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Ablation of Peripheral Dopaminergic Nerves Stimulates Malignant Tumor Growth by Inducing Vascular Permeability Factor/Vascular Endothelial Growth Factor-Mediated Angiogenesis

¹ Department of Biochemistry and Molecular Biology and Mayo Clinic Cancer Center, Mayo Clinic Foundation, Rochester, Minnesota; ² Department of Medical Oncology, and ³ Signal Transduction and Biogenic Amines Laboratory, Chittaranjan National Cancer Institute, Calcutta, India; ⁴ Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; and ⁵ Department of Pathology, Institute of Postgraduate Medical Education and Research, Calcutta, India.

Many important physiological and pathological processes are modulated by angiogenesis. It has been shown that initiation of this angiogenic process is an essential early step in the progression of malignant tumors. We report here that ablation of peripheral dopaminergic nerves markedly increased angiogenesis, microvessel density, microvascular permeability, and growth of malignant tumors in mice. Endogenous peripheral dopamine acted through D₂ receptors as significantly more angiogenesis and tumor growth was observed in D₂ dopamine receptor knockout mice in comparison with controls. The vascular endothelial growth factor receptor 2 phosphorylation, which is critical for promoting angiogenesis, was also significantly more in tumor endothelial cells collected from the dopamine-depleted and D₂ dopamine receptor knockout animals. These results reveal that peripheral endogenous neurotransmitter dopamine might be an important physiological regulator of vascular endothelial growth factor-mediated tumor angiogenesis and growth and suggest a novel link between endogenous dopamine, angiogenesis, and tumor growth.

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