Smooth muscle FGF/TGFβ cross talk regulates atherosclerosis progression

• Published in: EMBO molecular medicine Vol. 8; no. 7; pp. 712 - 728
• Main Authors: Chen, Pei‐Yu, Qin, Lingfeng, Li, Guangxin, Tellides, George, Simons, Michael
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2016; EMBO Press; John Wiley and Sons Inc
• Subjects: Animals; Apolipoprotein E; Arteriosclerosis; Atherosclerosis; Atherosclerosis - pathology; Binding sites; Cell Differentiation; Cell growth; Cell Proliferation; Coronary artery; Coronary Vessels - pathology; EMBO04; EMBO46; Experiments; Extracellular matrix; FGF/TGFβ; Fibroblast growth factors; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Fibroblasts; Gene expression; Genotype & phenotype; Growth factors; High fat diet; Humans; Kinases; Ligands; Mice, Knockout; Muscle contraction; Muscle, Smooth - pathology; Myocytes, Smooth Muscle - physiology; Phenotypes; Phosphorylation; Research Article; Signal Transduction; Smooth muscle; smooth muscle cells; Studies; Transforming Growth Factor beta - metabolism; atherosclerosis; smooth muscle cells; FGF/TGFβ
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201506181

The conversion of vascular smooth muscle cells (SMCs) from contractile to proliferative phenotype is thought to play an important role in atherosclerosis. However, the contribution of this process to plaque growth has never been fully defined. In this study, we show that activation of SMC TGFβ signaling, achieved by suppression of SMC fibroblast growth factor (FGF) signaling input, induces their conversion to a contractile phenotype and dramatically reduces atherosclerotic plaque size. The FGF/TGFβ signaling cross talk was observed in vitro and in vivo . In vitro , inhibition of FGF signaling increased TGFβ activity, thereby promoting smooth muscle differentiation and decreasing proliferation. In vivo , smooth muscle‐specific knockout of an FGF receptor adaptor Frs2 α led to a profound inhibition of atherosclerotic plaque growth when these animals were crossed on Apoe −/− background and subjected to a high‐fat diet. In particular, there was a significant reduction in plaque cellularity, increase in fibrous cap area, and decrease in necrotic core size. In agreement with these findings, examination of human coronary arteries with various degrees of atherosclerosis revealed a strong correlation between the activation of FGF signaling, loss of TGFβ activity, and increased disease severity. These results identify SMC FGF/TGFβ signaling cross talk as an important regulator of SMC phenotype switch and document a major contribution of medial SMC proliferation to atherosclerotic plaque growth. Synopsis TGFβ signaling promotes smooth muscle cell (SMC) proliferative‐to‐contractile phenotype switch. FGF signaling input is the critical regulator of SMC TGFβ signaling: A decline in FGF signaling input leads to increased TGFβ signaling. FGF regulates TGFβ signaling via control of let‐7 miRNA levels in SMCs. Increasing severity of atherosclerotic coronary artery disease is associated with a progressive increase in FGF and decrease in TGFβ signaling activity in medial smooth muscle cells. Inhibition of smooth muscle cell FGF signaling inhibits atherosclerosis in Apoe‐deficient mice on high‐fat diet. Graphical Abstract TGFβ signaling promotes smooth muscle cell (SMC) proliferative‐to‐contractile phenotype switch. FGF signaling input is the critical regulator of SMC TGFβ signaling: A decline in FGF signaling input leads to increased TGFβ signaling.