Sex differences and the role of endothelial Nrf2 in the modulation of blood pressure and vascular reactivity

Introduction: Males are at higher risk than females in the development and severity of hypertension. Endothelial cell (EC) dysfunction contributes to these differences. Nrf2, a key regulator of antioxidant responses modulates EC function. We hypothesize that Nrf2 regulates vascular tone and blood pressure (BP) differently between sexes. Methods: Constitutive EC Nrf2KO and Keap1KO male (M) and female (F) mice were studied. Anesthetized mice received varying intravenous doses of Angiotensin II (Ang II, 0.1, 1, 10 µg/kg), and acute BP changes were recorded. In a separate experiment, mice were infused with Ang II (600 ng/kg/min) for 4 days via osmotic minipump and were implanted with telemetry transducers to monitor BP in the conscious state (2 hrs/day). Blood vessels from femoral-to-popliteal arterial segments were isolated to examine vasoactive responses to flow and acetylcholine (ACh), with and without N(gamma)-nitro-L-arginine methyl ester (L-NAME), and phenylephrine (PE) using pressure myography. Results: Intravenous administration of Ang II increased mean arterial pressure (MAP) in both WT and Nrf2KO mice, with Nrf2KO males showing a greater increase at a dose of 10 ug/kg (56.4±6.6%) compared to WT males (37.9%±1.4%; p<0.001). In Keap1KO mice, MAP did not rise. Chronic ANG II infusion raised MAP significantly in Nrf2KO males (141.2±3.3 mmHg) than in WT males (117.1±4.3 mmHg, p<0.05). MAP in Keap1KO males (130.4±6.7 mmHg) was similar to WT. Peak MAP occurred between days 3–4 and returned to baseline by day 7, except in Nrf2KO mice, where hypertension persisted. In females, no differences among groups were observed. However, Nrf2KO females had elevated pressure after pump emptying. In isolated perfused vessels, addition of L-NAME significantly reduced flow-mediated vasodilation in Keap1KO mice (M: -39.5±4.6%, F: -21.9±4.2%, p<0.05) compared to WT (M: -14.3±4.0%, F: -15.2±3.6%, p<0.05), with greater effects in males. ACh responses were also reduced with L-NAME in Keap1KO mice (M: -54.5±6.7%, F: -46.4±6.3%, p<0.05) compared to WT (M: -36.5±5.8%, F: -33.7±5.7%, p<0.05). In Nrf2KO mice, vasodilatory responses to L-NAME were minimal, with significant reductions observed only in females (Flow: M: -10.3±3.9%, F: -11.8±4.1%, p<0.05; ACh: M: -18.2±4.7%, F: -20.3±5.1%, p<0.05). PE-mediated vasoconstriction was highest in Nrf2KO and lowest in Keap1KO mice, with more significant changes in males. Conclusion: Oxidative stress is tightly linked in the development of endothelial dysfunction and hypertension. In the present study, we found that modulation of EC Nrf2 alters BP and endothelial mediated vascular function. Systemic responses to the pro-oxidant Ang II are augmented in male Nrf2KO mice while isolated vascular responses are largely similar between male and female mice. These data suggest that sex specific characteristics may present as determining factors in the development and resistance to vascular pathologies. Supported by Theodore F. Hubbard Foundation This abstract was presented at the American Physiology Summit 2025 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.