Abstract Body: Immune cells like dendritic cells (DCs) and T cells are essential for the development of hypertension. Upregulation of the vasoactive peptide endothelin-1 (ET-1) is key in the progression of hypertension. ET-1 acting via its ET_A receptor raises blood pressure and promotes end-organ damage and inflammation. DCs and T cells express ET-1 receptors and respond to changing levels of ET-1. However, it is unknown whether activation of the ET-1/ET_A receptor axis on DCs or T cells is critical in driving hypertension, or if a differential activation of this axis in immune cells leads to the sex differences that exist in the pathophysiology of this disease. We hypothesized that activation of the ET-1/ ET_A axis on immune cells is crucial in the development of hypertension, with a more prominent role in males than females. Male and female mice lacking ET_A receptor on DCs (DC ET_A KO) or on T cells (T cell ET_A KO) and floxed ET_A control mice were given the nitric oxide synthase inhibitor L-NAME (0.5 mg/mL) in drinking water for 3 wks to induce hypertension. Systolic blood pressure (SBP) was measured 3 times/wk via tail cuff plethysmography. Glomerular filtration rate (GFR) was evaluated at baseline and after L-NAME treatment via the transcutaneous FITC-sinistrin clearance method. Absence of ET_A receptor on DCs resulted in a ~10 mmHg decrease in SBP at baseline in both sexes, and this difference increased throughout the protocol in males (Floxed ET_A vs. DC ET_A KO: L-NAME: 150.8±6.7 vs. 130.8±2.6 mmHg, n=4/group, p=0.002), but not in females (137.4±5.7 vs. 137.2±2.4 mmHg, n=3/group). Lack of the ET_A receptor on T cells led to a similar decrease of ~10 mmHg in SBP at baseline. However, the difference in SBP widened when males were challenged with L-NAME (Floxed ET_A vs. T cell ET_A KO: 135.2±2.0 vs. 118.0±4.1, n=11/group, p=0.003), whereas the group difference in SBP disappeared in females (131.5±4.0 vs. 132.4±4.7, n=8-9/group). Following L-NAME, GFR trended to decline in control male mice, while it increased in T cell ET_A KO males. Our data suggest that activation of ET_A receptors on DCs and T cells modulates SBP in response to a hypertensive insult in males, but not in females. Additionally, absence of ET-1/ ET_A axis activation on T cells suggests improved renal function during hypertension. Our results suggest that the use of ET_A antagonism in the clinic may be more protective during hypertension in males than females.