A local proinflammatory signalling loop facilitates adverse age-associated arterial remodeling

Mingyi Wang, Gaia Spinetti, Robert E. Monticone, Jing Zhang, James Wu, Liqun Jiang, Benjamin Khazan, Richard Telljohann, Edward G. Lakatta

Research output: Contribution to journalArticlepeer-review

Abstract

Background: The coincidence of vascular smooth muscle cells (VSMC) infiltration and collagen deposition within a diffusely thickened intima is a salient feature of central arterial wall inflammation that accompanies advancing age. However, the molecular mechanisms involved remain undefined. Methodology/Principal Findings: Immunostaining and immunoblotting of rat aortae demonstrate that a triad of proinflammatory molecules, MCP-1, TGF-β1, and MMP-2 increases within the aortic wall with aging. Exposure of VSMC isolated from 8-mo-old rats (young) to MCP-1 effects, via CCR-2 signaling, both an increase in TGF-β1 activity, up to levels of untreated VSMC from 30-mo-old (old) rats, and a concurrent increase in MMP-2 activation. Furthermore, exposure of young VSMC to TGF-β1 increases levels of MCP-1, and MMP-2 activation, to levels of untreated VSMC from old rats. This autocatalytic signaling loop that enhances collagen production and invasiveness of VSMC is effectively suppressed by si-MCP-1, a CCR2 antagonist, or MMP-2 inhibition. Conclusions/Significance: Threshold levels of MCP-1, MMP-2, or TGF-β1 activity trigger a feed-forward signaling mechanism that is implicated in the initiation and progression of adverse age-associated arterial wall remodeling. Intervention that suppressed this signaling loop may potentially retard age-associated adverse arterial remodeling.

Original languageEnglish (US)
Article numbere16653
JournalPloS one
Volume6
Issue number2
DOIs
StatePublished - 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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