Dopamine regulates endothelial progenitor cell mobilization from mouse bone marrow in tumor vascularization
Debanjan Chakroborty, Uttio Roy Chowdhury, Chandrani Sarkar, Rathindranath Baral, Partha Sarathi Dasgupta, Sujit Basu
Debanjan Chakroborty, Uttio Roy Chowdhury, Chandrani Sarkar, Rathindranath Baral, Partha Sarathi Dasgupta, Sujit Basu
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Research Article Oncology

Dopamine regulates endothelial progenitor cell mobilization from mouse bone marrow in tumor vascularization

Abstract

Mobilization of endothelial progenitor cells (EPCs) from the bone marrow and their subsequent participation in neovessel formation are implicated in tumor growth and neovascularization. As the neurotransmitter dopamine (DA) modulates adult endothelial cell function, we hypothesized that DA might have a regulatory role in mobilization of EPCs from the bone marrow niche. We show that there was a significant decrease in bone marrow DA content and an increase in EPC mobilization in tumor-bearing mice associated with tumor neovascularization. DA treatment of tumor-bearing mice inhibited EPC mobilization and tumor growth through its D2 receptors, as DA treatment failed to inhibit EPC mobilization in tumor-bearing mice treated with a specific DA D2 receptor antagonist and in tumor-bearing mice lacking the D2 receptor. In addition, we found that DA, through D2 receptors, exerted its inhibitory effect on EPC mobilization through suppression of VEGFA-induced ERK1/ERK2 phosphorylation and MMP-9 synthesis. These findings reveal a new link between DA and EPC mobilization and suggest a novel use for DA and D2 agents in the treatment of cancer and other diseases involving neovessel formation.

Authors

Debanjan Chakroborty, Uttio Roy Chowdhury, Chandrani Sarkar, Rathindranath Baral, Partha Sarathi Dasgupta, Sujit Basu

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Figure 3

DA inhibits incorporation of BM-derived cells into tumor vasculature and has no effect on the viability of CEPCs.

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DA inhibits incorporation of BM-derived cells into tumor vasculature and...
(A and B) Tie2/lacZ transgenic BM cells were transplanted into lethally irradiated syngenic mice, followed by tumor transplantation. Tumor sections were incubated with X-gal and anti-CD31 to enumerate incorporation of lacZ+ BM-derived cells into tumor vasculature (arrows). (C) Percentage of β-gal–positive blood vessels. Figures are representative of 3 separate experiments. Scale bars: 50 μm. (D–K) DA had no effect on viability of CD45–VEGFR2+ cells, including EPCs. Viability of cells was determined by flow cytometry based on 7AAD uptake. (D and E) Respective isotype controls. (F–K) After excluding dead cells, debris, and red blood cells, CD45– cells were gated. (F, H, and J) VEGFR2+ plus 7AAD+ cells were quantitated out of the gated CD45– cell population. (G, I, and K) Upper-right quadrants show the 7AAD+ nonviable cells among the CD45–VEGFR2+ cells. Figures are representative of 4 separate experiments for each group.