The neurotransmitter dopamine modulates vascular permeability in the endothelium.
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 beta-catenin. VPF/VEGF induced phosphorylations of VE-cadherin, beta-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.


CONCLUSIONS
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.
Bhattacharya
Resham
R
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA. mukhopadhyay.debabrata@mayo.edu.
Sinha
Sutapa
S
Yang
Su-Ping
SP
Patra
Chittaranjan
C
Dutta
Shamit
S
Wang
Enfeng
E
Mukhopadhyay
Debabrata
D