Enhanced proliferation and migration of vascular smooth muscle cells in response to vascular injury under hyperglycemic conditions is controlled by β3 integrin signaling

Manikandan Panchatcharam, Sumitra Miriyala, Fanmuyi Yang, Michael Leitges, Magdalena Chrzanowska-Wodnicka, Lawrence A. Quilliam, Paul Anaya, Andrew J. Morris, Susan S. Smyth

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Atheroma formation and restenosis following percutaneous vascular intervention involve the growth and migration of vascular smooth muscle cells (SMCs) into neointimal lesions, in part due to changes in the extracellular matrix. While some clinical studies have suggested that, in comparison to non-diabetics, β3 integrin inhibition in diabetic patients confers protection from restenosis, little is known regarding the role of β3 integrin inhibition on SMC responses in this context. To understand the molecular mechanisms underlying integrin-mediated regulation of SMC function in diabetes, we examined SMC responses in diabetic mice deficient in integrin β3 and observed that the integrin was required for enhanced proliferation, migration and extracellular regulated kinase (ERK) activation. Hyperglycemia-enhanced membrane recruitment and catalytic activity of PKCβ in an integrin β3-dependent manner. Hyperglycemia also promoted SMC filopodia formation and cell migration, both of which required αVβ3, PKCβ, and ERK activity. Furthermore, the integrin-kinase association was regulated by the αVβ3 integrin ligand thrombospondin and the integrin modulator Rap1 under conditions of hyperglycemia. These results suggest that there are differences in SMC responses to vascular injury depending on the presence or absence of hyperglycemia and that SMC response under hyperglycemic conditions is largely mediated through β3 integrin signaling.

Original languageEnglish
Pages (from-to)965-974
Number of pages10
JournalInternational Journal of Biochemistry and Cell Biology
Volume42
Issue number6
DOIs
StatePublished - Jun 2010

Bibliographical note

Funding Information:
We thank Jessica Caicedo and Paul Mueller for animal husbandry, Kirk McNaughton for assistance with histology, and Robert Bagnell for assistance with electron microscopy. This work was supported by grants HL080166 , HL074219 and HL078663 from NIH (S.S.S.), a Beginning Grant-in-Aid from the American Heart Association (M.P.), grant 0950118G from the American Heart Association (M.W.), and CA108647 from NIH (L.Q.). A portion of this work was presented in abstract form at the American Heart Association Scientific Sessions in 2007.

Keywords

  • Hyperglycemia
  • Intima
  • Proliferation
  • Restenosis
  • Smooth muscle cells

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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