Antenatal sildenafil citrate treatment increases offspring blood pressure in the placental-specific Igf2 knockout mouse model of FGR.

Fetal growth restriction (FGR), where a fetus fails to reach its genetic growth potential, affects up to 8% of pregnancies and is a major risk factor for stillbirth and adulthood morbidity. There are currently no treatments for FGR but candidate therapies include the phosphodiesterase-5 inhibitor sildenafil citrate (SC). Randomised clinical trials in women demonstrated no effect of SC on fetal growth in cases of severe early onset FGR, however, long-term health outcomes on the offspring are unknown. This study aimed to assess the effect of antenatal SC treatment on metabolic and cardiovascular health in offspring by assessing postnatal weight gain, glucose tolerance, systolic blood pressure and resistance artery function in a mouse model of FGR, the placental-specific insulin-like growth factor 2 (PO) knockout mouse. SC was administered subcutaneously (10 mg.kg-1) daily from embryonic day (E)12.5. Antenatal SC treatment did not alter fetal weight or viability but increased postnatal weight gain in WT female offspring (P<0.05), and reduced glucose sensitivity in both WT (P<0.01) and P0 (P<0.05) female offspring when compared with controls. Antenatal SC treatment increased systolic blood pressure in both male (WT versus WT-SC; 117±2 versus 140±3mmHg, P<0.0001, P0 versus P0-SC; 113±3 versus 140±4mmHg, P<0.0001, mean±SEM) and female (WT versus WT-SC; 121±2 versus 140±2mmHg, P<0.0001, P0 versus P0-SC; 117±2 versus 144±4mmHg, P<0.0001) offspring at 8 and 13 weeks of age. Increased systolic blood pressure was not attributed to altered mesenteric artery function. In utero exposure to SC may result in metabolic dysfunction and elevated blood pressure in later life.