Abstract Body: Type 2 Diabetes Mellitus is characterized by chronic hyperglycemia and impaired insulin secretion. Lipid peroxidation and oxidative stress contribute to its complications by promoting inflammation and vascular dysfunction. A model to study lipid peroxidation uses tert-Butyl hydroperoxide (t-BHP). Recent evidence suggests that lipid peroxidation by-products can activate olfactory receptor 2 (Olfr2), triggering oxidative stress and activating NLR family pyrin domain containing 3 inflammasome (NLRP3), absent in melanoma 2 (AIM2) and related inflammatory pathways. However, the link between Olfr2 activation through lipid peroxidation and vascular dysfunction remains unclear. We hypothesize that lipid peroxidation induces vascular dysfunction through Olfr2 activation. Methods: Thoracic aortas from 14–16-week-old male wild-type, lean and db/db mice were mounted in a wire myograph. Concentration-response curves to phenylephrine and acetylcholine (1 nM to 30 µM) were obtained before and after 30-minute incubations with t-BHP (100 nM) or citral (10 µM) plus t-BHP (100 nM) or only citral (10 µM). Olfr2, NLRP3, and AIM2 expression was assessed by qPCR. Data are expressed as mean ± S.E.M. (n=4-6) and the negative logarithm of the effective concentration 50 (pEC₅₀) and the maximum efficacy (E_max) were calculated by non-linear regression curve. *p<0.05 was considered significant. Results: t-BHP reduced acetylcholine-induced relaxation in wild-type (E_max=39.7 ± 5.5%*; pEC₅₀=6.1 ± 0.2 vs E_max=80.4 ± 6.4%; pEC₅₀=6.5 ± 0.1) and db/db mice (E_max=3.3 ± 2.3%*; pEC₅₀=6.1 ± 0.4 vs E_max=15.1 ± 2.3%; pEC₅₀=6 ± 0.1), and increased phenylephrine-induced contraction in wild-type (E_max=7.5 ± 0.3*; pEC₅₀=7.2 ± 0.1 vs E_max=4.7 ± 0.2; pEC₅₀=7.0 ± 0.1) and lean (E_max=7.8 ± 0.4*; pEC₅₀=7.5 ± 0.1 vs E_max=4.7 ± 0.4; pEC₅₀=7.2 ± 0.2). In contrast, citral plus t-BHP enhanced relaxation in wild-type (E_max=78.3 ± 2.9%*; pEC₅₀=6.2 ± 0.4) and db/db mice (E_max=10.9 ± 3.3%*; pEC₅₀=6.2 ± 0.4), while attenuating contractile responses in wild-type (E_max=5.3 ± 0.3*; pEC₅₀=6.7 ± 0.1), lean (E_max=5.4 ± 0.3*; pEC₅₀=7.3 ± 0.2), and db/db mice (E_max=4.7 ± 1*; pEC₅₀=7.6 ± 1.0) versus t-BHP. Citral alone had no effect on contraction in wild-type (p=0.7). t-BHP increased Olfr2, NLRP3, and AIM2 expression, which was reduced by citral plus t-BHP in wild-type aortas. Conclusions: These results suggest that Olfr2 activation contributes to lipid peroxidation-induced vascular dysfunction.