title: Dopamine inhibits pulmonary edema through the VEGF-VEGFR2 axis in a murine model of acute lung injury.
abstract: The neurotransmitter dopamine and its dopamine receptor D2 (D2DR) agonists are known to inhibit vascular permeability factor/vascular endothelial growth factor (VEGF)-mediated angiogenesis and vascular permeability. Lung injury is a clinical syndrome associated with increased microvascular permeability. However, the effects of dopamine on pulmonary edema, a phenomenon critical to the pathophysiology of both acute and chronic lung injuries, have yet to be established. Therefore, we sought to determine the potential therapeutic effects of dopamine in a murine model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Compared with sham-treated controls, pretreatment with dopamine (50 mg/kg body wt) ameliorated LPS-mediated edema formation and lowered myeloperoxidase activity, a measure of neutrophil infiltration. Moreover, dopamine significantly increased survival rates of LPS-treated mice, from 0-75%. Mechanistically, we found that dopamine acts through the VEGF-VEGFR2 axis to reduce pulmonary edema, as dopamine pretreatment in LPS-treated mice resulted in decreased serum VEGF, VEGFR2 phosphorylation, and endothelial nitric oxide synthase phosphorylation. We used D2DR knockout mice to confirm that dopamine acts through D2DR to block vascular permeability in our lung injury model. As expected, a D2DR agonist failed to reduce pulmonary edema in D2DR(-/-) mice. Taken together, our results suggest that dopamine acts through D2DR to inhibit pulmonary edema-associated vascular permeability, which is mediated through VEGF-VEGFR2 signaling and conveys protective effects in an ALI model.
authors: Dept. of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Guggenheim 1334, 200 First St. S.W., Rochester, MN 55905, USA.
authors: Pawan K
authors: PK
authors: Vohra
authors: Luke H
authors: LH
authors: Hoeppner
authors: Gunisha
authors: G
authors: Sagar
authors: Shamit K
authors: SK
authors: Dutta
authors: Sanjay
authors: S
authors: Misra
authors: Rolf D
authors: RD
authors: Hubmayr
authors: Debabrata
authors: D
authors: Mukhopadhyay
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D004298:Dopamine / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D010766:Phosphorylation; D011654:Pulmonary Edema / Q000188:drug therapy* / Q000503:physiopathology; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D018492:Dopamine Antagonists; D008070:Lipopolysaccharides; D017448:Receptors, Dopamine D2; D042461:Vascular Endothelial Growth Factor A; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D040301:Vascular Endothelial Growth Factor Receptor-2; D004298:Dopamine