Abstract P149: VEGF Inhibitor-Induced Hypertension and Renal Injury: Prevention by Aspirin?

Abstract

Vascular endothelial growth factor inhibitor (VEGFi)-induced hypertension and renal injury in cancer patients mimic the clinical phenotype of preeclampsia. ET-1 has been implicated to be involved. Since aspirin can prevent the onset of preeclampsia, we hypothesized that co-treatment of the VEGFi sunitinib (SU) with aspirin might be beneficial and may improve ET-1 status. Male WKY rats were treated with vehicle, 14 mg/kg/day SU, or SU + low or high dose aspirin (5 or 100 mg/kg/day) for 8 days. Mean arterial pressure (MAP) was measured via radiotelemetry. On day 8, 24h urine was collected to determine albuminuria and prostanoid (PGF2α and TxB2) levels. Plasma endothelin-1 (ET-1) was measured via ELISA. Endothelial dysfunction was assessed in iliac vessels and reactive oxygen species (ROS) was measured via aortic superoxide anion production. Renal cyclooxygenase (COX)-1, COX-2 and ET-1 mRNA expression were determined via PCR. SU induced a rapid and sustained increase in MAP (24±2 versus 1±1 mmHg in vehicle on day 6; P<0.001), which was blunted by both low and high aspirin doses (18±3 and 13±4 mmHg respectively on day 6; P<0.05 versus SU). Plasma ET-1 was increased by SU (2.2±0.3 versus 1.4±0.1 pg/ml in vehicle; P<0.05) and this was not affected by aspirin. SU increased albuminuria (1.2±0.2 versus 0.3±0.1 mg/24h in vehicle; P<0.05) which was prevented by high, but not low dose aspirin (0.5±0.1 and 1.3±0.1 mg/24h, respectively), suggesting that this effect is COX-2 dependent. Although renal mRNA expression levels were unchanged, renal COX-2 and ET-1 mRNA expression correlated positively, suggesting that ET-1 upregulates COX-2. SU increased ROS production 2.5-fold (P<0.05 versus vehicle) and this was prevented by both aspirin doses. SU did not induce endothelial dysfunction, nor did it alter prostanoid levels. However, both aspirin doses reduced TxB2 (P<0.05 versus vehicle). In conclusion, high rather than low dose aspirin was more efficacious for the prevention of VEGFi-induced hypertension and renal injury, suggesting that its beneficial effects largely involve COX-2 inhibition. Aspirin may be a novel intervention to allow cancer patients to gain the full benefit of VEGFi without deleterious cardiovascular and renal side effects.