title: Mechanism of hypertension and proteinuria during angiogenesis inhibition: evolving role of endothelin-1.
abstract: Angiogenesis inhibition by blocking vascular endothelial growth factor (VEGF)-mediated signalling with monoclonal antibodies or tyrosine kinase inhibitors has become an established treatment of various forms of cancer. This treatment is frequently associated with the development of hypertension and proteinuria. As VEGF increases the expression and the activity of nitric oxide synthase in endothelial cells, a decrease in the bioavailability of nitric oxide has been proposed as a key mechanism leading to hypertension during angiogenesis inhibition. However, results of clinical and experimental studies exploring this possibility are conflicting. Rarefaction, that is a structural decrease of microcirculatory vessels, has been reported during antiangiogenic treatment, but evidence that it plays a role in development of hypertension is lacking. Elevated circulating and urinary levels of endothelin-1 have been observed in clinical and experimental studies with angiogenesis inhibitors. Furthermore, the observation that endothelin receptor blockers can prevent or revert the rise in blood pressure during angiogenesis inhibition and attenuate proteinuria provides strong evidence that an activated endothelin-signalling pathway is a final common mediator of angiogenesis inhibition-induced rise in blood pressure and renal toxicity.
authors.affiliation: Department of Internal Medicine, Pharmacology and Vascular Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Lankhorst
authors.forename: Mariëtte H W
authors.initials: MH
authors.lastname: Kappers
authors.forename: Joep H M
authors.initials: JH
authors.lastname: van Esch
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
authors.forename: Anton H
authors.initials: AH
authors.lastname: van den Meiracker
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D019332:Endothelin-1 / Q000502:physiology*; D006801:Humans; D006973:Hypertension / Q000503:physiopathology*; D011507:Proteinuria / Q000503:physiopathology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000502:physiology; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology
chemical_list: D020533:Angiogenesis Inhibitors; D019332:Endothelin-1; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor