title: The emerging role of endothelin-1 in the pathogenesis of pre-eclampsia.
abstract: Pre-eclampsia (PE) is the most frequently encountered medical complication during pregnancy. It is characterized by a rise in systemic vascular resistance with a relatively low cardiac output and hypovolemia, combined with severe proteinuria. Despite the hypovolemia, renin-angiotensin system (RAS) activity is suppressed and aldosterone levels are decreased to the same degree as renin. This suggests that the RAS is not the cause of the hypertension in PE, but rather that its suppression is the consequence of the rise in blood pressure. Abnormal placentation early in pregnancy is widely assumed to be an important initial event in the onset of PE. Eventually, this results in the release of anti-angiogenic factors [in particular, soluble Fms-like tyrosine kinase-1 (sFlt-1)] and cytokines, leading to generalized vascular dysfunction. Elevated sFlt-1 levels bind and inactivate vascular endothelial growth factor (VEGF). Of interest, VEGF inhibition with drugs like sunitinib, applied in cancer patients, results in a PE-like syndrome, characterized by hypertension, proteinuria and renal toxicity. Both in cancer patients treated with sunitinib and in pregnant women with PE, significant rises in endothelin-1 occur. Multiple regression analysis revealed that endothelin-1 is an independent determinant of the hypertension and proteinuria in PE, and additionally a renin suppressor. Moreover, studies in animal models representative of PE, have shown that endothelin receptor blockers prevent the development of this disease. Similarly, endothelin receptor blockers are protective during sunitinib treatment. Taken together, activation of the endothelin system emerges as an important pathway causing the clinical manifestations of PE. This paper critically addresses this concept, taking into consideration both clinical and preclinical data, and simultaneously discusses the therapeutic consequences of this observation.
authors.affiliation: Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The NetherlandsDivision Obstetrics & Prenatal Medicine, Department of Obstetrics & Gynaecology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Langeza
authors.initials: L
authors.lastname: Saleh
authors.affiliation: Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Koen
authors.initials: K
authors.lastname: Verdonk
authors.affiliation: Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The NetherlandsDivision Obstetrics & Prenatal Medicine, Department of Obstetrics & Gynaecology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Willy
authors.initials: W
authors.lastname: Visser
authors.affiliation: Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Anton H
authors.initials: AH
authors.lastname: van den Meiracker
authors.affiliation: Department of Internal Medicine, Division of Vascular Medicine & Pharmacology, Room EE1418, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands a.danser@erasmusmc.nl.
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
mesh_terms: D000818:Animals; D019332:Endothelin-1 / Q000502:physiology*; D005260:Female; D006439:Hemodynamics; D006801:Humans; D011225:Pre-Eclampsia / Q000209:etiology* / Q000503:physiopathology; D011247:Pregnancy; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D017466:Receptors, Endothelin / Q000502:physiology; D012084:Renin-Angiotensin System / Q000502:physiology
chemical_list: D019332:Endothelin-1; D044140:Receptor, Angiotensin, Type 1; D017466:Receptors, Endothelin
keywords: angiotensin; auto-antibody; cancer; endothelial growth factor; endothelin-1; nitric oxide; pre-eclampsia; soluble Fms-like tyrosine kinase 1; vascular endothelial growth factor