Association Studies Suggest a Key Role for Endothelin-1 in the Pathogenesis of Preeclampsia and the Accompanying Renin–Angiotensin–Aldosterone System Suppression

Abstract

P reeclampsia is a pregnancy-related disorder, clinically characterized by the new onset of proteinuria and hypertension in the second half of pregnancy, with a great effect on maternal and fetal morbidity and mortality worldwide. 1A better understanding of the pathogenic mechanisms underlying preeclampsia might help identifying biomarkers that allow early diagnosis and treatment of preeclampsia. Recently, disturbances in angiogenic balance (favoring antiangiogenic over proangiogenic factors), elevated endothelin-1 (ET-1) levels, and a suppressed renin-angiotensin-aldosterone system (RAAS) have been reported. [2][3][4] As a consequence, the ratio of the antiangiogenic soluble Fms-like tyrosine kinase-1 (sFlt-1) and the proangiogenic placental growth factor (PlGF) is now thought to be a reliable biomarker for the diagnosis of preeclampsia. 5 In fact, patients with a ratio ≥85 have a poor pregnancy outcome independent of their clinical diagnosis compared with patients with a ratio <85. 5Of interest, treatment of cancer patients with antiangiogenic drugs (which, like sFlt-1, prevent the actions of vascular endothelial growth factor [VEGF]) resulted in hypertension, proteinuria, renin suppression, and elevated ET-1 levels. 6 Animal studies with antiangiogenic drugs additionally revealed that the renal histological changes observed during such treatment, in particular glomerular endotheliosis, resembled the renal alterations observed in preeclampsia. 7 From the observation that the dual ET A/B receptor antagonist macitentan prevented both the rise in blood pressure and proteinuria during Abstract-Women with preeclampsia display low renin-angiotensin-aldosterone system activity and a high antiangiogenic state, the latter characterized by high levels of soluble Fms-like tyrosine kinase (sFlt)-1 and reduced placental growth factor levels. To investigate whether renin-angiotensin-aldosterone system suppression in preeclampsia is because of this disturbed angiogenic balance, we measured mean arterial pressure, creatinine, endothelin-1 (ET-1), and reninangiotensin-aldosterone system components in pregnant women with a high (≥85; n=38) or low (<85; n=65) soluble Fms-like tyrosine kinase-1/placental growth factor ratio. Plasma ET-1 levels were increased in women with a high ratio, whereas their plasma renin activity and plasma concentrations of renin, angiotensinogen, and aldosterone were decreased. Plasma renin activity-aldosterone relationships were identical in both the groups. Multiple regression analysis revealed that plasma renin concentration correlated independently with mean arterial pressure and plasma ET-1. Plasma ET-1 correlated positively with soluble Fms-like tyrosine kinase-1 and negatively with plasma renin concentration, and urinary protein correlated with plasma ET-1 and mean arterial pressure. Despite the lower plasma levels of renin and angiotensinogen in the high-ratio group, their urinary levels of these components were elevated. Correction for albumin revealed that this was because of increased glomer...

Proton Pump Inhibitors Decrease Soluble fms-Like Tyrosine Kinase-1 and Soluble Endoglin Secretion, Decrease Hypertension, and Rescue Endothelial Dysfunction

“…31 Administering PPIs to HUVECs reduced endothelin-1 mRNA expression ( Figure 4C) and protein secretion ( Figure 4D). PPIs also decreased endothelin-1 mRNA expression in uterine microvascular endothelial cells ( Figure S6C).…”

Mechanisms of Hypertension and Renal Injury During Vascular Endothelial Growth Factor Signaling Inhibition

“…32,39 In preeclampsia, the rise in circulating ET-1 levels is directly related to the rise in the endogenous VEGF inhibitor sFlt-1. 40 As demonstrated in mice, showing a 65% to 85% decrease in ET-1 levels after knockout of the ET-1 gene in ECs, the main source of circulating ET-1 levels is vascular ECs. 41 Whether the observed rise in ET-1 after VSP inhibition is directly related to VEGF deprivation in ECs or indirectly to activation of these cells or both remains uncertain because of conflicting experimental findings.…”

Maternal Vascular Physiology in Preeclampsia

“…Endothelin-1 ET-1 is produced in endothelial cells and interacts with (1) ET A and ET B2 receptors in vascular smooth muscle cells to induce vasoconstriction, and (2) ET B1 receptor in endothelial cells to trigger the production of endothelium-derived vasodilators. 60 ET-1 concentrations are increased in the circulation of women with preeclampsia as compared with healthy pregnant women 61,62 and are greatest at the later stages of preeclampsia, indicating that ET-1 may be involved in the pathophysiology but not in the pathogenesis of preeclampsia. 60 Increases in ET-1 production, downregulation of ET B1 receptor in endothelial cells, and upregulation of ET B2 and ET A receptors in vascular smooth muscle cells may all contribute to reduced relaxation and increased vasoconstriction in pregnancies with preeclampsia.…”