Abstract Body: Angiotensin II (ANG) type 1 receptor (AT₁R) belongs to the 7-membrane superfamily of G protein-coupled receptors (GPCR) which have the largest class of drug targets. AT₁Rs can adopt different conformations that can bias G-protein coupling (particularly Gaq) or b-arrestin signaling. The b-arrestin pathway is reported to be cardioprotective while the canonical Gaq-dependent pathway is typically associated with the detrimental effects of ANG. We hypothesize that selective and inducible activation of the AT₁R Gaq pathway in the absence of b-arrestin signaling in vascular smooth muscle (SMC) results in hypertension and vascular dysfunction via an AT₁R-dependent mechanism. We generated an AT₁R mutant (AT₁R^TSTS-AAAA) which ablates the phosphorylation sites for GPCR kinases (GRK) in the C-terminal to impair b-arrestin recruitment and to induce a Gaq bias. Transgenic mice were made with a construct that induces both AT₁R^TSTS-AAAA and tdTomato expression in response to Cre-recombinase. Primary fibroblasts cultured from AT₁R^TSTS-AAAA mice exhibited a Cre-induced expression of tdTomato and marked increase in phosphorylated-extracellular signal-regulated kinase (P-ERK) in response to ANG when compared to mice cells expressing wildtype AT₁R. Mice carrying inducible AT₁R^TSTS-AAAA were bred with tamoxifen-inducible SMC-specific CRE (SMC^CreERT2, S-TSTS) mice. Transgene expression in S-TSTS mice was successfully activated by tamoxifen as measured by the expression of the embedded tdTomato reporter in the aorta SMC. S-TSTS mice exhibited a trend of increased systolic blood pressure (SBP) 1 week after tamoxifen injection (147.76 ± 13.21 vs. 108.85 ± 4.58 mmHg). Candesartan (10 mg/kg/day in drinking water) was then administered to S-TSTS mice once hypertension was established. Candesartan treatment for 1 week reversed the hypertension in S-TSTS mice (100.00 ± 2.88 mmHg). Interestingly, 2 weeks after ending candesartan treatment, SBP was once again elevated in S-TSTS mice (142.01 ± 7.65 vs. 90.35 ± 1.14 mmHg, p<0.05). In addition, mesenteric arteries from transgenic mice exhibited a robust increase in ANG-induced constriction when compared to control mice (ANG, max constriction 60.25 ± 4.78% vs. 14.12 ± 4.72%, p<0.05). Our findings support the hypothesis that signaling through the Gaq-dependent pathway in SMC leads to increased vasoconstriction and hypertension through an AT₁R-dependent mechanism.