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3037 Background: Hypertension is the most common side effect in trials with inhibitors of vascular endothelial growth factor (VEGF) signaling, although the underlying pathophysiology is unclear. As the use of anti-VEGF therapy is increasing, hypertension and related serious adverse events are likely to become more important. Methods: To better understand this pathophysiology,blood pressure and vascular function parameters were assessed in this substudy of a phase I trial in patients with advanced solid tumours treated with BAY 57–9352, an oral VEGF receptor 2 (VEGFR2) inhibitor. Blood pressure, flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NMD) and pulse-wave velocity (PWV) were measured at baseline and after 5 weeks of daily treatment in 10 patients. Patients were spread out over different cohorts, taking different dosages of study drug. Results: Mean systolic blood pressure increased from 129.0 mm Hg to 139.4 mm Hg after 5 weeks of treatment (difference 10.4 mm Hg; 95% confidence interval (CI) 5.0–15.7 mm Hg; p=0.002). Mean diastolic blood pressure increased from 80.9 to 87.4 mm Hg (difference 6.5 mm Hg; 95% CI 1.7–11.3; p=0.013). Endothelium-dependent vasodilatation (FMD) decreased from 5.6% to 3.0% (95% CI 1.1–3.9%; p=0.003). NMD, indicating endothelium-independent vasodilatation, also decreased from 12.9% to 7.7% (95% CI 2.7–7.6%; p=0.001). Arterial stiffness (PWV), increased from 9.4 m/s to 10.3 m/s (p=0.07). Conclusions: Inhibition of VEGFR2 significantly increases systolic and diastolic blood pressure. As VEGF enhances endothelial nitric oxide (NO) synthetase activity, the clear decrease in FMD could be explained by reduced bioavailability of NO. The decrease in NMD may be a direct effect of VEGFR2 inhibition on vascular smooth muscle cells. However, a more likely hypothesis for these profound vascular effects is a reduced number of microvessels (i.e. rarefaction). As the microcirculation is largely responsible for peripheral resistance, the rarefaction associated with VEGFR2 inhibition is likely to increase peripheral resistance and lead to hypertension. [Table: see text]