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The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor

Abstract

Angiogenesis has an essential role in many important pathological and physiological settings. It has been shown that vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), a potent cytokine expressed by most malignant tumors, has critical roles in vasculogenesis and both physiological and pathological angiogenesis. We report here that at non-toxic levels, the neurotransmitter dopamine strongly and selectively inhibited the vascular permeabilizing and angiogenic activities of VPF/VEGF. Dopamine acted through D2 dopamine receptors to induce endocytosis of VEGF receptor 2, which is critical for promoting angiogenesis, thereby preventing VPF/VEGF binding, receptor phosphorylation and subsequent signaling steps. The action of dopamine was specific for VPF/VEGF and did not affect other mediators of microvascular permeability or endothelial-cell proliferation or migration. These results reveal a new link between the nervous system and angiogenesis and indicate that dopamine and other D2 receptors, already in clinical use for other purposes, might have value in anti-angiogenesis therapy.

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Figure 1: Ascites fluid accumulation following i.p. injection of MOT tumor cells.
Figure 2: Inhibitory effects of dopamine on tumor cell adhesion and peritoneal angiogenesis.
Figure 3: Selective inhibitory effects of dopamine on vascular permeabilizing and angiogenic effects of VPF/VEGF.
Figure 4: Immunohistochemical staining for the D2 receptor in ears of normal and Ad-vpf/vegf–injected athymic mice collected at the height of the angiogenic response.
Figure 5: Immunoblot shows 85 kD D2 receptors in extracts of HUVEC but not in control NIH3T3 or MCF7 cells.
Figure 6: Effects of dopamine and various dopamine agonists and antagonists on VPF/VEGF-induced HUVEC proliferation and migration.
Figure 7: Dopamine and the D2 receptor agonists inhibit VPF/VEGF-mediated signaling by inducing internalization of VEGFR-2.

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Acknowledgements

We thank D.R. Senger and J. Lawler for their comments and criticisms and K. Datta for technical help. This work was partly supported by NIH grants to D.M., and H.F.D., by the Massachusetts Department of Public Health, by the Department of Defense to D.M., and under terms of a contract from the National Foundation for Cancer Research.

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Correspondence to Debabrata Mukhopadhyay.

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Basu, S., Nagy, J., Pal, S. et al. The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor. Nat Med 7, 569–574 (2001). https://doi.org/10.1038/87895

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