Abstract and Introduction
Preeclampsia is a hypertensive disorder of pregnancy and the clinical manifestation of severe endothelial dysfunction associated with maternal and foetal morbidity and mortality. The primum movens of the disease is the defect of invasion of the uterine arteries by foetal syncytiotrophoblasts, which causes a maladaptive placental response to chronic hypoxia and the secretion of the soluble form of type 1 vascular growth endothelial factor receptor, also called soluble fms-like tyrosine kinase 1 (sFlt-1), the major player in the pathophysiology of the disease. Among its different effects, sFlt-1 induces abnormal sensitivity of the maternal vessels to the vasoconstrictor angiotensin II. This leads to the hypertensive phenotype, recently shown to be abrogated by the administration of sildenafil citrate, which can potentiate the vasodilatory mediator nitrite oxide. This review focuses on the mechanisms of maternal endothelial dysfunction in preeclampsia and discusses the therapeutic window of sildenafil use in the context of preeclampsia, based on the results from preclinical studies and clinical trials. Safety issues recently reported in neonates have considerably narrowed this window.
Preeclampsia: A Worldwide Syndrome Without a Cure
Preeclampsia is a clinical syndrome occurring after 20 weeks of gestation and typically characterized on the maternal side by new-onset hypertension and proteinuria (>300 mg/day) and other maternal organ dysfunctions, such as renal failure, liver microangiopathy, neurological or haematological complications, utero-placental dysfunction or foetal growth restriction. The pathophysiology relies on a defective invasion of uterine arteries by the extravillous cytotrophoblasts (of unknown causes). A history of preeclampsia is found in up to 12% of cases of intrauterine growth retardation (IUGR) and is associated with preterm birth and foetal death, particularly in its early-onset presentation. The health and economic burden associated worldwide with this syndrome are considerable since 2–8% of pregnant women globally will develop preeclampsia, mostly after 35 weeks of gestational age.[3,4] Immediate maternal mortality due to preeclampsia is estimated to be as high as 50 000 deaths each year, the majority of which are in low-income countries. Longer term, preeclampsia (especially early-onset preeclampsia and recurring preeclampsia) is also associated with an increased risk of cardiovascular events, including fatal ones.[5–9] Beyond this, preeclampsia also increases the cardiovascular risk profile in the offspring, while hypertension, stroke and cognitive impairment are more frequent.[11–13] However, this issue is complex since lifestyle and genes overlap here.
To date, no specific therapeutic intervention has been proven to reduce any of these risks, short or long term and, except for placental delivery, caregivers are left with very few preventive or curative options. Pre- and postpartum hypertension are routinely treated with nonspecific, short-life agents, such as nicardipine, labetalol and alpha-methyldopa.
Endothelial Dysfunction in Preeclampsia: Angiogenic Imbalance and Angiotensin II Sensitivity
Understanding of the pathophysiology of the maternal syndrome has advanced over the last 15 years. In short, it has been repeatedly demonstrated that a preeclamptic placenta secretes several antiangiogenic factors in excess, which contribute to endothelial dysfunction in the mother. It has long been known that the hallmark of such endothelial dysfunction is the exaggerated arterial response to angiotensin II (AngII), whereas pregnancy is assumed to be a state of relative resistance to vasopressors.
Among the antiangiogenic factors, soluble fms-like tyrosine kinase 1 (sFlt-1) is central to the maternal phenotype. sFlt-1 is the soluble form of type 1 vascular endothelial growth factor receptor (VEGFR-1) and acts by trapping and neutralizing both vascular endothelial growth factor A (VEGF-A) and placental growth factor (PlGF), two pro-angiogenic growth factors. Its pathogenic role was first demonstrated in a seminal clinical trial in 2003 in a rat model of preeclampsia shortly after the observation by a team of oncologists that bevacizumab, a monoclonal antibody targeting VEGF-A, like sFlt-1, was frequently complicated by a preeclampsia-like syndrome.[15,16] Strategies that aim to reduce sFlt1 concentration in maternal blood using (nonspecific) extracorporeal devices have shown conflicting results and are not routinely prescribed at the bedside.[17,18]
Sildenafil as a New Hope in the Search for a Cure for Preeclampsia
Recently Burke et al. demonstrated that in the sFlt-1-induced mouse model of preeclampsia, an increased concentration of sFlt-1 was mechanistically involved in abnormal AngII sensitivity and that this abnormal sensitivity could be abrogated by the administration of sildenafil citrate (SC), a phosphodiesterase 5 (PDE5) inhibitor. By diminishing the PDE5-mediated catabolism of cyclic guanosine monophosphate [cGMP; the biological mediator of the potent vasodilator nitric oxide (NO)], SC artificially increases NO-induced vasodilation (Figure 1). This is particularly important in the setting of preeclampsia, where the bioavailability of NO is reduced and is thought to lead to hypertension, platelet aggregation and cellular inflammation.
Mechanisms of vessel relaxation and effect of SC. Relaxation of the vasculature is dependent on the cross-talk between endothelial and smooth muscle cells. The NO is produced by the eNOS and can be induced by various stimuli, including VEGF through VEGFR-2. The gas freely crosses the membrane of the smooth muscle cell to activate cGMP synthase (cGS). The second messenger then stimulates phosphokinase G (PKG), which leads to the dephosphorylation of myosin through direct activation of myosin light chain phosphatase (MLCP) or inhibition of myosin light chain kinase (MLCK) by a reduction the cytoplasmic concentration of calcium (Ca2+). This last phenomenon relies on PKG-dependent stimulation of the membranous and sarcoplasmic Ca2+ adenosine triphosphatase and the Na+–Ca2+ exchanger, which pump out the divalent cation from the cytoplasm. By inhibiting PDE5, SC prevents the degradation of cGMP in 5′-GMP, thus sustaining the cellular stock of cGMP and the relaxation state [20,21]. GTP, guanosine-5′-triphosphate; SR, sarcoplasmic reticulum.
SC was first developed to treat heart failure, but it eventually became the drug of choice to treat erectile dysfunction and then pulmonary hypertension. Of note, SC has no effect on female sexual dysfunction. Based on the observation that vessels from preeclamptic women have a preserved vasodilatory response to NO, PDE5 inhibitors were actually tested in the setting of preeclampsia as early as 2004. Since then, promising in vitro and in vivo animal studies have been published, but in the clinical trials testing SC, the outcome of women with preeclampsia was less favourable. In addition, major safety issues regarding neonates have recently been published and were widely reported in the lay press. This review aims to clarify the perspectives afforded by the most recent experimental and clinical studies. We performed a literature search using the PubMed database, with PDE5, sildenafil, preeclampsia, foetal growth retardation and pregnancy as Medical Subject Headings (MeSH) keywords and with no date limitation.
Nephrol Dial Transplant. 2019;34(11):1819-1826. © 2019 Oxford University Press