Research article
The neurotransmitter dopamine modulates vascular permeability in the endothelium
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* Corresponding author: Debabrata Mukhopadhyay mukhopadhyay.debabrata@mayo.edu
- † Equal contributors
1 Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA
2 Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
Journal of Molecular Signaling 2008, 3:14 doi:10.1186/1750-2187-3-14
Published: 28 July 2008Abstract
Background
Vascular permeability factor/Vascular endothelial growth factor (VPF/VEGF), a multifunctional cytokine, is a potent inducer of vascular permeability, an important early step in angiogenesis. It is known that the neurotransmitter dopamine can inhibit VPF/VEGF mediated angiogenesis, in particular microvascular permeability, but the effectors of this action remain unclear.
Results
Here, we define the signaling pathway modulated by dopamine that inhibits VPF/VEGF induced vascular permeability in endothelial cells. Signals from VPF/VEGF lead to changes in the phosphorylation of tight junction protein zonula occludens (ZO-1) and adherens junction proteins like VE-cadherin and associated catenins, thus weakening endothelial cell-cell adhesion and increasing vascular permeability. We found VEGF receptor-2 (VEGFR-2) to be part of a multi-protein complex involving ZO-1, VE-cadherin and β-catenin. VPF/VEGF induced phosphorylations of VE-cadherin, β-catenin and ZO-1 were inhibited by dopamine treatment. Association of occludin with ZO-1 and ZO-1 with VE-cadherin were significantly inhibited by dopamine in VEGF treated cells. Furthermore, we identified Src as an important target for dopamine-mediated inhibition of VPF/VEGF induced permeability.
Conclusion
Taken together, our results provide molecular insights of dopamine function in the vascular endothelium and suggest a central role of Src in regulating key molecules that control vascular permeability.