Morphine stimulates vascular endothelial growth factor-like signaling in mouse retinal endothelial cells.
Go/Gi coupled G-protein receptor mediated transactivation is critical in the activation of receptor tyrosine kinases (RTK). Here we show that mu opioid receptor (MOR) transactivates Flk1 and platelet-derived growth factor-beta (PDGF-beta) receptors and its agonist morphine stimulates pro-angiogenic and survival-promoting signaling in mouse retinal endothelial cells (mREC). Morphine stimulates mREC proliferation in a dose dependent fashion and promotes survival to the same extent as vascular endothelial growth factor164 (VEGF164). Morphine stimulates mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and Akt phosphorylation in a time dependent manner like VEGF in mREC. Moreover, analogous to VEGF, morphine stimulates oncogenic signal transducer and activator of transcription 3 (STAT3) signaling. Morphine as well as VEGF-induced phospho-STAT3 and phospho-Flk1 immunoprecipitated with MOR-associated proteins. In addition morphine also stimulated MOR associated PDGF-beta receptor phosphorylation. Consistent with the relationship between VEGF and MOR we found that VEGF upregulates MOR protein and RNA expression in mREC. These data suggest that MOR associates and transactivates RTKs for Flk1 and PDGF-beta, which may have a compounding effect on angiogenic signaling in endothelium. Therefore, G-Protein coupled receptors including MOR provide novel targets to develop anti-angiogenic agents.
Chen
Chunsheng
C
Vascular Biology Center, Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, Mayo Mail Code 480, Minneapolis, Minnesota 55455, USA.
Farooqui
Mariya
M
Gupta
Kalpna
K
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology*; D009924:Organ Culture Techniques; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000187:drug effects / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D012171:Retinal Vessels / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D000701:Analgesics, Opioid; D012333:RNA, Messenger; D017450:Receptors, Opioid, mu; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D009020:Morphine; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases