Animal models of preeclampsia: investigating pathophysiology and therapeutic targets

Hypertensive disorders of pregnancy-chronic hypertension, gestational hypertension, and preeclampsia-are uniquely challenging as the pathology and its therapeutic management simultaneously affect mother and fetus, sometimes putting their well-being at odds with each other. Preeclampsia, in particular, is one of the most feared complications of pregnancy. Often presenting as new-onset hypertension and proteinuria during the third trimester, preeclampsia can progress rapidly to serious complications, including death of both mother and fetus. While the cause of preeclampsia is still debated, clinical and pathological studies suggest that the placenta is central to the pathogenesis of this syndrome. In this review, we will discuss the current evidence for the role of abnormal placentation and the role of placental factors such as the antiangiogenic factor, sFLT1 (soluble fms-like tyrosine kinase 1) in the pathogenesis of the maternal syndrome of preeclampsia. We will discuss angiogenic biomarker assays for disease-risk stratification and for the development of therapeutic strategies targeting the angiogenic pathway. Finally, we will review the substantial long-term cardiovascular and metabolic risks to mothers and children associated with gestational hypertensive disorders, in particular, preterm preeclampsia, and the need for an increased focus on interventional studies during the asymptomatic phase to delay the onset of cardiovascular disease in women.

Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality. The pathophysiology of preeclampsia remains largely unknown. It has been hypothesized that placental ischemia is an early event, leading to placental production of a soluble factor or factors that cause maternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. Here, we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1 that fall after delivery. We demonstrate that increased circulating sFlt1 in patients with preeclampsia is associated with decreased circulating levels of free VEGF and PlGF, resulting in endothelial dysfunction in vitro that can be rescued by exogenous VEGF and PlGF. Additionally, VEGF and PlGF cause microvascular relaxation of rat renal arterioles in vitro that is blocked by sFlt1. Finally, administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia. These observations suggest that excess circulating sFlt1 contributes to the pathogenesis of preeclampsia.

Pre-eclampsia is a complication of pregnancy that is associated with substantial maternal and fetal morbidity and mortality. The disease presents with new-onset hypertension and often proteinuria in the mother, which can progress to multi-organ dysfunction, including hepatic, renal and cerebral disease, if the fetus and placenta are not delivered. Maternal endothelial dysfunction due to circulating factors of fetal origin from the placenta is a hallmark of pre-eclampsia. Risk factors for the disease include maternal comorbidities, such as chronic kidney disease, hypertension and obesity; a family history of pre-eclampsia, nulliparity or multiple pregnancies; and previous pre-eclampsia or intrauterine fetal growth restriction. In the past decade, the discovery and characterization of novel antiangiogenic pathways have been particularly impactful both in increasing understanding of the disease pathophysiology and in directing predictive and therapeutic efforts. In this Review, we discuss the pathogenic role of antiangiogenic proteins released by the placenta in the development of pre-eclampsia and review novel therapeutic strategies directed at restoring the angiogenic imbalance observed during pre-eclampsia. We also highlight other notable advances in the field, including the identification of long-term maternal and fetal risks conferred by pre-eclampsia.