Ablation of peripheral dopaminergic nerves stimulates malignant tumor growth by inducing vascular permeability factor/vascular endothelial growth factor-mediated angiogenesis.
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.
Department of Biochemistry and Molecular Biology and Mayo Clinic Cancer Center, Mayo Clinic Foundation, Rochester, Minnesota 55905, USA.
Sujit
S
Basu
Chandrani
C
Sarkar
Debanjan
D
Chakroborty
Janice
J
Nagy
Rita Basu
RB
Mitra
Partha Sarathi
PS
Dasgupta
Debabrata
D
Mukhopadhyay
D000818:Animals; D002455:Cell Division / Q000502:physiology; D003714:Denervation / Q000379:methods; D004298:Dopamine / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D016627:Oxidopamine; D010525:Peripheral Nerves / Q000187:drug effects / Q000503:physiopathology*; D010766:Phosphorylation; D017448:Receptors, Dopamine D2 / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D017448:Receptors, Dopamine D2; D042461:Vascular Endothelial Growth Factor A; D016627:Oxidopamine; D040301:Vascular Endothelial Growth Factor Receptor-2; D004298:Dopamine