ACE2 downregulation is associated with adverse cardiovascular and reproductive outcomes in female mice on high fat diet

Diet-induced obesity is a growing concern among women of reproductive age, as it can significantly impact both maternal and fetal health. A key mechanism linking obesity to cardiometabolic dysfunction is the imbalance between the classical (pressor) and the counter-regulatory (protective) arms of the renin angiotensin system (RAS): angiotensin (Ang)-II, via Ang-II type 1 receptor, promotes vasoconstriction, oxidative stress and inflammation, while Ang-converting enzyme 2 (ACE2) counteracts these effects by metabolizing Ang-II into the vasodilatory and anti-inflammatory Ang-(1-7). The objective of the current 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 ACE2/Ang-(1-7) axis. Female C57BL/6J mice at 8 weeks of age were assigned to either a HFD (60 kcal% fat) or a regular diet (RD, 22 kcal% fat). Glucose and insulin tolerance tests were performed to assess metabolic function, echocardiography was conducted to evaluate changes in cardiac structure and function, and radiotelemetry was employed to monitor changes in blood pressure (BP), heart rate (HR), baroreflex sensitivity, and autonomic function. Following 10-12 weeks’ dietary exposure, HFD-fed females developed both glucose and insulin intolerance compared to RD-fed controls. Echocardiography revealed that HFD-exposed females exhibited impaired cardiac function with reduced ejection fraction (70.45% in HFD vs. 74.70% in RD, p< 0.001) and fractional shortening (38.80% in HFD vs. 42.69% in RD, p< 0.001). Telemetry recordings revealed that HFD exposure led to significantly elevated mean arterial BP (103.7 mmHg in HFD vs. 91.65 mmHg in RD, p< 0.01) and HR (551.9 in HFD vs. 470 bpm in RD, p< 0.001). In addition, HFD-exposed females exhibited reduced spontaneous baroreflex sensitivity (2.236 ms/mmHg in HFD vs. 3.169 ms/mmHg in RD, p< 0.01) and dampened parasympathetic tone (HR increase following i.p. atropine injection: 143.4 bpm in HFD vs. 274.1 bpm in RD, P< 0.01). The above cardiometabolic dysfunction persisted or further exacerbated during pregnancy (these females were paired with RD-fed males following 12-weeks’ dietary exposure), with elevated maternal serum sFlt-1 levels (3-fold increase over RD-fed controls), a marker for preeclampsia. Although HFD exposure did not alter rate of pregnancy, delivery or litter size, pups from HFD dams suffered low birth weight (0.9 ± 0.06 g in HFD vs. 1.2 ± 0.05 g in RD, p< 0.01) and markedly increased post-natal mortality (93% in HFD vs. 19% in RD, p< 0.0001). Examination of the RAS revealed reduced ACE2 expression in both the heart and the kidney of HFD-fed females, coinciding with reduced plasma ACE2 activity. Importantly, Ang-(1-7) infusion (600 ng/kg/min) during weeks 10-12 of HFD feeding improved glucose tolerance AUC: 1932 in Ang-(1-7) group vs. 2320 in control group, p< 0.01 and reduced mean arterial BP 89.5 mmHg in Ang-(1-7) group vs 102.4 mmHg in control group, p< 0.05, further confirming the protective role of the ACE2/Ang-(1-7) axis. In conclusion, chronic HFD exposure in female mice results in profound cardiometabolic and reproductive dysfunction associated with ACE2 downregulation, and direct Ang-(1-7) infusion mitigates HFD-induced cardiometabolic dysfunction. The therapeutic effects of Ang-(1-7) infusion in improving pregnancy outcomes in HFD-fed females are currently under investigation. This work is supported in part by research grants from the NIH (HL150592 and HL163588) and the Department of Veterans Affairs (BX004294, BX005475 and BX007112). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.