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Vascular smooth muscle cell-derived transforming growth factor-? promotes maturation of activated, neointima lesion-like macrophages.

ABSTRACT: To define the contribution of vascular smooth muscle cell (SMC)-derived factors to macrophage phenotypic modulation in the setting of vascular injury.By flow cytometry, macrophages (M4) were the predominant myeloid cell type recruited to wire-injured femoral arteries, in mouse, compared with neutrophils or eosinophils. Recruited macrophages from injured vessels exhibited a distinct expression profile relative to circulating mononuclear cells (peripheral blood monocytes; increased: interleukin-6, interleukin-10, interleukin-12b, CC chemokine receptor [CCR]3, CCR7, tumor necrosis factor-?, inducible nitric oxide synthase, arginase 1; decreased: interleukin-12a, matrix metalloproteinase [MMP]9). This phenotype was recapitulated in vitro by maturing rat bone marrow cells in the presence of macrophage-colony stimulating factor and 20% conditioned media from cultured rat SMC (sM?) compared with maturation in macrophage-colony stimulating factor alone (M0). Recombinant transforming growth factor (TGF)-?1 recapitulated the effect of SMC conditioned media. Macrophage maturation studies performed in the presence of a pan-TGF-? neutralizing antibody, a TGF-? receptor inhibitor, or conditioned media from TGF-?-depleted SMCs confirmed that the SMC-derived factor responsible for macrophage activation was TGF-?. Finally, the effect of SMC-mediated macrophage activation on SMC biology was assessed. SMCs cocultured with sM? exhibited increased rates of proliferation relative to SMCs cultured alone or with M0 macrophages.SMC-derived TGF-? modulates the phenotype of maturing macrophages in vitro, recapitulating the phenotype found in vascular lesions in vivo. SMC-modulated macrophages induce SMC activation to a greater extent than control macrophages.

SUBMITTER: Ostriker A

PROVIDER: S-EPMC3966963 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Vascular smooth muscle cell-derived transforming growth factor-β promotes maturation of activated, neointima lesion-like macrophages.

Ostriker Allison A Horita Henrick N HN Poczobutt Joanna J Weiser-Evans Mary C M MC Nemenoff Raphael A RA

Arteriosclerosis, thrombosis, and vascular biology 20140213 4

<h4>Objective</h4>To define the contribution of vascular smooth muscle cell (SMC)-derived factors to macrophage phenotypic modulation in the setting of vascular injury.<h4>Approach and results</h4>By flow cytometry, macrophages (M4) were the predominant myeloid cell type recruited to wire-injured femoral arteries, in mouse, compared with neutrophils or eosinophils. Recruited macrophages from injured vessels exhibited a distinct expression profile relative to circulating mononuclear cells (periph ...[more]

PMID: 24526697

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Project description:Peroxisome proliferator-activated receptor-? (PPAR?) plays an important role in the vasculature; however, the role of PPAR? in abdominal aortic aneurysms (AAA) is not well understood. We hypothesized that PPAR? in smooth muscle cells (SMCs) attenuates the development of AAA. We also investigated PPAR?-mediated signaling pathways that may prevent the development of AAA.We determined whether periaortic application of CaCl(2) renders vascular SMC-selective PPAR? knockout (SMPG KO) mice more susceptible to destruction of normal aortic wall architecture.There is evidence of increased vessel dilatation in the abdominal aorta 6 weeks after 0.25M periaortic CaCl(2) application in SMPG KO mice compared with littermate controls (1.4 ± 0.3 mm [n = 8] vs 1.1 ± 0.2 mm [n = 7]; P = .000119). Results from SMPG KO mice indicate medial layer elastin degradation was greater 6 weeks after abluminal application of CaCl(2) to the abdominal aorta (P < .01). Activated cathepsin S, a potent elastin-degrading enzyme, was increased in SMPG KO mice vs wild-type controls. To further identify a role of PPAR? signaling in reducing the development of AAA, we demonstrated that adenoviral-mediated PPAR? overexpression in cultured rat aortic SMCs decreases (P = .022) the messenger RNA levels of cathepsin S. In addition, a chromatin immunoprecipitation assay detected PPAR? bound to a peroxisome proliferator-activated receptor response element (PPRE) -141 to -159 bp upstream of the cathepsin S gene sequence in mouse aortic SMCs. Also, adenoviral-mediated PPAR? overexpression and knockdown in cultured rat aortic SMCs decreases (P = .013) and increases (P = .018) expression of activated cathepsin S. Finally, immunohistochemistry demonstrated a greater inflammatory infiltrate in SMPG KO mouse aortas, as evidenced by elevations in F4/80 and tumor necrosis factor-? expression.In this study, we identify PPAR? as an important contributor in attenuating the development of aortic aneurysms by demonstrating that loss of PPAR? in vascular SMCs promotes aortic dilatation and elastin degradation. Thus, PPAR? activation may be potentially promising medical therapy in reducing the risk of AAA progression and rupture.

Dataset Information

Vascular smooth muscle cell-derived transforming growth factor-? promotes maturation of activated, neointima lesion-like macrophages.

Publications

Vascular smooth muscle cell-derived transforming growth factor-β promotes maturation of activated, neointima lesion-like macrophages.

Similar Datasets

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