Maternal perfluorooctane sulfonic acid exposure during rat pregnancy causes hypersensitivity to angiotensin II and attenuation of endothelium-dependent vasodilation in the uterine arteries †.

Epidemiological studies show a strong association between environmental exposure to perfluorooctane sulfonic acid (PFOS) and preeclampsia and fetal growth restriction; however, the underlying mechanisms are unclear. We tested the hypothesis that gestational PFOS exposure leads to pregnancy complications via alterations in uterine vascular endothelium-independent angiotensin II-related mechanisms and endothelium-derived factors such as nitric oxide. Pregnant Sprague-Dawley rats were exposed to PFOS 0.005, 0.05, 0.5, 5, 10, and 50 μg/mL through drinking water from gestational day 4 to 20, and dams with PFOS 50 μg/mL were used to assess mechanisms. PFOS exposure dose dependently increased maternal blood pressure but decreased fetal weights. Uterine artery blood flow was lower and resistance index was higher in the PFOS dams. In PFOS dams, uterine artery contractile responses to angiotensin II were significantly greater, whereas contractile responses to K+ depolarization and phenylephrine were unaffected. Plasma angiotensin II levels were not significantly different between control and PFOS dams; however, PFOS exposure significantly increased Angiotensin II type 1 receptor (AGTR1) and decreased AGTR2 protein levels in uterine arteries. Endothelium-dependent relaxation response to acetylcholine was significantly reduced with decreased endothelial nitric oxide synthase expression in the uterine arteries of PFOS dams. Left ventricular hypertrophy and fibrosis were observed, along with increased ejection fraction and fractional shortening in PFOS dams. These results suggest that elevated maternal PFOS levels decrease uterine blood flow and increase vascular resistance via heightened angiotensin II-mediated vasoconstriction and impaired endothelium-dependent vasodilation, which provides a molecular mechanism linking elevated maternal PFOS levels with gestational hypertension and fetal growth restriction.