Vascular smooth muscle cell phenotype is modulated by ligands of the lymphotoxin ? receptor and the tumor necrosis factor receptor

Objective: Vascular smooth muscle cells (VSMCs) undergo a phenotypic-switching process during the generation of unstable atheroma plaques. In this investigation, the potential implication of the tumor necrosis factor superfamily (TNFSF) ligands, in the gene expression signature associated with VSMC plasticity was studied. Material and methods: Human aortic (ha)VSMCs were obtained commercially and treated with the cytokine TNFSF14, also called LIGHT, the lymphotoxin alpha (LTo), the heterotrimer LTo1O2 or with vehicle for 72 h. The effect of the different treatments on gene expression was ana-lyzed by quantitative PCR and included the study of genes associated with myofibroblast-like cell function, osteochondrogenesis, pluripotency, lymphorganogenesis and macrophage-like cell function. Results: HaVSMCs displayed a change in myofibroblast-like cell genes which consisted in reduced COL1A1 and TGFB1 mRNA levels when treated with LTo or LIGHT and with augmented MMP9 expression levels when treated with LTo. LTo and LIGHT treatments also diminished the expres-sion of genes associated with osteochondrogenesis and pluripotency SOX9, CKIT, and KLF4. By contrary, all the above genes were no affected by the treatment with the trimer LT'1(32. In addi-tion, haVSMC treatment with LT', LT'1(32 and LIGHT altered lymphorganogenic cytokine gene expression which consisted of augmented CCL20 and CCL21 mRNA levels by LT' and a reduc-tion in the gene expression of CCL21 and CXCL13 by LIGHT and LT'1(32 respectively. Neither, LT' or LIGHT or LT'1(32 treatments affected the expression of macrophage-like cell markers in haVSMC. Conclusions: Altogether, indicates that the TNFSF ligands through their interconnected network of signaling, are important in the preservation of VSMC identity against the acquisition of a genetic expression signature compatible with functional cellular plasticity. (c) 2022 The Author(s). Published by Elsevier Espan tilde a, S.L.U. on behalf of Sociedad Espan tilde ola de Arteriosclerosis. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).