A Local Proinflammatory Signalling Loop Facilitates Adverse Age-Associated Arterial Remodeling

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

doi:10.1371/journal.pone.0016653

Abstract

BackgroundThe 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 FindingsImmunostaining 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/SignificanceThreshold 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.

Highlights

Coincident collagen deposition and vascular smooth muscle cell (VSMC) cellularity within a diffusely thickened arterial intima is a salient feature of species-wide mammalian arterial wall remodeling that accompanies aging [1,2,3]
We demonstrate, for the first time, that: 1) co-expression of monocyte chemoattractant protein-1 (MCP-1) and TGF-b1 is increased within the aged aortic wall; 2) MCP-1 treatment increases activation of TGF-b1 and its downstream signaling molecules, to produce collagen; 3) MCP-1 increases the invasive capability of young vascular smooth muscle cells (VSMC) in an MMP-2-dependent manner, to that level of old untreated cells; 4) following TGF-b1 treatment of young cells, MCP-1 production, MMP-2 activation and VSMC invasion increase, reaching the levels of untreated old cells
The novel findings of this study support the idea that a feedforward, MCP-1/MMP-2/TGF-b1, proinflammatory signalling loop triad, as depicted schematically in Figure 7, sustains processes that are associated with the arterial remodelling that accompanies advancing age

Summary

Introduction

Coincident collagen deposition and vascular smooth muscle cell (VSMC) cellularity within a diffusely thickened arterial intima is a salient feature of species-wide mammalian arterial wall remodeling that accompanies aging [1,2,3]. These age-associated alterations create a metabolically active microenvironment, especially in the thickened intima, and render it fragile, and vulnerable to pathologic stimuli, e.g., a high cholesterol diet, in older persons [1,2,3,4,5,6,7].

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