title: The regulation of vascular endothelial growth factor by hypoxia and prostaglandin F₂α during human endometrial repair.
abstract: BACKGROUND
  The human endometrium has an exceptional capacity for repeated repair after menses, but its regulation remains undefined. Premenstrually, progesterone levels fall and prostaglandin (PG) F₂α synthesis increases, causing spiral arteriole constriction. We hypothesized that progesterone withdrawal, PGF₂α, and hypoxia increase vascular endothelial growth factor (VEGF), an endometrial repair factor.
  
  
  RESULTS
  Endometrial biopsies were collected (n = 47) with ethical approval and consent. VEGF mRNA, quantified by quantitative RT-PCR, was increased during menstruation (P < 0.01).VEGF protein was maximally secreted from proliferative endometrial explants. Treatment of an endometrial epithelial cell line and primary human endometrial stromal cells with 100 nm PGF₂α or hypoxia (0.5% O₂) resulted in significant increases in VEGF mRNA and protein. VEGF was maximal when cells were cotreated with PGF(2α) and hypoxia simultaneously (P < 0.05-0.001). Secretory-phase endometrial explants also showed an increase in VEGF with cotreatment (P < 0.05). However, proliferative-phase explants showed no increase in VEGF on treatment with PGF₂α and/or hypoxia. Proliferative tissue was induced to increase VEGF mRNA expression when exposed to progesterone and its withdrawal in vitro but only in the presence of hypoxia and PG. Hypoxia-inducible factor-1α (HIF-1α) silencing with RNA interference suppressed hypoxia-induced VEGF expression in endometrial cells but did not alter PGF₂α-induced VEGF expression.
  
  
  CONCLUSIONS
  Endometrial VEGF is increased at the time of endometrial repair. Progesterone withdrawal, PGF₂α, and hypoxia are necessary for this perimenstrual VEGF expression. Hypoxia acts via HIF-1α to increase VEGF, whereas PGF₂α acts in a HIF-1α-independent manner. Hence, two pathways regulate the expression of VEGF during endometrial repair.
authors.affiliation: Centre for Reproductive Biology, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Maybin
authors.forename: Nikhil
authors.initials: N
authors.lastname: Hirani
authors.forename: Pamela
authors.initials: P
authors.lastname: Brown
authors.forename: Henry N
authors.initials: HN
authors.lastname: Jabbour
authors.forename: Hilary O D
authors.initials: HO
authors.lastname: Critchley
mesh_terms: D000328:Adult; D001706:Biopsy; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015237:Dinoprost / Q000378:metabolism*; D004717:Endometrium / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D004958:Estradiol / Q000097:blood; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D008597:Menstrual Cycle / Q000502:physiology*; D008875:Middle Aged; D015735:Mifepristone / Q000494:pharmacology; D011374:Progesterone / Q000037:antagonists & inhibitors / Q000097:blood; D012333:RNA, Messenger / Q000378:metabolism; D012038:Regeneration / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D055815:Young Adult
chemical_list: D016861:Cyclooxygenase Inhibitors; C497442:HIF1A protein, human; D006727:Hormone Antagonists; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D015735:Mifepristone; D011374:Progesterone; D004958:Estradiol; D015237:Dinoprost; D007213:Indomethacin