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Widespread consumption of diets high in fat, sugars and salt (Western diet, WD) is associated arterial stiffening, which is a major independent risk factor for cardiovascular disease (CVD). Notably, while WD feeding increases the risk of CVD in both males and females, the latter are more prone to develop arterial stiffening. However, the mechanisms underlying WD-induced arterial stiffening are poorly understood, particularly in females, and there are currently no specific treatments targeted at vascular stiffening.Tissue transglutaminase 2 (TG2) is an enzyme that mediates the cross-linking and stabilization of extracellular matrix proteins such as collagen, and promotes the polymerization of actin stress fibers of the cytoskeleton. It is ubiquitously expressed and abundantly present in the vasculature. Mounting evidence implicates TG2 activation in the pathogenesis of arterial stiffening and vascular fibrosis. Herein we propose that TG2 activation is central to WD-induced arterial stiffening and sought to determine the efficacy of cystamine (a non-specific competitive inhibitor of TG2) for reducing arterial stiffening in the setting of WD consumption. Accordingly, we fed 20 female mice (4 weeks old) a WD (4.65 kcal/g of food, fat 46% kcals, high-fructose corn syrup 17.5%, sucrose 17.5%, protein 17.6%, salt 1.6%) for 43 weeks. Ten of these mice received cystamine (40 mg/Kg/d in the drinking water) during their last 8 weeks on the WD. Another group of female mice (n=10) fed regular chow was used as reference controls. Aortic stiffness was measured in vivo via ultrasound-based pulse wave velocity and ex vivo by aortic explant atomic force microscopy. Vasomotor responses were assessed in isolated aortic rings via wire myography.Cystamine did not influence glucose homeostasis (intraperitoneal glucose tolerance test) or blood pressure (tail-cuff) (control 77.208±2.229 mm Hg versus WD 77.208±6.077 versus WD+Cystamine 76.297±7.894), but it was associated with increased body weight (control 26.860±2.215 grams versus WD 25.320±2.889 versus WD+Cystamine 33.220±4.848, p