Maternal Kisspeptin-10 Treatment Partially Rescues Fetal and Postnatal Cardiac Programming Disrupted by Maternal Hypothyroidism

Cardiovascular diseases are the leading cause of global mortality and have been associated with alterations in fetal programming. Maternal hypothyroidism (MH) impairs placental function and induces intrauterine growth restriction (IUGR), both of which are risk factors for cardiovascular disease. Kisspeptin-10 (Kp10) has been shown to improve feto-placental development in hypothyroid rats, but its effects on intrauterine cardiac development remain unknown. MH was induced in Wistar rats using propylthiouracil (PTU), and Kp10 administration began on gestational day 8. Offspring hearts were analyzed at fetal day 18 and postnatal days 3 and 21. MH reduced fetal and postnatal body and heart mass, impaired cardiomyocyte proliferation, and dysregulated apoptotic and angiogenic markers. Maternal Kp10 administration enhanced postnatal weight gain, restored cardiomyocyte proliferation and nuclear density, and positively modulated apoptotic (Bax/Bcl2) and angiogenic (Vegf, Ang2, Flk1) pathways. However, it increased redox (8-OHdG) and endoplasmic reticulum (ER) stress (Grp78, Chop) mediators in fetal hearts, while reduced postnatal Chop expression in both sexes. Collectively, these findings demonstrate that maternal hypothyroidism disrupts cardiac development and postnatal cardiac programming, whereas maternal Kp10 administration partially mitigates these effects, highlighting novel mechanisms through which kisspeptin may positively regulate cardiac development.