Pregnancy-Dependent Cardioprotection via GPER Activation in Dahl Salt-Sensitive Rats with Superimposed Preeclampsia

Background: Preeclampsia is a hypertensive disorder of pregnancy that affects multiple organs, increasing cardiovascular risks for both the mother and offspring. This study investigated LNS8801, a selective and orally bioavailable GPER agonist, to improve cardiac function in virgin and pregnant Dahl salt-sensitive (SS/Jr) rats, a model of superimposed preeclampsia with exacerbated cardiac and renal dysfunction during pregnancy. Methods: Female Dahl SS/Jr rats bred at 18-20 weeks were randomized into four groups: Virgin + Vehicle, Virgin + LNS8801, Pregnant + Vehicle, and Pregnant + LNS8801. LNS8801 was orally administered in pregnant rats from gestational day (GD) 9 to 20 and an equivalent period in virgin controls. Cardiac function was assessed via echocardiography. Results: LNS8801 improved cardiac function in pregnant Dahl SS/Jr rats, enhancing global longitudinal, circumferential, and radial strain, as well as increasing systolic function compared to the vehicle-treated controls. Additionally, LNS8801 enhanced diastolic function, improving left ventricular compliance (E/A ratio) and early mitral annular velocity (e'), while reducing left ventricular filling pressures (E/e' ratio) in comparison to pregnant rats treated with vehicle. In contrast, LNS8801 had no significant effects on cardiac function and blood pressure in virgin Dahl SS/Jr rats, suggesting that pregnancy-related adaptations may enhance GPER-mediated cardioprotection. LNS8801 treatment significantly reduced proteinuria in both virgin and pregnant rats, indicating a pregnancy-independent renal protective effect. Conclusion: This study highlights the importance of pregnancy-specific adaptations on the cardiovascular effects of GPER activation. While LNS8801 demonstrated cardioprotective and antihypertensive benefits in pregnant Dahl SS/Jr rats, its effects were absent in virgin animals.