Abstract 15185: Vascular Endothelial Growth Factor Inhibition Results in Systemic Hypertension Mediated by Alterations in Endothelin-1, but Not by Alterations in Nitric Oxide or Reactive Oxygen Species
Purpose: Inhibition of Vascular Endothelial Growth Factor (VEGF) signaling is an established therapy for various forms of cancer. However, this therapy is associated with hypertension. VEGF signaling enhances NO production, which in turn may reduce endothelin (ET) and scavenge reactive oxygen species (ROS). We therefore hypothesized that hypertension resulting from VEGF inhibition is due to a loss of NO bioavailability and an increase in ROS and/or ET.
Methods: On different days, chronically instrumented swine (N=6) received i.v. infusion of either the endothelial NO synthase inhibitor Nω-Nitro-L-arginine (NLA), the ETA/ETB receptor blocker tezosentan or a combination of ROS scavengers (4-Hydroxy-2,2,6,6-Tetramethylpiperidine-1-oxyl, N-Acetyl-Cysteine and N-2-Mercaptoproprionyl-Glycine). Before and after these infusions hemodynamic parameters were recorded. These experiments were repeated after administration of the VEGF-receptor inhibitor sunitinib, 50 mg/day p.o. for 1 week.
Results: Sunitinib increased blood pressure and systemic vascular resistance reflecting vasoconstriction (Table). Following sunitinib, the rise in blood pressure and systemic vascular resistance induced by NLA increased, while the changes in blood pressure by ROS scavenging decreased. In contrast, while tezosentan had no effect under control conditions, it resulted in a decrease in blood pressure and systemic vascular resistance following sunitinib. Hence, tezosentan abrogated the sunitinib-induced vasoconstriction.
Conclusions: VEGF inhibition results in sustained hypertension. This hypertension is caused by enhanced ET-mediated vasoconstriction, but not by decreased NO-bioavailability or enhanced oxidative stress. These results warrant studies into the efficacy of ET receptor blockade in limiting the hypertensive side effects of VEGF inhibition.
- © 2011 by American Heart Association, Inc.