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(Circulation Research. 2004;94:1301.)
© 2004 American Heart Association, Inc.

Molecular Medicine

Role of Fibroblast Growth Factor-2 Isoforms in the Effect of Estradiol on Endothelial Cell Migration and Proliferation

B. Garmy-Susini, E. Delmas^*, P. Gourdy^*, M. Zhou, C. Bossard, B. Bugler, F. Bayard, A. Krust, A.C. Prats, T. Doetschman, H. Prats, J.F. Arnal

From INSERM U589 (B.G.-S., E.D., P.G., C.B., B.B., F.B., A.C.P., H.P., J.F.A.), Institut L. Bugnard, CHU Rangueil, Toulouse France; IGBMC (A.K.), Strasbourg, France; and the Department of Molecular Genetics (M.Z., T.D.), Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Correspondence to J.F. Arnal, INSERM U589, Institut L. Bugnard, CHU Rangueil, 31403 Toulouse, France. E-mail arnal{at}toulouse.inserm.fr

Both 17ß-estradiol (E₂) and fibroblast growth factor-2 (FGF2) stimulate angiogenesis and endothelial cell migration and proliferation. The first goal of this study was to explore the potential link between this hormone and this growth factor. E₂-stimulated angiogenesis in SC Matrigel plugs in Fgf2^+/+ mice, but not in Fgf2^–/– mice. Cell cultures from subcutaneous Matrigel plugs demonstrated that E₂ increased both migration and proliferation in endothelial cells from Fgf2^+/+ mice, but not from in Fgf2^–/– mice. Several isoforms of fibroblast growth factor-2 (FGF2) are expressed: the low molecular weight 18-kDa protein (FGF2^lmw) is secreted and activates tyrosine kinase receptors (FGFRs), whereas the high molecular weight (21 and 22 kDa) isoforms (FGF2^hmw) remains intranuclear, but their role is mainly unknown. The second goal of this study was to explore the respective roles of FGF2 isoforms in the effects of E₂. We thus generated mice deficient only in the FGF2^lmw (Fgf2^lmw–/–). E₂ stimulated in vivo angiogenesis and in vitro migration in endothelial cells from Fgf2^lmw–/– as it did in Fgf2^+/+ mice. E₂ increased FGF2^hmw protein abundance in endothelial cell cultures from Fgf2^+/+ and Fgf2^lmw–/– mice. As shown using siRNA transfection, these effects were FGFR independent but involved FGF2-Interacting Factor, an intracellular FGF2^hmw partner. This is the first report for a physiological role for the intracellular FGF2^hmw found to mediate the effect of E₂ on endothelial cell migration via an intracrine action.

Key Words: mouse • estradiol • growth factor • endothelium • migration

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