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-CYCLEAND DECREASED FGF-R1 EXPRESSION IN MENORRHAGIA

Angiogenic growth factors play a critical role in the cyclic growth an d vascularization of normal endometrium. Herein, we report the express ion and localization of both basic fibroblast growth factor (FGF-2) an d its receptor (FGF-R1; flg) in human endometrium and demonstrate the markedly decreased FGF-R1 levels in menorrhagia. In situ hybridization using [S-35]-labeled riboprobe demonstrated distinct autoradiographic signals for FGF-2 mRNA in glandular epithelial and stromal cells in e ndometrium throughout the menstrual cycle, with the strongest hybridiz ation signal in stromal cells of the proliferative endometrium relativ e to that of the secretory endometrium. Moreover, RNAse protection ass ay 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 int ensity of FGF-R1 staining was markedly diminished in the stromal cells of secretory endometrium, which corresponded with the reduced FGF-2 m RNA expression. In contrast, the endometrial glandular epithelial cell s showed intense localization of FGF-R1 protein throughout the menstru al cycle, which paralleled FGF-2 mRNA expression. Colocalization of FG F-2 and FGF-R1 in stroma and stimulation of DNA synthesis and phosphol ipase C activation by FGF-2 in these cells demonstrates that FGF-2 act s in an autocrine manner in endometrial stroma. Western immunoblotting showed that FGF-R1 immunoprotein was markedly reduced or absent in wo men with menorrhagia throughout the cycle relative to that of normal c ycling women, suggesting that FGF-R1 is critical for endometrial ''mat uration'' and regeneration of the normal endometrium following menstru ation.