Soluble Guanylate Cyclase Activators Increase cGMP Expression and Improve Vascular Function and Placental Ischemia‐Induced Hypertension

Abstract

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, nitric oxide (NO), which typically binds to soluble guanylate cyclase (sGC), and synthesizes cGMP, to facilitate vasodilation, is depleted in PE and contributes to vascular dysfunction. A novel class of drug, sGC activators, which are in clinical trials for pulmonary hypertension and heart failure, have been shown to bind to the sGC molecule and increase cGMP activity independently of NO. However, the therapeutic potential of sGC activators during PE is not known. We tested the hypothesis that sGC activators attenuate blood pressure in a placental ischemic rat model of PE by increasing cGMP production and 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 (sGC‐A, 16 ppm, BAY 60‐2770) ‐supplemented diets, ad libitum, from GD14–19. On GD19, blood pressure was measured via indwelling catheter and uterine arteries were harvested to determine endothelium‐dependent vasorelaxation and cGMP expression. To determine the effect of sGC activator treatment on vascular function, uterine arteries from placebo or sGC activator‐supplemented rats were mounted on a wire myograph and pre‐constricted, followed by endothelium‐dependent vasorelaxation. A subset of uterine arteries from these rats were also prepared to determine expression of cGMP. RUPP surgery significantly increased mean arterial blood pressure (Sham+P, n=20, 105±9 mmHg; RUPP+P, n=19, 126±13 mmHg; P<0.05), and this was attenuated by treatment with the sGC activator (RUPP+sGC‐A, n=11, 107±8 mmHg; P<0.05). RUPP surgery induced endothelial dysfunction in uterine arteries (% relaxation, Sham+P, n=6, 92±2 %; RUPP+P, n=5, 34±12%, P<0.05), which was restored in the sGC activator treated group (RUPP+sGC‐A, n=5, 103±2%, P<0.05). Finally, cGMP was reduced in uterine arteries of RUPP‐operated animals (Sham+P, n=3, 0.11±0.009 pmol/mg; RUPP+P, n=3, 0.033±0.009 pmol/mg, P<0.05); however, sGC activation significantly increased cGMP production in the treated group (RUPP+sGC‐A, n=3, 0.127±0.013 pmol/mg, P<0.05). The results of this study demonstrate that activating sGC can reduce blood pressure by restoring cGMP production and improving vascular function in the RUPP rat. In conclusion, these findings suggest there could be a therapeutic potential for treating PE with sGC activators.Support or Funding InformationThis research was supported by the American Heart Association (18POST33990293) and the National Institutes of Health (P01HL051971, P20GM104357).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.