Abstract
Objectives Spiral artery remodeling by extravillous trophoblasts (EVT) at 12–14 weeks’ gestation is a mysterious mechanism for human and rodent placentation. In preeclampsia, failure of this process has been revealed by pathological search; however, the regulatory system of EVT invasion in early pregnancy remains unclear. Here we clarified uPA system, a major protease in the human body, under normal and hypoxic condition, to examine whether hypoxia-induced factor (HIF) and uPA system contribute to the fair placentation under low oxygen. Methods Placental villi (5–10 w GA defined by ultrasound) were obtained at artificial abortion after written informed consent. Villi were minced and EVT was separated with Percoll and Matrigel-based method. The culture was performed under 20% and 5% oxygen condition, with or without some cells knocked down the hypoxia-induced factor (HIF) with siRNA. Invasion assay was performed using Boyden Chamber assay. Expressions of HIF, uPA and receptor uPAR, inhibitor PAI-1 were defined with Western Blot, ELISA and immunostaining. Results Cell invasion was increased under 5% oxygen compared to 20%. Dose-dependent decrease of intracellular HIF protein by siRNA was defined, and invasive capacity was significantly decreased in the presence of siRNA for HIF. HIF protein was located on nuclear, and uPAR was immunolocalized to cell membrane. The production of HIF, uPA and uPAR was increased in 5%. The production of uPA and uPAR were also decreased in the presence of the siRNA. Conclusions Up-regulation of uPAR by hypoxia may enhance EVT invasion during the early first trimester through increased HIF expression. Because hypoxic conditions are regarded as normal in the uterus of early pregnancy, the uPA system in human trophoblasts, induced by HIF, enhanced invasive capacity for uterine spiral arteries, which, if I failed, may play a key role in preeclampsia in early pregnancy. Disclosures N. Koike: None. T. Tsunemi: None. J. Akasaka: None. A. Shigemitsu: None. K. Naruse: None. H. Kobayashi: None.
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