fgf2+/+) mice, E2 increased both the velocity of reendothelialization and the number of circulating EPCs. In contrast, the effect of E2 was abolished on both parameters in mice deficient in both FGF2lmw and FGF2hmw mice (Fgf2-/-), demonstrating that FGF2 is absolutely required for these stimulating effects of E2. In chimeric mice by grafting Fgf2-/- bone marrow (BM) to Fgf2+/+ (Fgf2-/- BM => Fgf2+/+) mice, the effect of E2 on both reendothelialization and EPC levels was abolished, whereas both effects of E2 in Fgf2+/+ BM => Fgf2-/- mice was similar to that observed in Fgf2+/+ mice, demonstrating only medullar, but not extramedullar, FGF2 is required for both effect of E2. As E2 was found to increase FGF2hmw, but not FGF2lmw, abundance in vascular homogenates, the effect of E2 in mice deficient only in the FGF2lmw (Fgf2lmw-/-) was studied. In these mice, E2 accelerated reendothelialization, but did not increase circulating EPCs. Furthermore, E2 also accelerated reendothelialization in Fgf2lmw+/+ BM => Fgf2-/-. In chimeric green fluorescent protein (GFP)-BM => WT mice, en face confocal microscopy revealed scarce incorporation of BM-derived GFP cells into the regenerated endothelial monolayer in placebo and E2-treated mice. In conclusion, medullar FGF2hmw is necessary and sufficient to mediate the accelerative effect of E2 on reendothelialization. Medullar FGF2lmw is necessary to mediate E2-induced EPC mobilization, although not absolutely required for the acceleration of reendothelialization.

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