title: Smooth muscle FGF/TGFβ cross talk regulates atherosclerosis progression.
abstract: 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 Frs2α 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.
authors.affiliation: Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, USA pei-yu.chen@yale.edu michael.simons@yale.edu.
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Chen
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Lingfeng
authors.initials: L
authors.lastname: Qin
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, CT, USA Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, China.
authors.forename: Guangxin
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: George
authors.initials: G
authors.lastname: Tellides
authors.affiliation: Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, USA Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA pei-yu.chen@yale.edu michael.simons@yale.edu.
authors.forename: Michael
authors.identifier: 0000-0003-0348-7734
authors.initials: M
authors.lastname: Simons
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000473:pathology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D003331:Coronary Vessels / Q000473:pathology*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D016212:Transforming Growth Factor beta; D005346:Fibroblast Growth Factors
keywords: FGF/TGFβ; atherosclerosis; smooth muscle cells