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Acute vascular effects of vascular endothelial growth factor inhibition in the forearm arterial circulation

Cameron, Alan C.a; Welsh, Paula; Neves, Karla B.a; Newby, David E.b; Touyz, Rhian M.a; Lang, Ninian N.a

doi: 10.1097/HJH.0000000000002230
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Objective: Although vascular endothelial growth factor inhibition (VEGFi) represents a major therapeutic advance in oncology, it is associated with hypertension and adverse vascular thrombotic events. Our objective was to determine whether VEGFi caused direct vascular dysfunction through increased endothelin-1 (ET-1) activity or impaired endothelial vasomotor or fibrinolytic function.

Methods: Using forearm venous occlusion plethysmography, we measured forearm blood flow during intra-arterial infusions of bevacizumab (36–144 μg/dl forearm volume per minute) administered for 15–60 min in healthy volunteers (n = 6–8). On two separate occasions in 10 healthy volunteers, we further measured forearm blood flow and tissue plasminogen activator (t-PA) release during intra-arterial bradykinin infusion (100 and 1000 pmol/min) in the presence and absence of bevacizumab (144 μg/dl forearm volume per minute), and the presence and absence of endothelin A receptor antagonism with BQ-123 (10 nmol/min). Plasma t-PA and plasminogen activator inhibitor-1 (PAI-1) concentrations were measured at baseline and with each dose of bradykinin.

Results: Baseline blood flow and plasma ET-1, t-PA and PAI-1 concentrations were unaffected by bevacizumab. Bradykinin caused dose-dependent vasodilatation (P < 0.0001) and t-PA release (P < 0.01) but had no effect on plasma PAI-1 concentrations. Neither bevacizumab nor BQ-123 affected bradykinin-induced vasodilatation and t-PA release.

Conclusion: Acute exposure to bevacizumab does not directly cause endothelial vasomotor or fibrinolytic dysfunction in healthy young volunteers.

aBHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow

bBHF Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, UK

Correspondence to Dr Alan C. Cameron, BSc (Hons), MB ChB, MRCP, BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom. Tel: +44 141 330 8271; fax: +44 141 330 3360; e-mail: alan.cameron.2@glasgow.ac.uk.

Received 4 June, 2019

Revised 1 August, 2019

Accepted 1 August, 2019

This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0

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