Mechanistic insights into atrazine-driven endothelial dysfunction: The contribution of endoplasmic reticulum stress.

Atrazine (ATZ) is one of the most used herbicides worldwide. To date, its impact on vascular function and the potential role as a risk factor for cardiometabolic diseases remain poorly investigated. Here, we demonstrated using mouse aorta rings and an endothelial cell line that ATZ selectively impairs endothelial function without affecting vascular smooth muscle responsiveness. In isolated mouse aorta, ATZ exposure (100 nM and 1 µM) did not alter phenylephrine-induced contraction or sodium nitroprusside-mediated relaxation, indicating preserved smooth muscle function. However, ATZ significantly reduced acetylcholine- and isoprenaline-induced relaxation, suggesting a specific disruption of NO signaling. In bovine aortic endothelial cells, short-term ATZ exposure (100 nM, 30 min) affected eNOS activity in terms of a reduced eNOS dimer/monomer ratio, accompanied by decreased NO production and increased reactive oxygen species (ROS) generation, implicating eNOS uncoupling as the primary early source of oxidative stress. Prolonged exposure (100 nM, 6 h) triggered endoplasmic reticulum (ER) stress through an increase in Nox4 and ROS levels, followed by the activation of PERK/ATF4/CHOP axis. This was coupled to an increase in IL-6 and IL-8. After 24 h, PERK activation and Nox4 upregulation persisted with a trend of increase in ATF4/CHOP, suggesting a time-dependent modulation of ER stress pathways. Additionally, sustained ROS production and elevated IL-6 levels indicate a transition toward a pro-inflammatory phenotype. Overall, these findings reveal that ATZ rapidly compromises endothelial NO bioavailability, promotes oxidative stress, and activates ER stress and inflammatory pathways, highlighting its potential role in vascular dysfunction and chronic disease development.