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ACUTE EXPOSURE TO NANO‐TIO 2 PARTICLES CAUSES SEVERE ENDOTHELIUM‐ DEPENDENT DYSFUNCTION IN THE MIDDLE CEREBRAL ARTERY
Author(s) -
Branyan Kayla D.,
DeVallance Evan,
Abukabda A,
kelley Kelley,
Nurkiewicz Timothy R.,
Chantler Paul D.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.722.23
Subject(s) - febuxostat , endothelial dysfunction , medicine , oxidative stress , xanthine oxidase inhibitor , middle cerebral artery , xanthine oxidase , cerebral arteries , endothelium , pharmacology , acetylcholine , cerebral circulation , phenylephrine , anesthesia , hyperuricemia , chemistry , blood pressure , biochemistry , ischemia , uric acid , enzyme
Background The use of engineered nanomaterials (ENM) is increasing; 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 key in regulating cerebral blood flow and any dysfunction may increase the risk of stroke. The direct impact of exposure to nano‐titanium dioxide (TiO 2 ) on cerebral microvasculature is unknown. Methods To determine whether acute nano‐TiO 2 exposure causes cerebral endothelial dysfunction, intratracheal instillation was used to deliver 240 μg of TiO 2 suspended in 300 μl of sterile PBS vehicle to male and female Sprague‐Dawley rats 24 hours prior to surgery. The middle cerebral arteries (MCAs) were isolated and hung in a pressurized myobath. To assess endothelial‐dependent function, MCAs were challenged with increasing doses of acetylcholine (ACh; endo dependent dilation) and phenylephrine (PE; α‐adrenergic‐mediated constrictor). As endothelial dysfunction can be caused by oxidative stress, possibly through increased xanthine oxidase activity. To explore this, MCAs were incubated with Febuxostat (10 μM), a xanthine oxidase inhibitor, for 30 mins prior to treatment with Ach. To examine the effects of oxidative stress on MCA function we then exposed MCAs to the XO‐specific inhibitor, febuxostat (10 μM) for 30 min prior to ACh‐induced dilation. Results TiO 2 exposure decreased MCA endothelium‐dependent dilation (p<0.05) in both sexes. 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‐TiO 2 compared to controls, suggesting overall MCA function was significantly decreased with nano‐TiO 2 exposure. Conclusion These data provide evidence that acute exposure to nano‐TiO 2 significantly impairs MCA endothelium‐dependent dilation and constriction. However, incubation with a XO inhibitor limits this dysfunction but only in males, suggesting 1) a contributory role for XO in mediating TiO 2 toxicity in the vasculature, and 2) an interesting sex‐related difference in the compromised cerebral microvascular health after nano‐TiO 2 exposure. Experiments are underway to discover the underlying mechanism(s) that contribute to these observations. Support or Funding Information NIH ES015022 (TRN); NIHGMS 1P20 GM‐109098 (PDC), AHA 16PRE30820000 (ED) This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .