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Cycle‐dependent endometrial expression and hormonal regulation of the fibulin‐1 gene

Fibulin‐1 is a secreted protein associated with elastic matrix fibres and basement membranes. It plays a role in stabilizing blood vessels and can also regulate cell motility and invasiveness. We studied the regulation of the fibulin‐1 gene in the rat and human endometrium, an organ where cyclic tissue remodeling and angiogenesis take place. The rat fibulin‐1C and ‐1D‐specific DNA sequences were first identified and a comparison of the deduced amino acid sequence with the mouse and human counterparts showed a very strong conservation. The exon–intron structure was also maintained. Primers were derived for RT‐PCR analysis of fibulin‐1 expression in rat endometrium. The highest levels of fibulin‐1C and ‐1D transcripts were measured at metestrous and diestrous, and in early pregnancy at day 3 post‐coitum. In vivo studies showed stimulation of endometrial fibulin‐1D expression after estrogen application, an effect prevented by parallel treatment with progesterone. Analysis of human endometrial tissues indicated that the fibulin‐1D transcript levels were higher during the mid‐secretory phase than during the proliferative and early secretory phases. Cultured human endometrial stromal cells treated with progesterone responded with a dramatic increase of fibulin‐1 protein expression. This was enhanced by parallel treatment with epidermal growth factor and prevented by application of the antiprogestin RU486. Altogether the results show a cycle‐dependent regulation of endometrial fibulin‐1 expression controlled by both progesterone and estrogen. Based on its implication in tissue remodeling and angiogenesis, fibulin‐1 may play an important role in endometrial receptivity for embryo implantation. Mol. Reprod. Dev. 68: 279–287, 2004. © 2004 Wiley‐Liss, Inc.