Endothelial Nitric Oxide synthase (eNOS) in Preeclampsia: An Update

Abstract

Preeclampsia (PE) is a common pregnancy-related hypertensive disorder and is a leading cause of maternal and perinatal morbidity and mortality. The incidence of PE and its associated health care costs have been increasing in the United States over the past three decades. Pregnancies complicated by PE put both the mother and child at increased risk for chronic illnesses such as cardiovascular disease, cerebrovascular disease, and cognitive impairment later in life. To date, there is no effective treatment for PE and the etiology of PE is largely unknown. While human epidemiological studies have established an association between various genetic factors and PE, a causative link between genes associated with PE and PE development has been difficult to establish. Human studies have shown that variants in eNOS (endothelial nitric oxide synthase, also known as NOS3) gene are associated with PE, and animal experimental studies have provided evidence to show the potential functional connection between the eNOS gene and PE. Here we review several studies that investigated the role of eNOS in PE, as well as studies that described how manipulating the eNOS/NO pathway could aid in disease intervention.

Figure 1:

The potential role of pre-existing maternal conditions in risk of PE. Detrimental factors (blue stars) from low degree inflammation and hypertensive conditions caused by eNOS polymorphisms influence both endothelial cells and placentation negatively. Poor placentation increases antiangiogenic (sFlt1) and inflammatory (TNFα) factors and decreases angiogenic factors (VEGF, PLGF) in maternal circulation. Placental dysregulation of these factors worsens endothelial dysfunction and PE symptoms.

Figure 2:

Mechanism illustrating the potential role of eNOS in PE. eNOS−/− placentas develop hypoxia/ischemia, which causes fetal growth restriction, while maternal symptoms of PE are not exhibited because sFlt1 production is low due to a lack of eNOS. When eNOS−/− mice overexpress sFlt1 through exogenous source (Adv-sFlt1), they exhibit aggravated endothelial dysfunction and symptoms of PE (more severe hypertension, endotheliosis, and proteinuria). ⊣: inhibiting sFlt1 production.