Abstract Body (Do not enter title and authors here): Background: Smoke or vaporizer aerosol from different tobacco or marijuana products can cause vascular endothelial dysfunction in humans and rodents. Mechanisms of acute smoke-induced endothelial dysfunction are complex and remain ambiguous. We reported that endothelial functional impairment by tobacco smoke is dependent on intact vagus nerves, leading us to hypothesize that endothelial function impaired by smoke/aerosol from tobacco or marijuana relies on vagal input from the airway. Methods: We used Sprague-Dawley rats at 10-12 weeks of age (n=8/group; 4M+4F). Rats were anesthetized by ketamine/xylazine and exposed to one session of exposure to smoke/aerosol of tobacco (Marlboro Red) or marijuana (~10% THC) cigarettes, e-cigarettes (JUUL), or IQOS (American HeatSticks). Exposure was pulsatile (10 cycles of 5s 2x/min for 5 min via nosecone). Endothelial function was assessed as flow-mediated dilation (FMD) in the femoral artery pre- (baseline) and post-exposure. Surgical bilateral cervical vagotomy was performed in the anesthetized rats post-baseline FMD (before exposure). Sham surgical procedures were carried out without severing vagus nerves. We used paired Student t tests to compare FMD values in each group pre- and post-exposure. Significance was P<.05. Results: FMD was decreased from pre- to post-exposure in all exposed sham groups as expected, whereas the impairment of FMD by smoke/aerosol exposure was completely abrogated in all vagotomized groups (Figure), with no apparent effect of sex. The pre- vs. post-exposure FMD values (mean±SD) in exposed sham groups were 16.0±3.0% vs. 6.7±3.1% for tobacco cigarettes, 13.1±2.3% vs. 5.0±2.3% for JUUL, 14.3±3.0% vs. 6.0±2.2% for IQOS, and 16.2±4.9% vs. 7.1±3.6% for marijuana. For exposed vagotomized groups, pre- vs. post-exposure FMD values were 13.3±3.7% vs. 12.6±3.7% for tobacco cigarettes, 12.8±2.6% vs. 13.0±3.2% for JUUL, 13.9±2.2% vs. 13.3±2.7% for IQOS, and 14.4±4.2% vs. 15.1±5.0% for marijuana. Heart rate was increased and respiratory rate was decreased in vagotomized groups as expected. Conclusions: Inhaling smoke or aerosol causes vascular endothelial impairment via a common mechanism involving vagal stimulation from the airway.