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

Cameron, Alan C. and Welsh, Paul and Neves, Karla B. and Newby, David E. and Touyz, Rhian M. and Lang, Ninian N. (2020) Acute vascular effects of vascular endothelial growth factor inhibition in the forearm arterial circulation. Journal of Hypertension, 38 (2). pp. 257-265. ISSN 0263-6352 (https://doi.org/10.1097/HJH.0000000000002230)

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Abstract

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.

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