Abstract 4342016: Prenatal activation of the G protein-coupled estrogen receptor (GPER) improves placental oxygenation and enhances offspring cardiac function in preeclampsia.

Abstract

Introduction: Preeclampsia (PE) is a pregnancy disorder linked to placental dysfunction and long-term cardiovascular risk in the offspring. While activation of the G protein-coupled estrogen receptor (GPER) improves maternal cardiac health in PE rats, its effect on offspring heart outcomes remains unclear. This study evaluates whether in utero treatment improves placental oxygenation and cardiac dysfunction in the offspring. Methods: Two preclinical PE models were used: an experimental model — the reduced uterine perfusion pressure (RUPP) — and the Dahl salt-sensitive (Dahl SS/Jr) rat, a genetic model of superimposed PE. PE dams were treated from gestational day 9 to 20 with either the selective GPER agonist G-1, its purified active enantiomer LNS8801, or vehicle. Normal pregnant rats served as controls. In vivo placental oxygenation was assessed by photoacoustic imaging, and fetal cardiac function by intrauterine echocardiography. Postnatal outcomes in 10-week-old pups included myocardial perfusion, cardiac strain, and blood pressure measurements. Results: In the RUPP model, placental oxygenation significantly improved following GPER activation compared to vehicle-treated RUPP rats. Similarly, in Dahl SS/Jr rats, selective GPER stimulation significantly enhanced placental oxygenation (p<0.05). These findings were accompanied by fetal functional benefits, as GPER activation improved fetal diastolic function, normalizing the early-to-late (E/A) ratio of left ventricular filling compared to fetuses from vehicle-treated mothers (p<0.05). Extending to offspring, prenatal GPER activation led to significantly higher myocardial peak enhancement values (p<0.05), indicating improved myocardial perfusion. Prenatal LNS8801 treatment also significantly normalized mean arterial pressure compared to pups from vehicle-treated dams (p<0.05). Offspring from vehicle-treated Dahl SS/Jr dams exhibited elevated cardiac global longitudinal strain (GLS), indicating increased myocardial stress likely due to impaired perfusion and elevated blood pressure. Prenatal LNS8801 administration prevented this rise in GLS, significantly reducing cardiac strain (p<0.05). Conclusion: In utero GPER activation enhances placental oxygen saturation and extends cardiovascular benefits at least 10 weeks into postnatal life in offspring exposed to PE. These findings highlight GPER-targeted interventions as a promising strategy to reduce the intergenerational impact of this obstetric disease.