title: A local proinflammatory signalling loop facilitates adverse age-associated arterial remodeling.
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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America. mingyiw@grc.nia.nih.gov
authors.forename: Mingyi
authors.initials: M
authors.lastname: Wang
authors.forename: Gaia
authors.initials: G
authors.lastname: Spinetti
authors.forename: Robert E
authors.initials: RE
authors.lastname: Monticone
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: James
authors.initials: J
authors.lastname: Wu
authors.forename: Liqun
authors.initials: L
authors.lastname: Jiang
authors.forename: Benjamin
authors.initials: B
authors.lastname: Khazan
authors.forename: Richard
authors.initials: R
authors.lastname: Telljohann
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
mesh_terms: D000375:Aging / Q000473:pathology* / Q000502:physiology*; D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000378:metabolism / Q000473:pathology* / Q000502:physiology*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport; D051381:Rats; D054390:Receptors, CCR2 / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D053773:Transforming Growth Factor beta1; D003094:Collagen; D020778:Matrix Metalloproteinase 2