The Endothelin Type A Receptor as a Potential Therapeutic Target in Preeclampsia

Abstract

Preeclampsia (PE) is a disorder of pregnancy typically characterized by new onset hypertension after gestational week 20 and proteinuria. Although PE is one of the leading causes of maternal and perinatal morbidity and death worldwide, the mechanisms of the pathogenesis of the disease remain unclear and treatment options are limited. However, there is increasing evidence to suggest that endothelin-1 (ET-1) plays a critical role in the pathophysiology of PE. Multiple studies report that ET-1 is increased in PE and some studies report a positive correlation between ET-1 and the severity of symptoms. A number of experimental models of PE are also associated with elevated tissue levels of prepro ET-1 mRNA. Moreover, experimental models of PE (placental ischemia, sFlt-1 infusion, Tumor necrosis factor (TNF) -α infusion, and Angiotensin II type 1 receptor autoantibody (AT1-AA) infusion) have proven to be susceptible to Endothelin Type A (ET_A) receptor antagonism. While the results are promising, further work is needed to determine whether ET antagonists could provide an effective therapy for the management of preeclampsia.

Keywords: blood pressure; cardiovascular; endothelin; endothelium; hypertension; placenta; preeclampsia; pregnancy; vascular smooth muscle.

Figure 1

Factors leading to hypertension in response to placental ischemia. Placental ischemia is associated with increases in several factors, such as matrix metalloproteinases (MMPs), angiotensin II type 1 receptor autoantibody (AT1-AA), tumor necrosis factor-α (TNF-α), soluble endoglin, and soluble fms-like tyrosine kinase-1 (sFlt-1). MMPs cleave big endothelin to active endothelin. These circulating factors lead to increased levels of vascular endothelin-1 (ET-1) expression and subsequent ET_A activation, resulting in hypertension. ET antagonists may reduce hypertension, therefore improving maternal and fetal outcomes.