Pregnancy-Dependent Cardioprotection via GPER Activation in Dahl Salt-Sensitive Rats
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Background
Preeclampsia is a hypertensive disorder of pregnancy that affects multiple organs, including the heart, increasing long-term cardiovascular risks for both the mother and offspring. While the G protein-coupled estrogen receptor (GPER) has cardioprotective effects, its role in pregnancy-associated cardiac dysfunction, particularly in chronic hypertension, remains unclear, given the significant physiological adaptations that occur during pregnancy, including hormonal fluctuations and hemodynamic changes. This study investigated whether LNS8801, a selective and orally bioavailable GPER agonist, could improve cardiac function in virgin and pregnant Dahl salt-sensitive (SS/Jr) rats, a model of chronic hypertension exacerbated by pregnancy.
Methods
Female Dahl SS/Jr rats, both virgin and pregnant, were randomized into four groups: Virgin + Vehicle, Virgin + LNS8801, Pregnant + Vehicle, and Pregnant + LNS8801. LNS8801 (800 µg/kg/day, given orally) was administered in pregnant rats from gestational day (GD) 9 to 20 and for an equivalent period in virgin controls. Cardiac function was assessed via echocardiography, including speckle-tracking strain analysis and conventional systolic and diastolic parameters. Mean arterial pressure and proteinuria were also measured.
Results
LNS8801 significantly improved cardiac function in pregnant Dahl SS/Jr rats, enhancing global longitudinal, circumferential, and radial strain, as well as increasing systolic function. 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 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 in shaping 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, underscoring the influence of the physiological and hormonal environment on GPER-mediated responses. These findings provide a foundation for further exploration of GPER as a therapeutic target for pregnancy-associated cardiovascular dysfunction and preeclampsia, reinforcing the need for pregnancy-specific approaches in drug development.
