Pregnancy-dependent cardioprotection via GPER activation in Dahl salt-sensitive rats with superimposed preeclampsia

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 G protein-coupled estrogen receptor (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. Female Dahl SS/Jr rats bred at 18-20 wk were randomized into four groups: Virgin + Vehicle, Virgin + LNS8801, Pregnant + Vehicle, and Pregnant + LNS8801. LNS8801 was orally administered in pregnant rats from <i>gestational day</i> (GD) <i>9</i> to <i>20</i> and an equivalent period in virgin controls. Cardiac function was assessed via echocardiography. LNS8801 improved cardiac function in pregnant Dahl SS/Jr rats, enhancing global longitudinal, circumferential, and radial strain, as well as increasing systolic function compared with the vehicle-treated controls. In addition, 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. This study highlights the importance of pregnancy-specific adaptations on the cardiovascular effects of GPER activation. Although LNS8801 demonstrated cardioprotective and antihypertensive benefits in pregnant Dahl SS/Jr rats, its effects were absent in virgin animals.<b>NEW & NOTEWORTHY</b> In this work, GPER (G protein-coupled estrogen receptor) was investigated as a novel therapeutic target for managing cardiovascular complications in preeclampsia. Activation of GPER by the selective agonist LNS8801 significantly improved cardiac function during pregnancy, with no effect on virgin animals, suggesting a pregnancy-specific impact. It also reduced blood pressure in pregnant Dahl SS/Jr rats with superimposed preeclampsia.