FGF signaling contributes to atherosclerosis by enhancing the inflammatory response in vascular smooth muscle cells

Qi,Ming; Xin,Shijie

doi:10.3892/mmr.2019.10249

FGF signaling contributes to atherosclerosis by enhancing the inflammatory response in vascular smooth muscle cells

Authors:
- Ming Qi
- Shijie Xin
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Affiliations: Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
Published online on: May 16, 2019 https://doi.org/10.3892/mmr.2019.10249
Pages: 162-170
Copyright: © Qi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The contractile to synthetic phenotypic switching of vascular smooth muscle cells (VSMCs) in response to fibroblast growth factor (FGF) has been previously described. However, the role of the inflammatory response induced by FGF signaling in VSMCs and its occurrence in atherosclerosis remains unclear. In the present study, FGF signaling promoted a contractile to secretory phenotypic transition in VSMCs. VSMCs (primary human aortic smooth muscle cells) treated with FGF exhibited a decrease in the protein expression levels of factors involved in contractility and the secretion of various chemokines was increased, as assessed by reverse transcription‑quantitative PCR and ELISA. Additionally, inhibition of FGF signaling by silencing FGF receptor substrate 2 (FRS2) decreased the protein expression levels of various chemokines. Furthermore, VSMCs in the medial layers of arteries from apolipoprotein E‑deficient mice and human atherosclerotic samples exhibited an increase in FGF signaling that was identified to be associated with an increase in the protein expression levels of pro‑inflammatory molecules, including C‑C motif chemokine ligand 2, C‑X‑C motif chemokine ligand (CXCL) 9, CXCL10 and CXCL11, compared with wild‑type mice and healthy control samples, respectively. The present results suggested that FGF signaling induced dedifferentiation of contractile VSMCs and the transition to a secretory phenotype, which may be involved in the progression of atherosclerosis. Collectively, the present results suggested that the FGF signaling pathway may represent a novel target for the treatment of atherosclerosis.

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1	Libby P, Ridker PM and Hansson GK: Progress and challenges in translating the biology of atherosclerosis. Nature. 473:317–325. 2011. View Article : Google Scholar : PubMed/NCBI
2	Sanz J and Fayad ZA: Imaging of atherosclerotic cardiovascular disease. Nature. 451:953–957. 2008. View Article : Google Scholar : PubMed/NCBI
3	Bennett MR, Sinha S and Owens GK: Vascular smooth muscle cells in atherosclerosis. Circ Res. 118:692–702. 2016. View Article : Google Scholar : PubMed/NCBI
4	Liu R, Leslie KL and Martin KA: Epigenetic regulation of smooth muscle cell plasticity. Biochim Biophys Acta. 1849:448–453. 2015. View Article : Google Scholar : PubMed/NCBI
5	Burns WR, Wang Y, Tang PC, Ranjbaran H, Iakimov A, Kim J, Cuffy M, Bai Y, Pober JS and Tellides G: Recruitment of CXCR3+ and CCR5+ T cells and production of interferon-gamma-inducible chemokines in rejecting human arteries. Am J Transplant. 5:1226–1236. 2005. View Article : Google Scholar : PubMed/NCBI
6	Ahmad U, Ali R, Lebastchi AH, Qin L, Lo SF, Yakimov AO, Khan SF, Choy JC, Geirsson A, Pober JS and Tellides G: IFN-gamma primes intact human coronary arteries and cultured coronary smooth muscle cells to double-stranded RNA- and self-RNA-induced inflammatory responses by upregulating TLR3 and melanoma differentiation-associated gene 5. J Immunol. 185:1283–1294. 2010. View Article : Google Scholar : PubMed/NCBI
7	Tellides G and Pober JS: Inflammatory and immune responses in the arterial media. Circ Res. 116:312–322. 2015. View Article : Google Scholar : PubMed/NCBI
8	Kawai-Kowase K and Owens GK: Multiple repressor pathways contribute to phenotypic switching of vascular smooth muscle cells. Am J Physiol Cell Physiol. 292:C59–C69. 2007. View Article : Google Scholar : PubMed/NCBI
9	Lindner V and Reidy MA: Proliferation of smooth muscle cells after vascular injury is inhibited by an antibody against basic fibroblast growth factor. Proc Natl Acad Sci USA. 88:3739–3743. 1991. View Article : Google Scholar : PubMed/NCBI
10	Jackson CL and Reidy MA: Basic fibroblast growth factor: Its role in the control of smooth muscle cell migration. Am J Pathol. 143:1024–1031. 1993.PubMed/NCBI
11	Chen PY, Qin L, Barnes C, Charisse K, Yi T, Zhang X, Ali R, Medina PP, Yu J, Slack FJ, et al: FGF regulates TGF-β signaling and endothelial-to-mesenchymal transition via control of let-7 miRNA expression. Cell Rep. 2:1684–1696. 2012. View Article : Google Scholar : PubMed/NCBI
12	Chen PY, Qin L, Tellides G and Simons M: Fibroblast growth factor receptor 1 is a key inhibitor of TGFβ signaling in the endothelium. Sci Signal. 7:ra902014. View Article : Google Scholar : PubMed/NCBI
13	Chen PY, Qin L, Baeyens N, Li G, Afolabi T, Budatha M, Tellides G, Schwartz MA and Simons M: Endothelial-to-mesenchymal transition drives atherosclerosis progression. J Clin Invest. 125:4514–4528. 2015. View Article : Google Scholar : PubMed/NCBI
14	Chen PY, Qin L, Li G, Tellides G and Simons M: Fibroblast growth factor (FGF) signaling regulates transforming growth factor beta (TGFβ)-dependent smooth muscle cell phenotype modulation. Sci Rep. 6:334072016. View Article : Google Scholar : PubMed/NCBI
15	Chen PY, Qin L, Li G, Tellides G and Simons M: Smooth muscle FGF/TGFβ cross talk regulates atherosclerosis progression. EMBO Mol Med. 8:712–728. 2016. View Article : Google Scholar : PubMed/NCBI
16	Lebastchi AH, Khan SF, Qin L, Li W, Zhou J, Hibino N, Yi T, Rao DA, Pober JS and Tellides G: Transforming growth factor beta expression by human vascular cells inhibits interferon gamma production and arterial media injury by alloreactive memory T cells. Am J Transplant. 11:2332–2341. 2011. View Article : Google Scholar : PubMed/NCBI
17	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
18	Ornitz DM and Itoh N: The fibroblast growth factor signaling pathway. Wiley Interdiscip Rev Dev Biol. 4:215–266. 2015. View Article : Google Scholar : PubMed/NCBI
19	Chen PY, Simons M and Friesel R: FRS2 via fibroblast growth factor receptor 1 is required for platelet-derived growth factor receptor beta-mediated regulation of vascular smooth muscle marker gene expression. J Biol Chem. 284:15980–15992. 2009. View Article : Google Scholar : PubMed/NCBI
20	Kouhara H, Hadari YR, Spivak-Kroizman T, Schilling J, Bar-Sagi D, Lax I and Schlessinger J: A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell. 89:693–702. 1997. View Article : Google Scholar : PubMed/NCBI
21	Eswarakumar VP, Lax I and Schlessinger J: Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev. 16:139–149. 2005. View Article : Google Scholar : PubMed/NCBI
22	Gotoh N: Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins. Cancer Sci. 99:1319–1325. 2008. View Article : Google Scholar : PubMed/NCBI
23	Hughes SE: Localisation and differential expression of the fibroblast growth factor receptor (FGFR) multigene family in normal and atherosclerotic human arteries. Cardiovasc Res. 32:557–569. 1996. View Article : Google Scholar : PubMed/NCBI
24	Zhou J, Tang PC, Qin L, Gayed PM, Li W, Skokos EA, Kyriakides TR, Pober JS and Tellides G: CXCR3-dependent accumulation and activation of perivascular macrophages is necessary for homeostatic arterial remodeling to hemodynamic stresses. J Exp Med. 207:1951–1966. 2010. View Article : Google Scholar : PubMed/NCBI
25	Yu L, Qin L, Zhang H, He Y, Chen H, Pober JS, Tellides G and Min W: AIP1 prevents graft arteriosclerosis by inhibiting interferon-γ-dependent smooth muscle cell proliferation and intimal expansion. Circ Res. 109:418–427. 2011. View Article : Google Scholar : PubMed/NCBI
26	Rao RM, Yang L, Garcia-Cardena G and Luscinskas FW: Endothelial-dependent mechanisms of leukocyte recruitment to the vascular wall. Circ Res. 101:234–247. 2007. View Article : Google Scholar : PubMed/NCBI
27	Qin L, Huang Q, Zhang H, Liu R, Tellides G, Min W and Yu L: SOCS1 prevents graft arteriosclerosis by preserving endothelial cell function. J Am Coll Cardiol. 63:21–29. 2014. View Article : Google Scholar : PubMed/NCBI
28	Charo IF and Taubman MB: Chemokines in the pathogenesis of vascular disease. Circ Res. 95:858–866. 2004. View Article : Google Scholar : PubMed/NCBI
29	Tabas I and Glass CK: Anti-inflammatory therapy in chronic disease: Challenges and opportunities. Science. 339:166–172. 2013. View Article : Google Scholar : PubMed/NCBI
30	He C, Medley SC, Hu T, Hinsdale ME, Lupu F, Virmani R and Olson LE: PDGFRβ signalling regulates local inflammation and synergizes with hypercholesterolaemia to promote atherosclerosis. Nat Commun. 6:77702015. View Article : Google Scholar : PubMed/NCBI
31	Boring L, Gosling J, Cleary M and Charo IF: Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature. 394:894–897. 1998. View Article : Google Scholar : PubMed/NCBI
32	Gerszten RE, Garcia-Zepeda EA, Lim YC, Yoshida M, Ding HA, Gimbrone MA Jr, Luster AD, Luscinskas FW and Rosenzweig A: MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature. 398:718–723. 1999. View Article : Google Scholar : PubMed/NCBI
33	Zheng Y, Qin L, Zacarías NV, de Vries H, Han GW, Gustavsson M, Dabros M, Zhao C, Cherney RJ, Carter P, et al: Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature. 540:458–461. 2016. View Article : Google Scholar : PubMed/NCBI
34	Veillard NR, Steffens S, Pelli G, Lu B, Kwak BR, Gerard C, Charo IF and Mach F: Differential influence of chemokine receptors CCR2 and CXCR3 in development of atherosclerosis in vivo. Circulation. 112:870–878. 2005. View Article : Google Scholar : PubMed/NCBI
35	Heller EA, Liu E, Tager AM, Yuan Q, Lin AY, Ahluwalia N, Jones K, Koehn SL, Lok VM, Aikawa E, et al: Chemokine CXCL10 promotes atherogenesis by modulating the local balance of effector and regulatory T cells. Circulation. 113:2301–2312. 2006. View Article : Google Scholar : PubMed/NCBI
36	Zernecke A, Bot I, Djalali-Talab Y, Shagdarsuren E, Bidzhekov K, Meiler S, Krohn R, Schober A, Sperandio M, Soehnlein O, et al: Protective role of CXC receptor 4/CXC ligand 12 unveils the importance of neutrophils in atherosclerosis. Circ Res. 102:209–217. 2008. View Article : Google Scholar : PubMed/NCBI
37	Schwarz JB, Langwieser N, Langwieser NN, Bek MJ, Seidl S, Eckstein HH, Lu B, Schömig A, Pavenstädt H and Zohlnhöfer D: Novel role of the CXC chemokine receptor 3 in inflammatory response to arterial injury: Involvement of mTORC1. Circ Res. 104:189–200. 2009. View Article : Google Scholar : PubMed/NCBI
38	Tavakolian Ferdousie V, Mohammadi M, Hassanshahi G, Khorramdelazad H, Khanamani Falahati-Pour S, Mirzaei M, Allah Tavakoli M, Kamiab Z, Ahmadi Z, Vazirinejad R, et al: Serum CXCL10 and CXCL12 chemokine levels are associated with the severity of coronary artery disease and coronary artery occlusion. Int J Cardiol. 233:23–28. 2017. View Article : Google Scholar : PubMed/NCBI