Understanding these negative findings will be helpful for the development of future therapies. This could help to provide a possible explanation for the negative findings obtained with sildenafil in the above-mentioned clinical trials. The aim of our study is to evaluate the effects of sildenafil on NO-mediated vasodilation in the foetoplacental vasculature, to evaluate placental transfer in healthy and PE placentas, and to study placental expression levels of components of the NO pathway under healthy and PE conditions. recently showed that sildenafil crosses the placenta of healthy term pregnancies, however to our knowledge this has never been performed in PE placentas. Dual ex vivo perfusion of a single placental cotyledon is the only reliable experimental method to study drug transfer across the human placental barrier to date. Hence, besides transfer, study of the placenta can give insight into vascular effects of sildenafil in the foetus. When considering drugs for treatment in human pregnancy, it is essential to know the trans-placental transfer and effects on the placental vasculature. These results emphasise the importance of taking into account the possible effects that maternal medication use can have on the foetus. However, an international consortium of large multi-centre randomised controlled trials (the STRIDER study), investigating the effect of sildenafil compared to placebo on pregnancy outcome in extreme FGR due to placental insufficiency, was recently halted due to lack of beneficial effects in the first two cohorts and an increase in neonatal morbidity and mortality in the treatment group of one cohort. īecause of its potential to improve placental hypoperfusion by increasing systemic vasodilation, sildenafil has been considered for the treatment of PE and FGR over the last years. In PE animal models, sildenafil improved foetal outcome and diminished maternal symptoms by increasing blood flow to the uterus. Sildenafil is currently approved for the treatment of erectile dysfunction and pulmonary hypertension. Sildenafil, as a phosphodiesterase-5 (PDE5) inhibitor, enhances vasodilation mediated by the NO pathway, by inhibiting degradation of active cGMP into inactive GMP by PDE5. However, in women with PE these plasma levels are significantly lower. Throughout normal pregnancy there is an increase in maternal plasma levels of NO, as well as NO-stimulating factors such as vascular endothelial growth factor and placental growth factor. īesides regulation of vascular tone, NO also plays an important role in cytotrophoblast invasion of the receptive endometrium and subsequent spiral artery remodelling during early pregnancy. By activating soluble guanylate cyclase (sGC), NO induces an increase in production of cyclic guanosine 3′,5′-monophosphate (cGMP), leading to vasodilation through closure of Ca 2+ channels. NOS enzymes are present in various cell types including endothelial cells and foetal trophoblasts, and stimulation of these enzymes (e.g., by endothelial shear stress or oestrogen) results in the production of NO through catalysis of L-arginine. NO acts as an important vasodilator, synthesised by a family of nitric oxide synthases (NOS), predominantly endothelial NOS (eNOS) and inducible NOS (iNOS). One of the key features of this endothelial dysfunction is a decreased activity of the nitric oxide (NO) pathway, , ]. Therefore, developing new treatment options to treat PE and safely prolong pregnancy is of great importance.Īlthough the aetiology of PE remains largely unknown, it finds its origin in early pregnancy with suboptimal placentation, characterised by increased placental vascular resistance and hypoperfusion, leading to systemic endothelial dysfunction, , ]. The only cure is termination of pregnancy to deliver the placenta, which often leads to preterm birth of the foetus. Many antihypertensive agents have been studied over the years, but they at most temporarily stabilise the clinical manifestations of PE, without directly targeting placental hypoperfusion. Currently, PE treatment is aimed at symptom relief and prevention of further complications in an attempt to prolong pregnancy until term. For example, PE increases the maternal risk of developing cardiovascular disease and can cause persistent vascular dysfunction in the systemic and pulmonary circulation of the offspring, whereas preterm birth and low birthweight greatly increase the risk of cardiopulmonary morbidity and neurodevelopmental impairment later in life. Besides increasing the risk of adverse events during pregnancy, placenta-related diseases have lifelong consequences for the health of both mother and child. Suboptimal development of the placenta results in serious pregnancy complications such as preeclampsia (PE) and foetal growth restriction (FGR), that contribute significantly to perinatal and maternal morbidity and mortality.
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