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The significance of endothelin in platelet-activating factor-induced fetal growth restriction
Mark G Neerhof1, Saira Khan, Sylvia Synowiec
1Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, NorthShore University HealthSystem, Evanston, IL 60201, USA.
Insights
Platelet-activating factor (PAF) causes fetal growth restriction (FGR) in rats. Endothelin-1 (ET-1) is key in low-dose PAF-induced FGR, but other mechanisms dominate at higher doses.
Area of Science:
- Reproductive biology
- Developmental toxicology
- Pharmacology
Background:
- Fetal growth restriction (FGR) poses significant risks to pregnancy outcomes.
- Platelet-activating factor (PAF) is implicated in FGR pathogenesis.
- The role of endothelin-1 (ET-1) in PAF-induced FGR requires further elucidation.
Purpose of the Study:
- To investigate the involvement of endothelin-1 (ET-1) in carbamyl-platelet-activating factor (c-PAF)-induced fetal growth restriction (FGR) in rats.
- To determine the efficacy of ET-1 receptor A (ET(A)) antagonism in mitigating c-PAF-induced FGR.
Main Methods:
- Timed-pregnant rats received intravenous c-PAF (0.5, 1.0, or 2.5 µg/kg per h) or vehicle.
- Concurrent administration of an ET(A) antagonist (10 or 20 mg/kg per d) or vehicle.
- Fetal and placental weights were measured, and placental preproET-1 mRNA expression was analyzed via RT-PCR.
Main Results:
- c-PAF administration resulted in dose-dependent reductions in fetal weight and non-dose-dependent reductions in placental weight.
- ET(A) antagonism ameliorated FGR at the lowest c-PAF dose (0.5 µg/kg per h) but not at higher doses.
- Placental preproET-1 mRNA expression increased with low-dose c-PAF but not with higher doses, suggesting a dose-dependent role for ET-1.
Conclusions:
- c-PAF infusion induces FGR in rats, affecting both fetal and placental development.
- ET-1 plays a critical role in the pathophysiology of low-dose c-PAF-induced FGR.
- At higher c-PAF doses, FGR is mediated by ET-1-independent mechanisms, indicating complex pathways involved in growth restriction.
Abstract:
The significance of endothelin-1 (ET-1) in platelet-activating factor (PAF)-induced fetal growth restriction (FGR) was evaluated in timed-pregnant rats receiving intravenous carbamyl-PAF (c-PAF; 0.5, 1.0, or 2.5 µg/kg per h) or vehicle, with or without ET-1 receptor A (ET(A)) antagonist (10 or 20 mg/kg per d) for 7 days beginning on gestation day 14. Tissues were collected on day 21. Carbamyl-PAF reduced fetal weights dose dependently. Placental weights were significantly reduced but not dose dependently. ET(A) antagonism prevented FGR at the 0.5, but not the 1.0 and 2.5 µg/kg per h c-PAF doses. Correspondingly, placental, but not uterine, preproET-1 messenger RNA (mRNA) expression (determined by reverse transcription-polymerase chain reaction) was increased at 0.5 µg/kg per h but not at higher c-PAF doses. In summary, c-PAF infusion results in fetal and placental growth restriction in the rat. At low doses of c-PAF, ET-1 is central to the pathophysiology of PAF-induced FGR. At higher c-PAF doses, FGR is induced by mechanisms other than ET-1 action.
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