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Anti-Angiogenic Agents Cause Hypertension Via Nitric Oxide Pathway

Vascular endothelial growth factor (VEGF) modulates blood pressure by regulating renal expression of nitric oxide synthase, according to researchers from Duke University in Durham, North Carolina.

This finding explains why anti-angiogenesis drugs - which are known to inhibit VEGF -- are associated with hypertension, Dr. Thomas M. Coffman and colleagues report in the August 4th online edition of Hypertension.

When the researchers treated normal mice with an antibody against the major VEGF receptor, VEGFR2, the result was "a rapid and sustained" rise in blood pressure of approximately 10 mm Hg.

The increase in blood pressure in the anti-VEGFR2 group "was associated with a significant reduction in renin mRNA expression in the kidney" and in urinary aldosterone excretion, according to the paper. Treatment also produced a marked decrease in neuronal and endothelial nitric oxide synthase expression in the kidney.

A proportionate "level of blood pressure increase in humans, if sustained, would translate into a significant increase in risk" for cardiovascular diseases and death, the researchers pointed out.

Mice treated with placebo sustained their normal blood pressure. However, when the researchers used N-nitro-L-arginine methyl ester (L-NAME) to inhibit nitric oxide production in the placebo group, differences in blood pressure between the two groups were "abolished."

"Our data suggest that VEGF, acting via VEGFR2, plays a critical role in blood pressure control by promoting nitric oxide synthase expression and nitric oxide activity," the authors conclude. "Anti-angiogenic agents targeting VEGF cause hypertension by interfering with this pathway."

Hypertension 2009.