MFG-E8 activates proliferation of vascular smooth muscle cells via integrin signaling

Mingyi Wang, Zongming Fu, James Wu, Jing Zhang, Liqun Jiang, Benjamin Khazan, Richard Telljohann, Mingming Zhao, Alexander W. Krug, Maria Pikilidou, Robert E. Monticone, Robert Wersto, Jennifer Van Eyk, Edward G. Lakatta

Research output: Contribution to journalArticlepeer-review

Abstract

An accumulation of milk fat globule EGF-8 protein (MFG-E8) occurs within the context of arterial wall inflammatory remodeling during aging, hypertension, diabetes mellitus, or atherosclerosis. MFG-E8 induces VSMC invasion, but whether it affects VSMC proliferation, a salient feature of arterial inflammation, is unknown. Here, we show that in the rat arterial wall in vivo, PCNA and Ki67, markers of cell cycle activation, increase with age between 8 and 30months. In fresh and early passage VSMC isolated from old aortae, an increase in CDK4 and PCNA, an increase in the acceleration of cell cycle S and G2 phases, decrease in the G1/G0 phase, and an increase in PDGF and its receptors confer elevated proliferative capacity, compared to young VSMC. Increased coexpression and physical interaction of MFG-E8 and integrin αvβ5 occur with aging in both the rat aortic wall in vivo and in VSMC in vitro. In young VSMC in vitro, MFG-E8 added exogenously, or overexpressed endogenously, triggers phosphorylation of ERK1/2, augmented levels of PCNA and CDK4, increased BrdU incorporation, and promotes proliferation, via αvβ5 integrins. MFG-E8 silencing, or its receptor inhibition, or the blockade of ERK1/2 phosphorylation in these cells reduces PCNA and CDK4 levels and decelerates the cell cycle S phase, conferring a reduction in proliferative capacity. Collectively, these results indicate that MFG-E8 in a dose-dependent manner coordinates the expression of cell cycle molecules and facilitates VSMC proliferation via integrin/ERK1/2 signaling. Thus, an increase in MFG-E8 signaling is a mechanism of the age-associated increase in aortic VSMC proliferation.

Original languageEnglish (US)
Pages (from-to)500-508
Number of pages9
JournalAging Cell
Volume11
Issue number3
DOIs
StatePublished - Jun 2012

Keywords

  • Aging
  • Cell cycle
  • MFG-E8
  • VSMC proliferation
  • Vascular remodeling

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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