Placental ischemia in preeclampsia (PE) results in hypertension and intrauterine growth restriction (IUGR). Stimulation of soluble guanylate cyclase (sGC) reduces blood pressure in the clinically relevant reduced uterine perfusion pressure (RUPP) rat model of PE implicating involvement in RUPP-induced hypertension. However, the contribution of sGC in the development of IUGR in PE is not known. Thus, this study demonstrated the efficacy of Riociguat, a sGC stimulator, in IUGR reversion in the RUPP rat model of PE, and tested the hypothesis that improvement in fetal weight occurs in association with improvement in placental perfusion, placental morphology, and placental nutrient transport protein expression. Sham or RUPP surgery was performed at gestational day 14 (G14) with administration of vehicle (Sham or RUPP) or the sGC stimulator (Riociguat, 10mg/kg/day, s.c.) (sGC-treated) until G20. Fetal weight was reduced (p=0.004) at G20 in RUPP but not sGC-treated RUPP compared to Sham, the control group. At G20, uterine artery resistance index (UARI) was increased (p=0.010) in RUPP indicating poor placental perfusion; proportional junctional zone surface area was elevated (p=0.035) indicating impaired placental development. These effects were ameliorated in sGC-treated RUPP. Placental protein expression of nutrient transporter heart fatty acid binding protein (hFABP) was increased (p=0.008) in RUPP but not sGC-treated RUPP suggesting a compensatory mechanism to maintain normal neurodevelopment. Yet, UARI (p<0.001), proportional junctional zone surface area (p=0.013), and placental hFABP protein expression (p=0.008) were increased in sGC-treated Sham suggesting a potential adverse effect of Riociguat. Collectively, these results suggest sGC contributes to IUGR in PE.

No abstract

Stimulation of soluble guanylate cyclase (sGC) improves fetal growth at gestational day 20 in the reduced uterine perfusion pressure (RUPP) rat model of placental ischemia suggesting a role for sGC in the etiology of intrauterine growth restriction (IUGR). This study tested the hypothesis that stimulation of sGC until birth attenuates asymmetric IUGR mitigating increased cardiovascular risk in offspring. Sham or RUPP surgery was performed at gestational day 14 (G14); vehicle or sGC stimulator, Riociguat (10mg/kg/day, s.c.) were administered G14 until birth. Birth weight was reduced in offspring from RUPP (intrauterine growth restricted or IUGR), sGC RUPP (sGC IUGR), and sGC Sham (sGC Control) compared to Sham (Control). Crown circumference was maintained but abdominal circumference was reduced in IUGR and sGC IUGR compared to Control indicative of asymmetrical growth. Gestational length was prolonged in sGC RUPP, and survival at birth was reduced in sGC IUGR. Probability of survival to postnatal day 2 was also significantly reduced in IUGR and sGC IUGR versus Control, and in sGC IUGR versus IUGR. At 4 months of age blood pressure was increased in male IUGR and sGC IUGR, but not male sGC Control born with symmetrical IUGR. Global longitudinal strain was increased and stroke volume was decreased in male IUGR and sGC IUGR compared to Control. Thus, late gestational stimulation of sGC does not mitigate asymmetric IUGR or increased cardiovascular risk in male sGC IUGR. Furthermore, late gestational stimulation of sGC is associated with symmetrical growth restriction in sGC Control implicating contraindications in normal pregnancy.