P29 MECHANISMS OF VASCULAR ENDOTHELIAL GROWTH FACTOR INHIBITION INDUCED HYPERTENSION

Kaisa Maki-Petaja; Adam McGeoch; Lucy Yang; Annette Hubsch; Carmel McEniery; Fraz Mir; Parag Gajendragadkar; Nicola Ramenatte; Gayathri Anandappa; Christoph Brune; Yoeri Boink; Carola Bibiane-Schonlieb; Paul Meyer; Simon Bond; Ian Wilkinson; Duncan Jodrell; Joseph Cheriyan

doi:10.1016/j.artres.2018.10.082

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Volume 24, Issue C, December 2018, Pages 87 - 88

P29 MECHANISMS OF VASCULAR ENDOTHELIAL GROWTH FACTOR INHIBITION INDUCED HYPERTENSION

Authors

Kaisa Maki-Petaja¹, Adam McGeoch², Lucy Yang¹, Annette Hubsch¹, Carmel McEniery¹, Fraz Mir¹, Parag Gajendragadkar¹, Nicola Ramenatte³, Gayathri Anandappa³, Christoph Brune⁴, Yoeri Boink⁴, Carola Bibiane-Schonlieb⁵, Paul Meyer⁶, Simon Bond⁷, Ian Wilkinson¹, Duncan Jodrell⁸, Joseph Cheriyan⁹

¹Division of Experimental Medicine and Immunotherapeutics, University of Cambridge, UK

²Division of Experimental Medicine and Immunotherapeutics, Univeristy of Cambridge, UK

³Dept of Oncology, University of Cambridge, UK

⁴Department of Applied Mathematics, University of Twente, the Netherlands

⁵Department of Applied Mathematics and Theoretical Physics, University of Cambridge, UK

⁶Department of Ophthalmology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

⁷Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

⁸Department of Oncology, University of Cambridge, UK

⁹Division of Experimental Medicine & Immunotherapeutics, University of Cambridge, UK

Available Online 4 December 2018.

DOI: 10.1016/j.artres.2018.10.082 How to use a DOI?
Abstract: Introduction: Drugs targeting Vascular Endothelial Growth Factor (VEGF) signaling pathway are approved therapies for cancer. Unfortunately, VEGF inhibitors lead to hypertension in 30-80% patients. Reduced nitric oxide synthase activity and increased vascular resistance have been proposed as potential mechanisms. We aimed to assess these mechanisms in oncology patients receiving VEGF inhibitor, pazopanib (NCT01392352).

Methods: 27 normotensive patients received pazopanib 800mg od. Endothelial function was assessed using forearm plethysmography with intra-arterial infusion of Acetylcholine (ACh), Sodium Nitroprusside (SNP) and L-N-monomethyl-arginine (L-NMMA). Also, Blood Pressure (BP), Pulse Wave Velocity (PWV), Cardiac Output (CO), and Peripheral Vascular Resistance (PVR) and capillary density in the eye were assessed. All measurements were taken at baseline, 2 and 12 weeks after initiation of the treatment.

Results: Following 12 weeks of treatment, systolic BP rose by 12 (95% CI:4–19) mmHg; P = 0.003, diastolic by 10 (95% CI:5–15) mmHg; P < 0.001, PWV by 1.3 (95% CI:0.3–2.2) m/s; P = 0.01, PVR by 11.1 (95% CI:7.7–14.6) mmHg*L/min; P < 0.001. Capillary density in the sclera reduced by 12 ± 18%; P = 0.02. Forearm blood flow response to ACh improved (P < 0.001), whereas SNP and L-NMMA responses were unchanged. A post-hoc colorimetric assay revealed in whole blood from healthy volunteers that pazopanib inhibited acetylcholinesterase activity by 35%.

Conclusion: Unexpectedly, pazopanib led to an increase in ACh response, but this is most likely due to the inhibition of acetylcholinesterase activity by pazopanib. Interestingly, we found that PVR was increased and capillary density reduced by the treatment, suggesting that capillary rarefaction could be one of the mechanisms behind VEGF inhibition induced hypertension.
Open Access: This is an open access article distributed under the CC BY-NC license.

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Journal: Artery Research
Volume-Issue: 24 - C
Pages: 87 - 88
Publication Date: 2018/12/04
ISSN (Online): 1876-4401
ISSN (Print): 1872-9312
DOI: 10.1016/j.artres.2018.10.082 How to use a DOI?
Open Access: This is an open access article distributed under the CC BY-NC license.

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ris enw bib

TY  - JOUR
AU  - Kaisa Maki-Petaja
AU  - Adam McGeoch
AU  - Lucy Yang
AU  - Annette Hubsch
AU  - Carmel McEniery
AU  - Fraz Mir
AU  - Parag Gajendragadkar
AU  - Nicola Ramenatte
AU  - Gayathri Anandappa
AU  - Christoph Brune
AU  - Yoeri Boink
AU  - Carola Bibiane-Schonlieb
AU  - Paul Meyer
AU  - Simon Bond
AU  - Ian Wilkinson
AU  - Duncan Jodrell
AU  - Joseph Cheriyan
PY  - 2018
DA  - 2018/12/04
TI  - P29 MECHANISMS OF VASCULAR ENDOTHELIAL GROWTH FACTOR INHIBITION INDUCED HYPERTENSION
JO  - Artery Research
SP  - 87
EP  - 88
VL  - 24
IS  - C
SN  - 1876-4401
UR  - https://doi.org/10.1016/j.artres.2018.10.082
DO  - 10.1016/j.artres.2018.10.082
ID  - Maki-Petaja2018
ER  -

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