Engineered nanomaterials (ENM) are present in numerous activities; however, proper EMN toxicological assessments are typically incomplete. Previous studies demonstrate that ENM exposure is linked to adverse cardiovascular outcomes, including stroke. The cerebral microcirculation is essential for blood flow regulation in the brain and as such, dysfunction may augment the risk of stroke. The impact of pulmonary nano-titanium dioxide (TiO2) exposure on the cerebral microcirculation is unknown. To determine if acute nano-TiO2 exposure mediates microvessel endothelial dysfunction, intra-tracheal instillation was used to deliver 240 µg of nano-TiO2 to male and female Sprague-Dawley rats 24 h prior to surgery. The middle cerebral arteries (MCAs) were then isolated and assessed for vasoactivity to acetylcholine (ACh) or phenylephrine (PE). Since endothelial dysfunction can be induced by elevation in rates of oxidant generation, potentially via increased endothelium-associated xanthine oxidase (XO) activity, we then exposed MCAs to the XO-specific inhibitor, febuxostat (10 μM) for 30 min prior to ACh-induced dilation. Nano-TiO2 exposure decreased MCA endothelium-dependent dilation (p<0.05) in both genders. However, febuxostat treatment restored the impaired dilation response in male rats whereas no effect was observed in females. Interestingly, PE-induced constriction of MCAs was also attenuated (p<0.05) in rats exposed to nano-TiO2 compared to controls, suggesting overall MCA function was significantly decreased with nano-TiO2 exposure. In toto, these data provide evidence demonstrating that MCA endothelium-dependent dilation and constriction is significantly impaired 24 h post exposure to nano-TiO2. Incubation with a XO inhibitor improves this dysfunction but only in males, suggesting 1) a contributory role for XO in mediating nano-TiO2 toxicity in the vasculature and 2) an interesting sex-related difference in the compromised cerebral microvascular health after nano-TiO2 exposure. Experiments are underway to discover the underlying mechanism(s) that contribute to these observations.