Vascular endothelial growth factor receptor 2 controls blood pressure by regulating nitric oxide synthase expression.

Published

Journal Article

Drugs and antibodies that interrupt vascular endothelial growth factor (VEGF) signaling pathways improve outcomes in patients with a variety of cancers by inhibiting tumor angiogenesis. A major adverse effect of these treatments is hypertension, suggesting a critical role for VEGF in blood pressure (BP) regulation. However, the physiological mechanisms underlying the control of BP by VEGF are unclear. To address this question, we administered a specific antibody against the major VEGF receptor, VEGFR2, to normal mice and assessed the consequences on BP. Compared with vehicle-treated controls, administration of the anti-VEGFR2 antibody caused a rapid and sustained increase in BP of approximately 10 mm Hg. This increase in BP was associated with a significant reduction in renin mRNA expression in the kidney (P=0.019) and in urinary excretion of aldosterone (P<0.05). Treatment with the anti-VEGFR2 antibody also caused a marked reduction in the expression of endothelial and neuronal NO synthases in the kidney. To examine the role of NO in the hypertension caused by blocking VEGFR2, mice were treated with N(omega)-nitro-L-arginine methyl ester (L-NAME) (20 mg/kg per day), an inhibitor of NO production. L-NAME administration abolished the difference in BP between the vehicle- and anti-VEGFR2-treated groups. Our data suggest that VEGF, acting via VEGFR2, plays a critical role in BP control by promoting NO synthase expression and NO activity. Interfering with this pathway is likely to be one mechanism underlying hypertension caused by antiangiogenic agents targeting VEGF.

Full Text

Duke Authors

Cited Authors

  • Facemire, CS; Nixon, AB; Griffiths, R; Hurwitz, H; Coffman, TM

Published Date

  • September 2009

Published In

Volume / Issue

  • 54 / 3

Start / End Page

  • 652 - 658

PubMed ID

  • 19652084

Pubmed Central ID

  • 19652084

Electronic International Standard Serial Number (EISSN)

  • 1524-4563

Digital Object Identifier (DOI)

  • 10.1161/HYPERTENSIONAHA.109.129973

Language

  • eng

Conference Location

  • United States