Fibroblast growth factor receptor-1 is a critical component for endometrial remodeling: localization and expression of basic fibroblast growth factor and FGF-R1 in human endometrium during the menstrual cycle and decreased FGF-R1 expression in menorrhagia

Angiogenic growth factors play a critical role in the cyclic growth and vascularization of normal endometrium. Herein, we report the expression and localization of both basic fibroblast growth factor (FGF-2) and its receptor (FGF-R1; flg) in human endometrium and demonstrate the markedly decreased FGF-R1 levels in menorrhagia. In situ hybridization using [35S]-labeled riboprobe demonstrated distinct autoradiographic signals for FGF-2 mRNA in glandular epithelial and stromal cells in endometrium throughout the menstrual cycle, with the strongest hybridization signal in stromal cells of the proliferative endometrium relative to that of the secretory endometrium. Moreover, RNAse protection assay revealed that the mRNA encoding FGF-2 and FGF-R1 was significantly higher in proliferative than in secretory endometrium (p < 0.05, p < 0.01). Immunohistochemistry using anti-flg antibody showed that the intensity of FGF-R1 staining was markedly diminished in the stromal cells of secretory endometrium, which corresponded with the reduced FGF-2 mRNA expression. In contrast, the endometrial glandular epithelial cells showed intense localization of FGF-R1 protein throughout the menstrual cycle, which paralleled FGF-2 mRNA expression. Colocalization of FGF-2 and FGF-R1 in stroma and stimulation of DNA synthesis and phospholipase C activation by FGF-2 in these cells demonstrates that FGF-2 acts in an autocrine manner in endometrial stroma. Western immunoblotting showed that FGF-R1 immunoprotein was markedly reduced or absent in women with menorrhagia throughout the cycle relative to that of normal cycling women, suggesting that FGF-R1 is critical for endometrial "maturation" and regeneration of the normal endometrium following menstruation.