P29: Mechanisms of Vascular Endothelial Growth Factor Inhibition Induced Hypertension

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-mono-methyl-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.