Essential role of bone marrow fibroblast growth factor-2 in the effect of estradiol on reendothelialization and endothelial progenitor cell mobilization.
17beta-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.
Fontaine
Vincent
V
INSERM U589, Institut L. Bugnard, Centre Hospitalier Universitaire Rangueil, Toulouse Cedex, France.
Filipe
Cédric
C
Werner
Nikos
N
Gourdy
Pierre
P
Billon
Audrey
A
Garmy-Susini
Barbara
B
Brouchet
Laurent
L
Bayard
Francis
F
Prats
Hervé
H
Doetschman
Thomas
T
Nickenig
Georg
G
Arnal
Jean-François
JF
D000818:Animals; D001011:Aorta / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects*; D016026:Bone Marrow Transplantation; D002339:Carotid Arteries / Q000166:cytology / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects*; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*
D020033:Protein Isoforms; D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2; D004958:Estradiol