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.