Sex differences in neurogenic hypertension: estrogen modulation of NADPH oxidase signaling in the rostral ventrolateral medulla

Abstract

Abstract Neurogenic hypertension is characterized by sustained sympathetic activation arising from dysregulation within the central autonomic network. The rostral ventrolateral medulla (RVLM) is a major sympathetic premotor region that integrates reflex, neurohumoral, inflammatory, and metabolic signals. Oxidative stress within the RVLM can increase neuronal excitability, enhance glutamatergic transmission, weaken nitric oxide-dependent GABAergic inhibition, and promote sympathetic activation. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are important sources of reactive oxygen species in this region. Direct anatomical evidence is the strongest for components of the NADPH oxidase 2 (NOX2) complex, whereas the cellular distribution and functional roles of Nox1, Nox4, and other isoforms remain less clearly defined. Current evidence more strongly supports RVLM Nox-related oxidative stress as a mechanism that amplifies and maintains established hypertension than as an independent initiator of chronic hypertension. Sex and ovarian hormone status modulate these redox and autonomic mechanisms. Estrogen signaling can influence neuronal excitability, inflammation, and oxidative balance, but its effects depend on receptor subtype, endocrine state, exposure pattern, age, and hypertensive background. Estradiol replacement after ovarian hormone loss may reduce RVLM oxidative stress, whereas prolonged exposure in intact cycling animals may increase superoxide production and Nox-related gene expression. Human studies also associate menopause with altered blood pressure, arterial stiffness, sympathetic activity, and baroreflex regulation, although direct evidence for estrogen receptor and Nox signaling within the human RVLM remains lacking. This review summarizes current evidence and highlights priorities for mechanistic and translational research.