Morphine stimulates vascular endothelial growth factor-like signaling in mouse retinal endothelial cells

Chunsheng Chen, Mariya Farooqui, Kalpna Gupta

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

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-β (PDGF-β) 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 (VEGF 164). 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-β 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-β, 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.

Original languageEnglish (US)
Pages (from-to)171-180
Number of pages10
JournalCurrent neurovascular research
Volume3
Issue number3
DOIs
StatePublished - Aug 15 2006

Keywords

  • FLR/KDR
  • G-protein coupled receptors
  • MAPK/ERK
  • Mu opioid receptor
  • PDGFR
  • Receptor tyrosine kinase
  • STAT3
  • Transactivation

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