Stimulation of soluble guanylate cyclase diminishes intrauterine growth restriction in a rat model of placental ischemia

Abstract

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.

Soluble guanylate cyclase stimulation in late gestation does not mitigate asymmetric intrauterine growth restriction or cardiovascular risk induced by placental ischemia in the rat

“…Collectively, these studies suggest that a reduction in NO bioavailability may contribute to endothelial dysfunction and the generation of oxidative stress in response to placental ischemia in the RUPP model of PE. Our laboratory previously reported that urinary, placental, and uterine artery cGMP are decreased in the RUPP model of placental ischemia in association with a reduction in fetal weight at gestation day 20 (G20) (19). We also showed that targeting the sGC pathway with a sGC stimulator, Riociguat, during late gestation restores the decrease in cGMP in association with improved uterine blood flow and placental morphology and attenuation of reduced fetal weight at G20 in the RUPP (19).…”

“…All animals undergoing surgical procedures were anesthetized using 2-5% isoflurane by inhalation. The Sham or RUPP procedure was performed at gestational day 14 (G14) with analgesics (Rodent MD's, Rimadyln, 2 mg/tablet, Bio-Serve, Flemington, NJ) provided before and for 3 days postsurgery (19). Completion of parturition was recorded on an hourly basis starting at day 21 of gestation (G21).…”

“…Only one male offspring per birth dam was used per study parameter with animals randomly selected and investigator(s) blinded to animal identification. Uterine artery resistance index (UARI) was measured at G20 as previously described (19) in the first three cohort of dams. To determine if serum and plasma hormones differed in vehicle and sGC Sham and RUPP dams, an additional cohort was utilized for collection of serum and plasma at G20.…”

“…A silver clip was also placed around both branches of the uterine artery (0.100 mm) to prevent a compensatory increase in flow to the uteroplacental units. The Sham procedure involved complete visualization of the uterine horns to ensure exposure to anesthesia and a comparable surgical procedure as the RUPP, all as previously described (4,19).…”

“…Our laboratory previously reported that urinary, placental, and uterine artery cGMP are decreased in the RUPP model of placental ischemia in association with a reduction in fetal weight at gestation day 20 (G20) (19). We also showed that targeting the sGC pathway with a sGC stimulator, Riociguat, during late gestation restores the decrease in cGMP in association with improved uterine blood flow and placental morphology and attenuation of reduced fetal weight at G20 in the RUPP (19). Collectively, these findings implicate an important role for impaired sGC-cGMP signaling in the pathogenesis of IUGR.…”