Microparticles from vascular endothelial growth factor pathway inhibitor-treated cancer patients mediate endothelial cell injury

Neves, K. B. , Rios, F. J. , Jones, R. , Evans, T. R. J. , Montezano, A. C. and Touyz, R. M. (2019) Microparticles from vascular endothelial growth factor pathway inhibitor-treated cancer patients mediate endothelial cell injury. Cardiovascular Research, 115(5), pp. 978-988. (doi:10.1093/cvr/cvz021) (PMID:30753341) (PMCID:PMC6452312)

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Abstract

Vascular endothelial growth factor pathway inhibitors (VEGFi), used as anti-angiogenic drugs to treat cancer are associated with cardiovascular toxicities through unknown molecular mechanisms. Endothelial cell-derived microparticles (ECMPs) are biomarkers of endothelial injury and are also functionally active since they influence downstream target cell signalling and function. We questioned whether microparticle (MP) status is altered in cancer patients treated with VEGFi and whether they influence endothelial cell function associated with vascular dysfunction. Plasma MPs were isolated from cancer patients before and after treatment with VEGFi (pazopanib, sunitinib, or sorafenib). Human aortic endothelial cells (HAECs) were stimulated with isolated MPs (106 MPs/mL). Microparticle characterization was assessed by flow cytometry. Patients treated with VEGFi had significantly increased levels of plasma ECMP. Endothelial cells exposed to post-VEGFi treatment ECMPs induced an increase in pre-pro-ET-1 mRNA expression, corroborating the increase in endothelin-1 (ET-1) production in HAEC stimulated with vatalanib (VEGFi). Post-VEGFi treatment MPs increased generation of reactive oxygen species in HAEC, effects attenuated by ETA (BQ123) and ETB (BQ788) receptor blockers. VEGFi post-treatment MPs also increased phosphorylation of the inhibitory site of endothelial nitric oxide synthase (eNOS), decreased nitric oxide (NO), and increased ONOO− levels in HAEC, responses inhibited by ETB receptor blockade. Additionally, gene expression of proinflammatory mediators was increased in HAEC exposed to post-treatment MPs, effects inhibited by BQ123 and BQ788. Our findings define novel molecular mechanism involving interplay between microparticles, the ET-1 system and endothelial cell pro-inflammatory and redox signalling, which may be important in cardiovascular toxicity and hypertension associated with VEGFi anti-cancer treatment. New and noteworthy: our novel data identify MPs as biomarkers of VEGFi-induced endothelial injury and important mediators of ET-1-sensitive redox-regulated pro-inflammatory signalling in effector endothelial cells, processes that may contribute to cardiovascular toxicity in VEGFi-treated cancer patients.

Item Type:Articles
Additional Information:Also funded by a BHF Chair award CH/12/429762 to R.M.T.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Rios, Dr Francisco and Evans, Professor Thomas and Jones, Professor Robert and Montezano, Dr Augusto and Touyz, Professor Rhian and Neves, Dr Karla Bianca
Authors: Neves, K. B., Rios, F. J., Jones, R., Evans, T. R. J., Montezano, A. C., and Touyz, R. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Cardiovascular Research
Publisher:Oxford University Press
ISSN:0008-6363
ISSN (Online):1755-3245
Published Online:11 February 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Cardiovascular Research 115(5): 978-988
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
617771BHF centre of excellenceRhian TouyzBritish Heart Foundation (BHF)RE/13/5/30177RI CARDIOVASCULAR & MEDICAL SCIENCES
750723Glasgow ECMCThomas EvansCancer Research UK (CRUK)C58789/A25174ICS - EXPERIMENTAL THERAPEUTICS
3003920Cancer Research UK Clinical Trials Unit - Core Programme FundingRobert JonesCancer Research UK (CRUK)C1348/A25355CS - Clinical Trials UInit Gartnavel
607382Vascular Noxs as therapeutic targets and biomarkers in hypertensionRhian TouyzBritish Heart Foundation (BHF)RG/13/7/30099RI CARDIOVASCULAR & MEDICAL SCIENCES