The role of NADPH oxidases in central nervous system regulation of hypertension: Mechanisms and therapeutic insights

Hypertension remains a leading global cause of cardiovascular morbidity and mortality, with a significant proportion attributed to central nervous system (CNS) dysregulation. Emerging evidence implicates NADPH oxidases (Nox), particularly Nox2 and Nox4, as pivotal sources of reactive oxygen species (ROS) in brain regions critical for blood pressure control. This review explores the region-specific expression, activation mechanisms, and downstream effects of Nox isoforms within the CNS, focusing on the blood pressure regulatory brain regions, including paraventricular nucleus (PVN), rostral ventrolateral medulla (RVLM), nucleus tractus solitarius (NTS), and circumventricular organs (CVOs). Nox-derived ROS disrupt redox homeostasis, impair baroreflex sensitivity, induce neuroinflammation, and enhance sympathetic nervous system (SNS) activity. The interplay between Nox, the renin-angiotensin system (RAS), and mitochondrial ROS amplifies oxidative signaling and establishes a vicious cycle of neurovascular dysfunction. Furthermore, we will highlight the potential of Nox-targeted interventions and antioxidant therapies, emphasizing their therapeutic promise in attenuating neurogenic hypertension. A deeper understanding of CNS Nox signaling may pave the way for more effective and precise antihypertensive strategies.