Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

The role of angiotensin ii in first trimester trophoblasts (#203)

Sarah J Delforce 1 , Saije K Morosin 1 , Eric Wang 2 , Claire T Roberts 3 , Eugenie R Lumbers 1 , Kirsty G Pringle 1
  1. School of Biomedical Sciences and Pharmacy, Priority Research Centre for Reproductive Health, University Of Newcastle, Newcastle, NSW, Australia
  2. Oregon Health and Science University, Portland, United States of America
  3. Discipline of Obstetrics and Gynaecology, School of Medicine, Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia

During the first trimester, normal placental development occurs in a low oxygen environment that is known to stimulate angiogenesis and proliferation via upregulation of vascular endothelial growth factor (VEGF), plasminogen activator inhibitor-1 (PAI-1/SERPINE1), angiopoietin -2/-1 ratio (ANGPT2/ANGPT1) and placental growth factor (PGF). Expression of the placental renin-angiotensin system (RAS) is highest in early pregnancy. Components of the RAS including angiotensin II type 1 receptor (AGTR1) mRNA are significantly upregulated in low oxygen and this is associated with increased VEGF expression. We postulated that low oxygen increases expression of VEGF and other proliferative/angiogenic factors through stimulation of the Ang II/AT1R RAS pathway in a first trimester human trophoblast cell line (HTR-8/SVneo). HTR-8/SVneo cells were cultured in 1%, 5% or 20% O2 with increasing concentrations of the AT1R antagonist (Losartan) for 48 hours. VEGFA, SERPINE1, ANGPT2/ANGPT1 and PGF mRNA expressions were determined by qPCR. PAI-1 and VEGF protein levels in the culture media were measured using ELISA. Low oxygen significantly increased the expression of VEGF, SERPINE1 and PGF (all P<0.01) but no effect of losartan treatment was observed. Low oxygen (1%) also significantly increased the expression of ANGPT2/ANGPT1 (P<0.01) and this was significantly reduced by losartan treatment (P<0.05). VEGF and PAI-1 protein were significantly increased in the culture media in low oxygen (both P<0.0001). Despite no change in VEGF mRNA expression with losartan treatment, VEGF levels in the supernatant were significantly reduced with losartan (P<0.0001). Cell viability (resazurin assay) was significantly increased in low oxygen (1%, P<0.001) and this effect was significantly reduced with losartan treatment (P<0.01). These highlight the functional role of Ang II/AT1R RAS pathway in the pro-angiogenic/pro-proliferative effects of low oxygen in placental development.