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.