Acute Temporal Regulation of Vascular Endothelial Growth/Permeability Factor Expression and Endothelial Morphology in the Baboon Endometrium by Ovarian Steroids

Abstract

We recently showed that endometrial vascular endothelial growth/permeability factor (VEG/PF) mRNA expression was decreased by ovariectomy of baboons and restored by chronic administration of estrogen. However, it remains to be determined whether this effect of estrogen reflects genomic up-regulation of VEG/PF and leads to an increase in microvascular permeability, an early physiological event in angiogenesis. Therefore, we determined the temporal expression of VEG/PF mRNA in glandular epithelial and stromal cells isolated by laser capture microdissection from and width of microvascular paracellular clefts that regulate vessel permeability in the endometrium of ovariectomized baboons after acute estradiol and/or progesterone administration. Endometrial VEG/PF mRNA levels were increased in five of five animals within 2 h of estradiol administration and remained elevated at 4 and 6 h. The net increase in glandular epithelial (7.31 +/- 2.72 attomol/fmol 18S ribosomal rRNA) and stromal (3.13 +/- 0.36) cell VEG/PF mRNA levels after estradiol administration was over 8-fold (P < 0.05) and 2.6-fold (P < 0.01) greater, respectively, than after vehicle (0.90 +/- 0.30, glands and 1.20 +/- 0.33, stroma). In contrast, endometrial VEG/PF mRNA expression was unaltered by progesterone. After estradiol treatment, endometrial paracellular cleft width was increased (P < 0.01) from a mean (+/-SE) of 71.6 +/- 4.6 nm at 0 h to 101.1 +/- 6.4 nm at 6 h, whereas vehicle or progesterone had no effect. We suggest that estrogen has a major role in regulating VEG/PF synthesis and early events in angiogenesis in the primate endometrium.

Recent advances in endometrial angiogenesis research

“…It is well known that oestrogen stimulates an increase in uterine blood flow and vasodilation. In baboons, oestrogen treatment significantly increased the paracellular cleft width between endometrial endothelial cells within 6 h [32]. The increase in cleft width and apparent opening of tight junctions between endothelial cells was considered to result in the increased vascular permeability associated with oestrogen administration.…”

“…Unlike oestrogen, the angiogenic effects of progesterone are believed to occur without concurrent vasodilation [33]. There was no change in endometrial endothelial paracellular cleft width 6 h after progesterone treatment in baboons [32]. Further research is needed to elucidate the mechanisms and pathways by which progesterone acts to promote endometrial angiogenesis, including its interaction with PRA and/or PRB in endometrial endothelial cells.…”

Conceptus-mediated endometrial vascular changes during early pregnancy in mares: an anatomic, histomorphometric, and vascular endothelial growth factor receptor system immunolocalization and gene expression study

“…The nature of the signals responsible for induction and control of endometrial angiogenesis has been the focus of many studies (Girling & Rogers 2005, Bourlev et al 2006, Hervé et al 2006. Estrogen is recognized as one of the driving forces for increased uterine blood flow through both rapid and delayed actions, via binding to its receptors in the uterine artery wall, and especially at the uterine artery endothelium (Heryanto & Rogers 2002, Mendelsohn 2002, Albrecht et al 2003.…”

Progestogen only contraception and endometrial break through bleeding

“…When applied together, MPA augmented the 17b-oestradiol response of VEGF expression in human endometrial epithelial cells and inhibited the 17b-oestradiol-induced VEGF expression in the stromal cells [48]. In contrast, studies in ovariectomised baboons have demonstrated that the addition of physiological doses of progesterone suppresses an oestradiol induced rise in VEGF [43]. Other in vivo studies using a mouse sponge assay to measure angiogenesis, demonstrated an increase with low dose LNG but not with higher doses of the same progestogen.…”

“…The human endometrium is capable of synthesising all members of the VEGF A family which contains five splice variants. Interestingly, the VEGF A gene has two regions that are homologous to oestrogen response elements (ERE) and numerous studies demonstrate an increase of VEGF production in response to oestrogen [43,44]. Hypoxia has also been shown to increase VEGF production [45].…”