Preeclampsia: 2-methoxyestradiol induces cytotrophoblast invasion and vascular development specifically under hypoxic conditions.
Inadequate invasion of the uterus by cytotrophoblasts is speculated to result in pregnancy-induced disorders such as preeclampsia. However, the molecular mechanisms that govern appropriate invasion of cytotrophoblasts are unknown. Here, we demonstrate that under low-oxygen conditions (2.5% oxygen), 2-methoxyestradiol (2-ME), which is a metabolite of estradiol and is generated by catechol-o-methyltransferase (COMT), induces invasion of cytotrophoblasts into a naturally-derived, extracellular matrix. Neither low-oxygen conditions nor 2-ME alone induces the invasion of cytotrophoblasts in this system; however, low-oxygen conditions combined with 2-ME result in the appropriate invasion of cytotrophoblasts into the extracellular matrix. Cytotrophoblast invasion under these conditions is also associated with a decrease in the expression of hypoxia-inducible factor-1alpha (HIF-1alpha), transforming growth factor-beta3 (TGF-beta3), and tissue inhibitor of metalloproteinases-2 (TIMP-2). Pregnant COMT-deficient mice with hypoxic placentas and preeclampsia-like features demonstrate an up-regulation of HIF-1alpha, TGF-beta3, and TIMP-2 when compared with wild-type mice; normal levels are restored on administration of 2-ME, which also results in the resolution of preeclampsia-like features in these mice. Indeed, placentas from patients with preeclampsia reveal lower levels of COMT and higher levels of HIF-1alpha, TGF-beta3, and TIMP-2 when compared with those from normal pregnant women. We demonstrate that low-oxygen conditions of the placenta are a critical co-stimulator along with 2-ME for the proper invasion of cytotrophoblasts to facilitate appropriate vascular development and oxygenation during pregnancy.
Lee
Soo Bong
SB
Division of Matrix Biology, CLS 11086, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Wong
Amy P
AP
Kanasaki
Keizo
K
Xu
Yong
Y
Shenoy
Vivek K
VK
McElrath
Thomas F
TF
Whitesides
George M
GM
Kalluri
Raghu
R
D000077584:2-Methoxyestradiol; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000254:growth & development; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000235:genetics; D010100:Oxygen / Q000494:pharmacology*; D011225:Pre-Eclampsia / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D014327:Trophoblasts / Q000187:drug effects* / Q000473:pathology / Q000502:physiology
D004958:Estradiol; D000077584:2-Methoxyestradiol; D002394:Catechol O-Methyltransferase; D010100:Oxygen