Ending restenosis: Inhibition of vascular smooth muscle cell proliferation by cAMP

Sarah A Smith, Andrew C Newby, Mark Bond

Research output: Contribution to journalArticle (Academic Journal)peer-review

13 Citations (Scopus)
80 Downloads (Pure)


Increased vascular smooth muscle cell (VSMC) proliferation contributes towards restenosis after angioplasty, vein graft intimal thickening and atherogenesis. The second messenger 3’ 5’ cyclic adenosine monophosphate (cAMP) plays an important role in maintaining VSMC quiescence in healthy vessels and repressing VSMC proliferation during resolution of vascular injury. Although the anti-mitogenic properties of cAMP in VSMC have been recognised for many years, it is only recently that we have gained a detailed understanding of the underlying signalling mechanisms. Stimuli that elevate cAMP in VSMC inhibit G1-S phase cell cycle progression by inhibiting expression of cyclins and preventing S-Phase Kinase Associated Protein-2 (Skp2-mediated degradation of cyclin-dependent kinase inhibitors. Early studies implicated inhibition of MAPK signalling, although this does not fully explain the anti-mitogenic effects of cAMP. The cAMP effectors, PKA and EPAC act together to inhibit VSMC proliferation by inducing CREB activity and inhibiting members of the RhoGTPases, which results in remodelling of the actin-cytoskeleton. Cyclic-AMP induced actin remodelling controls proliferation by modulating the activity of Serum Response Factor (SRF) and TEA Domain Transcription Factors (TEAD), which regulate expression of genes required for proliferation. Here we review recent research characterising these mechanisms, highlighting novel drug targets that may allow the anti-mitogenic properties of cAMP to be harnessed therapeutically to limit restenosis.
Original languageEnglish
Article number1447
Number of pages28
Issue number11
Early online date16 Nov 2019
Publication statusE-pub ahead of print - 16 Nov 2019


  • cAMP
  • VSMC
  • cell-cycle
  • actin
  • cytoskeleton
  • SRF
  • TEAD
  • CREB


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