New insight into the transcriptional regulation of vascular endothelial growth factor expression in the endometrium by estrogen and relaxin.

Increased uterine capillary permeability, which can be induced by both estrogen and relaxin, is required for endometrial growth and implantation. This effect is mediated in both cases by estrogen receptors (ERs), via stimulation of vascular endothelial growth factor (VEGF) expression. The sites on the VEGF promoter through which induction occurs, however, are completely unclear. We have used the technique of chromatin immunoprecipitation in vivo to localize the site of ER action and identify other transcription factors that are involved. We have found that ERa associates with Sp1/Sp3 at a GC-rich region of the promoter. More interesting, however, is the observation that estrogen also induces rapid, transient binding of hypoxia-inducible factor 1 (HIF-1), which mediates VEGF transcription in response to hypoxia, to the promoter. The estrogen-induced HIF-1 binding closely matches the estrogen-induced pattern of VEGF expression in the uterus, suggesting that HIF-1 is involved in that induction, and probably that of many other genes as well (HIF-1 is now known to regulate the expression of more than 40 genes). It is likely that studies now under way will also link relaxin-induced VEGF expression to HIF-1. This is based on the similarities in the effects of the two hormones on VEGF expression and on their shared ability to activate the PI3K and MAPK pathways, both of which can activate HIF-1.