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

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.

Prenatal systemic hypoxia-ischemia: A rat model of neurodevelopmental disorders related to prematurity

“…RUPP at E14 did not alter placental protein expression (i.e. nutrient transport) but impaired the placental development that lead to fetal oxidative stress and energetic imbalance (Coats et al, 2021;da Silva et al, 2021), as shown by increased pro-oxidation markers and lipid peroxidation, and reduced anti-oxidative markers in plasma (Rains et al, 2021) and in the aorta and mesenteric arteries (da Silva et al, 2021) of young and adult offspring. Increased water content, brain edema and impaired myogenic tone in the middle cerebral arteries have been reported after RUPP (Ryan et al, 2011).…”

“…-Body growth restriction, placental insufficiency and metabolic syndrome MIUH at E17 and RUPP at E14 resulted in hypotrophic pups at birth (Olivier et al, 2005;Delcour et al, 2011;Ohshima et al, 2016;Coats et al, 2021;Rains et al, 2021); whereas, TSHI at E18 did not (Mazur et al, 2010;Robinson et al, 2018). LBW persisted in 1 and 2 months-old MIUH rats according to sex (Delcour et al, 2011;Ohshima et al, 2016) but MIUH rats catched up BW at P90-110 (Delcour et al, 2011(Delcour et al, , 2012a.…”

“…Comparable procedures to reduce intrauterine blood flow in pregnant rats involve transient systemic HI (TSHI: clamping uterine arteries for 60 min at E18) as a model of placental insufficiency (Robinson et al, 2005;Jantzie et al, 2013), reduced uterine perfusion pressure (RUPP: permanent stenosis of uterine arteries from E14) as a model of preeclampsia (Granger et al, 2006;Clayton et al, 2018;Coats et al, 2021) or permanent stenosis of uterine arteries at E17 using ameroid constrictors (AC) as a model of hypertensive disease of pregnancy (Kitase et al, 2020). We thus postulate that all these procedures correspond to a prenatal systemic HI (PSHI) that could help to better understand the underlying mechanisms of the early emergence of EP (Jantzie et al, 2016).…”

Effect of Genetically Reduced Maternal Myostatin on Late Gestation Maternal, Fetal, and Placental Metabolomes in Mice

“…While 5′GMP can be a metabolite of the signaling molecule cGMP, it is also a building block of nucleic acids. Guanylate cyclase and cGMP have been studied in the context of placental and uterine vasodilation in pregnancy, particularly in preeclamptic models, yet in fetal serum, no differences in cGMP were found in males with intrauterine growth restriction; thus, whether fetal cGMP concentrations play any role in regulating fetal growth is not understood [ 53 , 54 ].…”

Placental Ischemia Says “NO” to Proper NOS-Mediated Control of Vascular Tone and Blood Pressure in Preeclampsia

“…Follow-up studies revealed that, despite the effect of riociguat on prolonging pregnancy of RUPP rats, it worsened the probability of their babies surviving at birth and postnatal day 2. Moreover, riociguat treatment during late pregnancy did not mitigate RUPP-induced asymmetric IUGR and increased cardiovascular risk in male offspring at 4 months of age [ 211 ]. Importantly, although the US Food and Drug Administration (FDA) agency has approved riociguat (Adempas, Bayer) for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), it is highlighted in its prescribing information that this medication has embryo-fetal toxicity and should not be administered to pregnant women.…”