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Akt controls vascular smooth muscle cell proliferation in vitro and in vivo by delaying G1/S exit

Eugenio Stabile1, Yi Fu Zhou, Motoyasu Saji

  • 1Cardiovascular Research Institute, Washington Hospital Center, 110 Irving St NW, 4B-1, Washington, DC 20010, USA. geko50@katamail.com

Circulation Research
|November 8, 2003
PubMed

Insights

Akt signaling promotes cell-cycle progression in vascular smooth muscle cells (SMCs). Inhibiting Akt with dominant-negative Akt mutant (AA-Akt) reduced SMC proliferation and neointima formation after vascular injury, mediated by p21Cip1.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cardiovascular Research

Background:

  • Constitutive activation of serine/threonine kinase Akt leads to uncontrolled cell-cycle progression.
  • Akt signaling plays a role in various cell types and in malignancy.
  • Understanding Akt's role in vascular smooth muscle cells (SMCs) is crucial for cardiovascular health.

Purpose of the Study:

  • To investigate how Akt activation modulates cell-cycle progression in vascular smooth muscle cells (SMCs) in vitro and in vivo.
  • To determine the effect of inhibiting Akt-dependent signaling on SMC proliferation and vascular injury response.
  • To elucidate the role of p21Cip1 in mediating Akt's effects on SMCs.

Main Methods:

  • Adenovirus-mediated transfection of a dominant-negative Akt mutant (AA-Akt) to inhibit Akt signaling.
  • In vitro studies involving serum stimulation of SMCs.
  • In vivo studies using balloon-induced vascular injury in animal models.
  • Analysis of cell proliferation, DNA synthesis, G1/S phase arrest, and neointima formation.
  • Experiments utilizing p21-/- mouse SMCs to assess the role of p21Cip1.

Main Results:

  • Inhibition of Akt signaling with AA-Akt significantly reduced SMC proliferation rate and DNA synthesis in vitro (P<0.01).
  • AA-Akt induced a significant arrest in G1/S phase exit in SMCs both in vitro and in vivo (P<0.01).
  • In vivo transfection with AA-Akt reduced SMC proliferation and neointima formation after vascular injury (P<0.01).
  • The effects of AA-Akt were partially mediated by increased p21Cip1 expression, as AA-Akt had no effect on p21-/- mouse SMC proliferation.

Conclusions:

  • Akt-dependent signaling enhances cell-cycle progression of nontransformed SMCs in vitro.
  • Akt signaling plays a significant role in the SMC response to vascular injury in vivo.
  • Akt signaling modulates normal tissue responses to stress and arterial wall responses to injury, potentially contributing to restenosis and atherosclerosis.
  • p21Cip1 is a key mediator of Akt's effects on SMC proliferation and vascular injury response.

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