The cAMP-producing agonist beraprost inhibits human vascular smooth muscle cell migration via exchange protein directly activated by cAMP

Jenny S McKean, Fiona Murray, George Gibson, Derryck A Shewan, Steven J Tucker, Graeme F Nixon

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Abstract

Aims During restenosis, vascular smooth muscle cells (VSMC) migrate from the vascular media to the developing neointima. Preventing VSMC migration is therefore a therapeutic target for restenosis. Drugs, such as prostacyclin analogues, that increase the intracellular concentration of cyclic adenosine monophosphate (cAMP) can inhibit VSMC migration but the mechanisms via which this occurs are unknown. Two main downstream mediators of cAMP are protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac). This study has examined the effects of the prostacyclin analogue beraprost on VSMC migration and investigated the intracellular pathways involved.
Methods and Results In a chemotaxis chamber, human saphenous vein VSMC migrated towards a platelet-derived growth factor-BB (PDGF) chemogradient. Incubation with therapeutically relevant concentrations of cAMP-producing agonist beraprost significantly decreased PDGF-induced migration. Direct activation of either PKA or Epac inhibited migration whereas inhibition of PKA did not prevent the anti-migratory effect of beraprost. Direct activation of Epac also prevented hyperplasia in ex vivo serum-treated human veins. Using fluorescence resonance energy transfer, we demonstrated that beraprost activated Epac but not PKA. The mechanisms of this Epac-mediated effect involved activation of Rap1 with subsequent inhibition of RhoA. Cytoskeletal rearrangement at the leading edge of the cell was consequently inhibited. Interestingly, Epac1 was localized to the leading edge of migrating VSMC.
Conclusions These results indicate that therapeutically relevant concentrations of beraprost can inhibit VSMC migration via a previously unknown mechanism involving the cAMP mediator Epac. This may provide a novel target which could blunt neointimal formation.
Original languageEnglish
Pages (from-to)546-555
Number of pages10
JournalCardiovascular Research
Volume107
Issue number4
Early online date19 Jun 2015
DOIs
Publication statusPublished - 1 Sep 2015

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Keywords

  • vascular smooth muscle cell
  • migration
  • prostacyclin
  • cAMP
  • Epac

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