Gasotransmitters: a solution for the therapeutic dilemma in preeclampsia?

P reeclampsia complicates 2% to 8% of all pregnancies and is a major contributor to maternal mortality worldwide. The only therapy is delivery, often before term. 1 Nitric oxide, carbon monoxide, and hydrogen sulfide are gasotransmitters that regulate vascular development, vascular tone, and affect antioxidant status. 2 Abnormalities in gasotransmitter signaling and production are linked to hypertension, atherosclerosis, and inflammation. 2 Drugs that enhance gasotransmitter signaling have proven therapeutic potential in the clinical and experimental setting. Gasotransmitters are involved in the vascular adaptations of normal pregnancy, 3–7 and experimental studies have shown that abnormal production is associated with preeclampsia. The aim of this review is to give an overview of the role of gasotransmitters in the physiology of pregnancy and relate their aberrant production to preeclampsia. Specific emphasis will be put on and overview their therapeutic potential for preeclampsia. Preeclampsia Preeclampsia is defined by hypertension and proteinuria during the second half of gestation. Although the exact cause of preeclampsia is unknown, the placenta and the maternal inflammatory response play a key role in its pathogenesis. Preeclampsia is often described as a 2-stage disease. During placentation in normal pregnancy, trophoblasts invade into the endometrium and spiral arteries resulting in spiral artery dilation. 1 In preeclampsia, trophoblast invasion is incomplete resulting in inadequate spiral artery remodeling and placental hypoperfusion; this is stage 1 of the disease. 1 Subsequently, the oxygen-deprived placenta produces factors that enter the maternal circulation, causing maternal endothelial dysfunc-tion and maternal immune response activation, leading to the signs of preeclampsia; this is stage 2 of the disease. 1 Some of the factors produced by the placenta are antian-giogenic factors, such as soluble fms-like tyrosine kinase receptor 1 (sFlt1). 14 They are (partly) responsible for the maternal syndrome in preeclampsia because increased sFlt1 is associated with reduced levels of its circulating proangio-genic ligands, placental growth factor, and vascular endothe-lial growth factor (VEGF). 14 In addition, preeclamptic women have less transforming growth factor-β caused by increased placental production of soluble transforming growth factor-β coreceptor endoglin (sEng). 15 Alterations in (anti)-angiogenic factors are thought to lead to endothelial dysfunction and consequently hypertension and proteinuria. The systemic inflammatory response is activated during normal pregnancy and exaggerated in preeclampsia. 13 An improper activated inflammatory response is linked to abnormal tropho-blast invasion, endothelial cell damage, and renal dysfunction. 13 Several proinflammatory factors, such as tumor necrosis factor-α and interleukin-6, are released by the preeclamptic placenta. …