Soluble Guanylate Cyclase in a Rodent Model of Preeclampsia: Is Benefit in the Mother Associated with Benefit in the Offspring?

Abstract

The initiating event in preeclampsia (PE) involves improper placental remodeling, placental ischemia, maternal hypertension and asymmetric intrauterine growth restriction (IUGR). IUGR offspring have increased risk for chronic disease such as hypertension and cardiovascular disease. Currently, the only treatment option for PE is delivery of the baby and placenta. Therefore, identifying maternal therapies for treatment for PE that do not inflict harm on the developing fetus are crucial. Nitric oxide (NO) is reduced in PE resulting in reduced blood flow and increased maternal blood pressure. Soluble guanylate cyclase (sGC) inducers, a component of the NO pathway, reduce maternal blood pressure and improve reduced fetal weight in a rodent model of PE induced by reduced uterine perfusion pressure (RUPP). However, the long‐term benefit or harm in the offspring is unknown. Thus, this study tested the hypothesis that maternal treatment with a sGC inducer will improve uterine blood flow and placental nutrient transport resulting in improvement in asymmetric growth restriction in the RUPP model of PE. Sham or RUPP was performed at day 14 of gestation followed by administration of vehicle or a sGC inducer (riociguat, 10mg/kg/day, s.c.) until gestation day 20 (G20) or birth. At G20 uterine artery resistance index (UARI) was significantly increased, indicative of poor placental perfusion, in vehicle‐treated RUPP (0.64±0.01 mm/s) vs. vehicle‐treated Sham (0.57±0.01 mm/s) (p<0.05), but was also increased in sGC‐treated Sham (0.64±0.01 mm/s) vs. vehicle‐treated Sham (p<0.05). Placental nutrient transporter heart fatty acid binding protein (hFABP) protein expression was also significantly increased in vehicle‐treated RUPP (821.5±55.6 A.U.) vs. vehicle‐treated Sham (588.8±30.4 A.U.) (p<0.05). Yet, placental hFABP protein expression was also significantly increased in sGC‐treated Sham (814.7±77.4 A.U.)(p<0.05); up‐regulation that may be a compensatory mechanism to maintain normal brain development. Although an increase in gestational length in women with risk of PE‐associated preterm delivery is beneficial, gestational length at birth was significantly lengthened in full‐term sGC‐treated RUPP, an increase of 24 hours vs. vehicle‐treated Sham. Asymmetric growth at birth was not abolished and treatment in the RUPP was associated with a significant decrease in survival at birth (26.3%±6.5 survival rate versus 62.3%±10.0 survival rate, sGC‐treated RUPP vs. vehicle‐treated Sham; p<0.05). Pup weight at birth was not asymmetric but was reduced in sGC‐treated Sham (5.3±0.2 grams) vs. vehicle‐treated Sham (5.9±0.2 grams) (p<0.05). Thus, these findings indicate that maternal interventions using sGC inducers during PE may not provide benefit to the developing fetus despite improvement in maternal blood pressure implicating caution in the translation of this agent to the clinical setting. Future studies will investigate the long‐term effect of this maternal therapeutic on cardiovascular risk in the offspring born to Sham and RUPP dams.Support or Funding InformationHL143459, P20GM121334, P20GM104357, HL51971, T32HL105324