ACE2 downregulation contributes to adverse cardiovascular and reproductive outcomes in female mice on high-fat diet

Obesity is a growing concern among women of reproductive age, as it can significantly impact both maternal and fetal health. A potential mechanism linking obesity to cardiometabolic dysfunction is the imbalance between the classical (pressor) and the compensatory (protective) arms of the renin-angiotensin system (RAS). The objective of this study was to investigate how high-fat diet (HFD) impacts cardiovascular and reproductive health in female mice and its associated mechanisms, with an emphasis on the protective angiotensin-converting enzyme 2 (ACE2)/angiotensin (Ang)-(1-7) axis. Female C57BL/6J mice at 8 wk of age were assigned to either a HFD (60 kcal% fat) or a regular diet (RD, 22 kcal% fat). Following 10-12 wk of dietary exposure, HFD-fed females exhibited significantly greater weight gain and glucose intolerance compared with RD-fed controls. Telemetry recordings revealed that HFD exposure led to significantly elevated blood pressure (BP), increased heart rate, reduced spontaneous baroreflex sensitivity, and dampened parasympathetic tone. The aforementioned cardiometabolic dysfunction persisted or further exacerbated during pregnancy. Although HFD exposure did not alter fertility (ability to conceive), delivery, or litter size, offspring from HFD mothers suffered low birth weight and markedly increased postnatal mortality. Examination of the RAS revealed reduced ACE2 mRNA and protein expression in both the heart and the kidney of HFD-fed females. Importantly, Ang-(1-7) infusion in HFD-fed females starting 2 wk before mating improved glucose tolerance, reduced BP, and improved offspring survival. In conclusion, downregulation of ACE2/Ang-(1-7) axis contributes to HFD-induced cardiometabolic and reproductive dysfunction in female mice.NEW & NOTEWORTHY This study identifies downregulation of ACE2 in the setting of high-fat diet-induced obesity as a contributing factor to maternal cardiometabolic dysfunction and adverse pregnancy outcomes. Restoring ACE2/Ang-(1-7) function may have therapeutic value in improving cardiovascular and reproductive functions in females with obesity.