Vascular endothelial growth factor in primate endometrium is regulated by oestrogen-receptor and progesterone-receptor ligands in vivo.
We investigated hormonal regulation of endometrial angiogenesis in menstruating primates. This study was designed to demonstrate: (i) that cell-specific vascular endothelial growth factor (VEGF) production and expression in monkey endometrium are regulated by steroid receptor ligands; and (ii) mifepristone (RU 486) alters VEGF production even in the absence of a progestin agonist. Endometrial VEGF production was compared by computer-assisted immunohistochemical analysis during induced hypoestrogenism and after oestradiol, progestin, or antiprogestin (mifepristone) treatment. VEGF gene expression was estimated by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) in endometrial samples from castrate cynomolgus monkeys, from intact monkeys in the luteal phase, and from monkeys treated for 20 days with levonorgestrel (LNG) or mifepristone. VEGF staining intensities in glandular epithelium and VEGF mRNA expression were highest in hypoestrogenic monkeys. Progestin treatment induced intense VEGF staining in the stroma. Gene expression of VEGF-189, but not other isoforms, was higher in progesterone- and progestin (LNG)-exposed endometria compared to mifepristone-exposed endometria or endometria from anovulatory cycles (P < 0.04). Mifepristone abolished VEGF staining in glandular epithelium almost completely. We conclude that VEGF protein and VEGF mRNA expression levels in primate endometrium depend on the steroidal milieu. Anti-angiogenic effects of mifepristone via suppression of VEGF production might represent a mechanism for its quelling effects on endometrium.
Greb
R R
RR
The Jones Institute for Reproductive Medicine, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk 23507, USA.
Heikinheimo
O
O
Williams
R F
RF
Hodgen
G D
GD
Goodman
A L
AL
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004717:Endometrium / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D004958:Estradiol / Q000097:blood / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D016912:Levonorgestrel / Q000494:pharmacology; D008024:Ligands; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics; D008252:Macaca fascicularis; D008597:Menstrual Cycle / Q000378:metabolism; D015735:Mifepristone / Q000494:pharmacology; D018919:Neovascularization, Physiologic; D016133:Polymerase Chain Reaction; D011374:Progesterone / Q000097:blood / Q000494:pharmacology; D045167:Progesterone Congeners / Q000494:pharmacology; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D017931:DNA Primers; D016228:Endothelial Growth Factors; D008024:Ligands; D008222:Lymphokines; D045167:Progesterone Congeners; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D015735:Mifepristone; D011374:Progesterone; D004958:Estradiol; D016912:Levonorgestrel