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Background: Transglutaminase 2 (TG2) is an enzyme involved in the pathogenesis of vascular remodeling in conditions of chronic over-nutrition and activation of the renin angiotensin aldosterone system (RAAS). Furthermore, it has been shown that pharmacologic inhibition of TG2 significantly reduces blood pressure in male rodents. However, the cell-specific role of TG2 activation in vascular smooth muscle cells (VSMC) in mediating the hypertensive response to RAAS overactivation has not been explored. Methods: We generated a novel inducible model (tamoxifen dose: 50 mg/kg/d oral for 6 weeks) of TG2 deletion in VSMC (VSMCTG2KO) by sequentially crossing Tgm2t/t floxed mice (loxP sites flanking exons 6-8 of the TG2, C polypeptide [Tgm2] gene) with male Myh11-CreERT2 positive mice. Effectiveness of the TG2 deletion was evaluated by immunohistochemistry and TG2 activity was determined by incorporation of Alexa Fluor488 Cadaverine.A cohort of fifteen-month-old wild-type and VSMC TG2KO male mice were implanted with deoxycorticosterone (DOCA; 50 mg, 21-day releasing pellets) and 1 % salt added to the drinking water. Systolic blood pressure was assessed by tail-cuff method prior to sacrifice. Ex vivo aortic stiffness was determined by atomic force microscopy. Student t-test or two-way ANOVA were used for statistical analysis as appropriate. The results were considered significant when p Results: administration of DOCA/salt induced increases in systolic blood pressure, augmented expression of TG2 in aorta, as well as increased aortic stiffness in wild-type mice (10.47±1.27kPA DOCA/salt vs. 3.91 + 1.01 kPa placebo). The VSMCTG2KO model exhibited 77% downregulation of TG2 expression in VSMC. VSMC TG2 KO suppressed DOCA/salt induced TG2 activity (29.13 + 2.22 arbitrary units (AU) in DOCA/salt vs 14.10 + 2.90 AU in KO cohort). This was accompanied by a significant improvement in DOCA/ salt-induced hypertension (SBP 142 ± 5.4 mmHg in DOCA/salt treated mice vs. 111.8 ± 6.2 mmHg in VSMCTG2KO). Conclusions: Our data demonstrate for the first-time the key role of TG2 activation in VSMC, in the regulation of hypertensive responses in in a male rodent model of RAAS activation.