Garmy-Susini B, Delmas E, Gourdy P, Zhou M, Bossard C, Bugler B, Bayard F, Krust A, Prats A C, Doetschman T, Prats H, Arnal J F
INSERM U589, Institut L. Bugnard, CHU Rangueil, 31403 Toulouse, France.
Circ Res. 2004 May 28;94(10):1301-9. doi: 10.1161/01.RES.0000127719.13255.81. Epub 2004 Apr 8.
Both 17beta-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 (FGF2lmw) is secreted and activates tyrosine kinase receptors (FGFRs), whereas the high molecular weight (21 and 22 kDa) isoforms (FGF2hmw) 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 FGF2lmw (Fgf2lmw-/-). E2 stimulated in vivo angiogenesis and in vitro migration in endothelial cells from Fgf2lmw-/- as it did in Fgf2+/+ mice. E2 increased FGF2hmw protein abundance in endothelial cell cultures from Fgf2+/+ and Fgf2lmw-/- mice. As shown using siRNA transfection, these effects were FGFR independent but involved FGF2-Interacting Factor, an intracellular FGF2hmw partner. This is the first report for a physiological role for the intracellular FGF2hmw found to mediate the effect of E2 on endothelial cell migration via an intracrine action.
17β-雌二醇（E2）和成纤维细胞生长因子-2（FGF2）均可刺激血管生成以及内皮细胞迁移和增殖。本研究的首要目标是探究这种激素与这种生长因子之间的潜在联系。E2可刺激Fgf2+/+小鼠皮下基质胶栓中的血管生成，但对Fgf2-/-小鼠无效。皮下基质胶栓的细胞培养表明，E2可增加Fgf2+/+小鼠内皮细胞的迁移和增殖，但对Fgf2-/-小鼠的内皮细胞无效。成纤维细胞生长因子-2（FGF2）有多种亚型表达：低分子量18-kDa蛋白（FGF2lmw）分泌后可激活酪氨酸激酶受体（FGFRs），而高分子量（21和22 kDa）亚型（FGF2hmw）则保留在细胞核内，但其作用主要未知。本研究的第二个目标是探究FGF2亚型在E2作用中的各自作用。因此，我们培育出仅缺乏FGF2lmw的小鼠（Fgf2lmw-/-）。与在Fgf2+/+小鼠中一样，E2可刺激Fgf2lmw-/-小鼠内皮细胞的体内血管生成和体外迁移。E2可增加Fgf2+/+和Fgf2lmw-/-小鼠内皮细胞培养物中FGF2hmw蛋白的丰度。如使用siRNA转染所示，这些作用不依赖FGFR，但涉及细胞内FGF2hmw的伴侣FGF2相互作用因子。这是首次报道细胞内FGF2hmw通过自分泌作用介导E2对内皮细胞迁移的生理作用。
