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

Allison Ostriker, Henrick N Horita, Joanna Poczobutt, Mary C M Weiser-Evans, Raphael A Nemenoff
Arteriosclerosis, Thrombosis, and Vascular Biology 2014, 34 (4): 877-86

OBJECTIVE: To define the contribution of vascular smooth muscle cell (SMC)-derived factors to macrophage phenotypic modulation in the setting of vascular injury.

APPROACH AND RESULTS: 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-α, 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 (sMϕ) compared with maturation in macrophage-colony stimulating factor alone (M0). Recombinant transforming growth factor (TGF)-β1 recapitulated the effect of SMC conditioned media. Macrophage maturation studies performed in the presence of a pan-TGF-β neutralizing antibody, a TGF-β receptor inhibitor, or conditioned media from TGF-β-depleted SMCs confirmed that the SMC-derived factor responsible for macrophage activation was TGF-β. Finally, the effect of SMC-mediated macrophage activation on SMC biology was assessed. SMCs cocultured with sMϕ exhibited increased rates of proliferation relative to SMCs cultured alone or with M0 macrophages.

CONCLUSIONS: SMC-derived TGF-β 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.

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