Vascular endothelial growth factor receptor 2 controls blood pressure by regulating nitric oxide synthase expression.
Vascular endothelial growth factor receptor 2 controls blood pressure by regulating nitric oxide synthase expression.
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DOI：
10.1161/hypertensionaha.109.129973
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发表时间：
2009-09
期刊：
影响因子：
--
通讯作者：
Coffman TM
中科院分区：
文献类型：
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作者：
Facemire CS;Nixon AB;Griffiths R;Hurwitz H;Coffman TM
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 to vehicle-treated controls, administration of the anti-VEGFR2 antibody caused a rapid and sustained increase in BP of ≈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 marked reduction in expression of endothelial and neuronal nitric oxide synthases (eNOS and nNOS) in the kidney. To examine the role of nitric oxide (NO) in the hypertension caused by blocking VEGFR2, mice were treated with Nω-nitro-L-arginine methyl ester (L-NAME) (20 mg/kg/day), an inhibitor of NO production. L-NAME administration abolished the difference in blood pressure between the vehicle- and anti-VEGFR2-treated groups. Our data suggest that VEGF, acting via VEGFR2, plays a critical role in blood pressure control by promoting NOS expression and NO activity. Interfering with this pathway is likely to be one mechanism underlying hypertension caused by anti-angiogenic agents targeting VEGF.
