title: Role of endothelin in preeclampsia and hypertension following antiangiogenesis treatment.
abstract: OBJECTIVE
  Preeclampsia is a systemic, pregnancy-related disorder featuring hypertension and proteinuria arising from placental overproduction of soluble FMS-like tyrosine kinase-1, resulting in an antiangiogenic state because of the inhibition of the vascular endothelial growth factor (VEGF) family. Similarly, antiangiogenetic treatment aimed at targeting VEGF in patients with cancer is associated with a preeclampsia-like syndrome. In this study we discuss the pathophysiological role of an activated endothelin system in both conditions.
  
  
  RESULTS
  In different experimental forms of preeclampsia, in clinical preeclampsia, and in cancer patients on antiangiogenic treatment, activation of the endothelin axis invariably occurs and this activation is directly related to the circulating level of sFlt-1 or the intensity of antiangiogenic treatment. Administration of endothelin receptor A-selective or dual endothelin receptor antagonists can prevent or largely attenuate the hypertension and proteinuria in experimental forms of preeclampsia, as well as in rats exposed to receptor tyrosine-kinase inhibitors targeting VEGF-signaling, supporting the concept that activation of the endothelin axis plays a key role in the manifestations of these disorders.
  
  
  CONCLUSIONS
  Activation of the endothelin axis has now emerged as a crucial player in the manifestations of preeclampsia and following antiangiogenic treatment. As a consequence, blockade of the endothelin system may be considered as a treatment option both in preeclampsia and in antiangiogenesis-induced hypertension and renal toxicity in patients with cancer.
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Langeza
authors.initials: L
authors.lastname: Saleh
authors.forename: Jan A H
authors.initials: JA
authors.lastname: Danser
authors.forename: Anton H
authors.initials: AH
authors.lastname: van den Meiracker
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D065130:Endothelin A Receptor Antagonists / Q000627:therapeutic use; D016232:Endothelins / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011225:Pre-Eclampsia / Q000188:drug therapy / Q000378:metabolism*; D011247:Pregnancy
chemical_list: D020533:Angiogenesis Inhibitors; D065130:Endothelin A Receptor Antagonists; D016232:Endothelins