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The Hippo pathway mediates inhibition of vascular smooth muscle cell proliferation by cAMP

Tomomi E Kimura1, Aparna Duggirala1, Madeleine C Smith1

  • 1Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol BS2 8HW, UK.

Journal of Molecular and Cellular Cardiology
|December 3, 2015
PubMed
Abstract

Insights

Elevating cyclic AMP (cAMP) in vascular smooth muscle cells (VSMC) inhibits YAP/TAZ-TEAD signaling, preventing cell proliferation. This mechanism offers a new therapeutic target for restenosis and graft failure.

Area of Science:

  • Vascular Biology
  • Cell Signaling
  • Molecular Medicine

Background:

  • Vascular smooth muscle cell (VSMC) proliferation contributes to restenosis and graft failure.
  • Intracellular cyclic AMP (cAMP) inhibits VSMC proliferation via poorly understood mechanisms involving actin cytoskeleton remodeling and gene expression.
  • The Hippo pathway, including YAP, TAZ, and TEAD, regulates cell growth and is implicated in VSMC biology.

Purpose of the Study:

  • To investigate the role of YAP, TAZ, and TEAD components of the Hippo pathway in mediating the anti-proliferative effects of cAMP in VSMCs.
  • To elucidate the molecular mechanisms by which cAMP-induced actin cytoskeleton remodeling influences YAP/TAZ-TEAD signaling and gene expression in VSMCs.

Main Methods:

  • VSMCs were treated with cAMP-elevating agents (forskolin, dibutyryl-cAMP, Cicaprost, adenosine).
  • RhoA activity, actin polymerization, and TEAD-luciferase reporter gene activity were assessed.
  • mRNA expression of pro-mitogenic genes (CCN1, CTGF, c-MYC, TGFB2) was analyzed.
  • YAP/TAZ function was inhibited using RNAi or Verteporfin, and constitutively-active YAP/TAZ mutants or RhoA were expressed.

Main Results:

  • cAMP elevation increased YAP/TAZ phosphorylation and nuclear export, inhibiting TEAD activity.
  • Inhibition of RhoA, ROCK, or actin polymerization mimicked cAMP's effects on TEAD activity.
  • Constitutively-active RhoA reversed cAMP's inhibitory effects on TEAD.
  • cAMP significantly reduced pro-mitogenic gene expression, an effect reversed by constitutively-active YAP/TAZ.
  • Inhibition of YAP/TAZ reduced VSMC proliferation, and blocking cAMP's effect with constitutively-active YAP/TAZ confirmed their role.

Conclusions:

  • cAMP-induced actin cytoskeleton remodeling inhibits YAP/TAZ-TEAD dependent expression of pro-mitogenic genes in VSMCs.
  • This pathway provides novel insight into the anti-mitogenic effects of cAMP.
  • Targeting the YAP/TAZ-TEAD pathway presents a potential therapeutic strategy for vascular proliferative diseases.
Keywords:
3′-5′-Cyclic adenosine monophosphateTAZTEADVSMCYAPcAMP

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