ENDOTHELIAL OXIDATIVE STRESS AND eNOS UNCOUPLING AS DETERMINANTS OF THE LOSS OF ENDOTHELIUM-DEPENDENT VASODILATION IN EARLY CARDIOVASCULAR DISEASES

Abstract

Introduction: Endothelial dysfunction emerges early in cardiovascular disease as a functional alteration preceding overt structural vascular lesions and is strongly shaped by redox imbalance and reduced nitric oxide bioavailability. Objectives: To integrate, from a mechanistic perspective, the physiological basis of endothelial signaling, the molecular mechanisms of oxidative stress and eNOS uncoupling, and their functional impact on endothelium-dependent vasodilation, with emphasis on early cardiovascular disease. Material and methods: Mechanistic narrative review of peer-reviewed literature from the last five years, in English, Portuguese, and Spanish, retrieved from indexed databases (PubMed/MEDLINE, Scopus, SciELO, and BVS), excluding grey literature and duplicates. Results: Endothelial oxidative stress decreases NO bioavailability through rapid chemical inactivation and impairment of NO–cGMP signaling, while promoting oxidation of critical cofactors. eNOS uncoupling represents a central inflection point by combining reduced NO synthesis with increased reactive oxygen species generation, reinforcing a self-sustained dysfunctional endothelial phenotype. Functionally, this drives progressive loss of endothelium-dependent vasodilation, with early hemodynamic and microvascular consequences detectable before advanced structural remodeling, thereby contributing to vascular stiffness and pro-inflammatory/pro-thrombotic shifts. Conclusions: The oxidative stress–eNOS uncoupling–loss of endothelium-dependent vasodilation axis constitutes a mechanistic continuum that shapes early cardiovascular disease. Coherent therapeutic strategies should target durable restoration of vascular redox balance, preservation of cofactors and NO–cGMP efficiency, and sustained eNOS recoupling.