Delayed conception or sildenafil prevents endothelial dysfunction in pregnant rats after renal ischemia-reperfusion

Nearly half of AKI patients are female and the incidence is rising. Pregnant women with a history of AKI experience disproportionately high adverse pregnancy outcomes even after clinical measures suggest renal recovery. Many adverse outcomes of pregnancy are mediated by endothelial dysfunction but the vascular consequences post-AKI in females remain to be identified. Furthermore, whether endothelial dysfunction is a mediator of poor pregnancy outcomes induced by a history of AKI is unexplored. We tested the hypothesis that renal ischemia-reperfusion (IR) results in sustained endothelial dysfunction in females in extra-renal, peripheral vascular tissues, and this contributes to adverse pregnancy outcomes post-IR as a model of AKI in rats. Female Sprague-Dawley rats underwent 45-min bilateral renal IR or sham surgery. Rats were randomized to sham, mated 30-days or 6-months post-IR, or placed on control chow or chow supplemented with sildenafil (phosphodiesterase-5 inhibitor, 12.5 mg/day) starting 15 days post-IR and throughout gestation. Mesenteric arteries isolated from rats that became pregnant 30-days post-IR exhibited lower acetylcholine-mediated vasorelaxation compared to sham controls. In contrast, rats allowed to recover for 6 months post-IR did not exhibit endothelial dysfunction in pregnancy, however, vascular contractility was increased. Sildenafil treatment in 30-day post-IR dams also restored endothelial function, lowered uterine artery resistance index, and improved fetal outcomes. These findings indicate that endothelial dysfunction contributes to adverse pregnancy outcomes after AKI and highlight vascular recovery, either via delaying conception or pharmacological intervention, as a potential preventative strategy for this high-risk pregnancy population.