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Mechanism of hypertension and proteinuria during angiogenesis inhibition: evolving role of endothelin-1

Lankhorst, Stephaniea; Kappers, Mariëtte H.W.a,b; van Esch, Joep H.M.a; Danser, A.H. Jana; van den Meiracker, Anton H.a

doi: 10.1097/HJH.0b013e32835c1d1b

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.

aDepartment of Internal Medicine, Pharmacology and Vascular Medicine, Erasmus MC, Rotterdam

bDepartment of Internal Medicine, Amphia Hospital, Breda, The Netherlands

Correspondence to Dr Anton H. van den Meiracker, Department of Internal Medicine, Room D432, Erasmus MC, ‘s Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. Tel: +31 010 7034220; e-mail:

Abbreviations: (s)Flt-1, (soluble) fms-like tyrosine kinase 1; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor antagonist; BP, blood pressure; CCB, calcium channel blocker; cGMP, cyclic guanosine monophosphate; eNOS, endothelial NO-synthase; ET-1, endothelin-1; FMD, flow-mediated dilatation; L-NMMA, L-NG-monomethyl arginine; MAP, mean arterial pressure; MAPK, mitogen-activated protein kinase; MPS, mononuclear phagocyte system; PlGF, placental growth factor; ROS, reactive oxygen species; RTKI, receptor tyrosine kinase inhibitor; TBARS, thiobarbituric acid reactive substances, VEGF(R); vascular endothelial growth factor (receptor), VSMC; vascular smooth muscle cell

Received 9 August, 2012

Revised 15 October, 2012

Accepted 31 October, 2012

© 2013 Lippincott Williams & Wilkins, Inc.