Preeclampsia (PE) is a pregnancy specific disorder associated with maternal hypertension and endothelial dysfunction caused by the release of anti-angiogenic and pro-inflammatory factors from the ischemic placenta. In addition, PE is associated with depletion of nitric oxide (NO), which, during normal pregnancy, binds to soluble guanylate cyclase (sGC), and synthesizes cGMP, to facilitate vasodilation. A recently developed drug, sGC activators have been shown to bind to the sGC molecule and increase activity independently of NO. However, whether these drugs might have therapeutic potential in PE is not known. We tested the hypothesis that sGC activators attenuates blood pressure in a placental ischemic rat by improving vascular function. Sprague-Dawley rats underwent Sham or RUPP (Reduced Uterine Perfusion Pressure) surgery on gestational day (GD) 14, where silver clips were placed on the abdominal aorta and branches of the ovarian artery to induce placental ischemia. Animals were then placed on placebo (P) or sGC activator (80 ppm, BAY 60-2770) -supplemented (sGC-A) diets, ad libitum, from GD14-19. To determine the effect of sGC activators on vascular function, uterine arteries were isolated from Sham and RUPP operated rats and mounted on a wire myograph. Vessels were pre-constricted and vasodilation was assessed by increasing doses of the sGC activator (Cinaciguat; Sigma, St Louis, MO). On GD19, RUPP surgery had significantly increased mean arterial blood pressure as expected (Sham+P, n =6, 100±6 mmHg; RUPP+P, n =6, 117±4 mmHg; P<0.01), and was attenuated by treatment with the sGC activator (RUPP+sGC-A, n =6, 108±6 mmHg; P=0.02). Interestingly, in the presence of sGC activators (Cinaciguat), uterine arteries isolated from RUPP rats exhibited significantly improved vasodilation at doses of 1μM (Sham, n =5, 7±0.5 %; RUPP, n =3, 25±0.8 %; P<0.01) and 5μM (Sham, n =5, 7±0.5 %; RUPP, n =3, 28±1 %; P<0.01) compared to the Sham group. The results of this study demonstrate that activating sGC can reduce blood pressure by improving vascular function in the RUPP rat. In conclusion, these findings suggest there could be a therapeutic potential for treating preeclampsia with sGC activators.