title: Fibroblast Growth Factor 12 Is a Novel Regulator of Vascular Smooth Muscle Cell Plasticity and Fate.
abstract: Vascular smooth muscle cells (VSMCs) modulate their phenotype between synthetic and contractile states in response to environmental changes; this modulation plays a crucial role in the pathogenesis of restenosis and atherosclerosis. Here, we identified fibroblast growth factor 12 (FGF12) as a novel key regulator of the VSMC phenotype switch.
  
  
  
  Using murine models and human specimens, we found that FGF12 was highly expressed in contractile VSMCs of normal vessel walls but was downregulated in synthetic VSMCs from injured and atherosclerotic vessels. In human VSMCs, FGF12 expression was inhibited at the transcriptional level by platelet-derived growth factor-BB. Gain- and loss-of-function experiments showed that FGF12 was both necessary and sufficient for inducing and maintaining the quiescent and contractile phenotypes of VSMCs. FGF12 inhibited cell proliferation through the p53 pathway and upregulated the key factors involved in VSMC lineage differentiation, such as myocardin and serum response factor. Such FGF12-induced phenotypic change was mediated by the p38 MAPK (mitogen-activated protein kinase) pathway. Moreover, FGF12 promoted the differentiation of mouse embryonic stem cells and the transdifferentiation of human dermal fibroblasts into SMC-like cells. Furthermore, adenoviral infection of FGF12 substantially decreased neointima hyperplasia in a rat carotid artery injury model.
  
  
  
  In general, FGF family members induce a synthetic VSMC phenotype. Interestingly, the present study showed the unanticipated finding that FGF12 belonging to FGF family, strongly induced the quiescent and contractile VSMC phenotypes and directly promoted VSMC lineage differentiation. These novel findings suggested that FGF12 could be a new therapeutic target for treating restenosis and atherosclerosis.
authors.affiliation: From the College of Pharmacy (S.-H.S., K.K., E.-K.J., W.S.), Department of Ophthalmology, College of Medicine (J.T.K.), Chung-Ang University, Seoul, Korea; Division of Vascular Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (Y.-W.K.); Division of Cardiovascular and Rare Disease, Center for Biomedical Sciences, Korea National Institute of Health, Osong, Cheongju, Chungbuk, Korea (J.-S.K.); Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam, Korea (S.S.B.); College of Pharmacy, Yonsei University, Incheon, Korea (J.-H.S.); STEMORE Co. Ltd., Incheon, Korea (J.-H.S.); and College of Pharmacy, Ajou University, Suwon, Korea (S.G.P.).
authors.forename: Sun-Hwa
authors.initials: SH
authors.lastname: Song
authors.affiliation: From the College of Pharmacy (S.-H.S., K.K., E.-K.J., W.S.), Department of Ophthalmology, College of Medicine (J.T.K.), Chung-Ang University, Seoul, Korea; Division of Vascular Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (Y.-W.K.); Division of Cardiovascular and Rare Disease, Center for Biomedical Sciences, Korea National Institute of Health, Osong, Cheongju, Chungbuk, Korea (J.-S.K.); Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam, Korea (S.S.B.); College of Pharmacy, Yonsei University, Incheon, Korea (J.-H.S.); STEMORE Co. Ltd., Incheon, Korea (J.-H.S.); and College of Pharmacy, Ajou University, Suwon, Korea (S.G.P.).
authors.forename: Kyungjong
authors.initials: K
authors.lastname: Kim
authors.affiliation: From the College of Pharmacy (S.-H.S., K.K., E.-K.J., W.S.), Department of Ophthalmology, College of Medicine (J.T.K.), Chung-Ang University, Seoul, Korea; Division of Vascular Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (Y.-W.K.); Division of Cardiovascular and Rare Disease, Center for Biomedical Sciences, Korea National Institute of Health, Osong, Cheongju, Chungbuk, Korea (J.-S.K.); Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam, Korea (S.S.B.); College of Pharmacy, Yonsei University, Incheon, Korea (J.-H.S.); STEMORE Co. Ltd., Incheon, Korea (J.-H.S.); and College of Pharmacy, Ajou University, Suwon, Korea (S.G.P.).
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Jo
authors.affiliation: From the College of Pharmacy (S.-H.S., K.K., E.-K.J., W.S.), Department of Ophthalmology, College of Medicine (J.T.K.), Chung-Ang University, Seoul, Korea; Division of Vascular Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (Y.-W.K.); Division of Cardiovascular and Rare Disease, Center for Biomedical Sciences, Korea National Institute of Health, Osong, Cheongju, Chungbuk, Korea (J.-S.K.); Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam, Korea (S.S.B.); College of Pharmacy, Yonsei University, Incheon, Korea (J.-H.S.); STEMORE Co. Ltd., Incheon, Korea (J.-H.S.); and College of Pharmacy, Ajou University, Suwon, Korea (S.G.P.).
authors.forename: Young-Wook
authors.initials: YW
authors.lastname: Kim
authors.affiliation: From the College of Pharmacy (S.-H.S., K.K., E.-K.J., W.S.), Department of Ophthalmology, College of Medicine (J.T.K.), Chung-Ang University, Seoul, Korea; Division of Vascular Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (Y.-W.K.); Division of Cardiovascular and Rare Disease, Center for Biomedical Sciences, Korea National Institute of Health, Osong, Cheongju, Chungbuk, Korea (J.-S.K.); Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam, Korea (S.S.B.); College of Pharmacy, Yonsei University, Incheon, Korea (J.-H.S.); STEMORE Co. Ltd., Incheon, Korea (J.-H.S.); and College of Pharmacy, Ajou University, Suwon, Korea (S.G.P.).
authors.forename: Jin-Sook
authors.initials: JS
authors.lastname: Kwon
authors.affiliation: From the College of Pharmacy (S.-H.S., K.K., E.-K.J., W.S.), Department of Ophthalmology, College of Medicine (J.T.K.), Chung-Ang University, Seoul, Korea; Division of Vascular Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (Y.-W.K.); Division of Cardiovascular and Rare Disease, Center for Biomedical Sciences, Korea National Institute of Health, Osong, Cheongju, Chungbuk, Korea (J.-S.K.); Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam, Korea (S.S.B.); College of Pharmacy, Yonsei University, Incheon, Korea (J.-H.S.); STEMORE Co. Ltd., Incheon, Korea (J.-H.S.); and College of Pharmacy, Ajou University, Suwon, Korea (S.G.P.).
authors.forename: Sun Sik
authors.initials: SS
authors.lastname: Bae
authors.affiliation: From the College of Pharmacy (S.-H.S., K.K., E.-K.J., W.S.), Department of Ophthalmology, College of Medicine (J.T.K.), Chung-Ang University, Seoul, Korea; Division of Vascular Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (Y.-W.K.); Division of Cardiovascular and Rare Disease, Center for Biomedical Sciences, Korea National Institute of Health, Osong, Cheongju, Chungbuk, Korea (J.-S.K.); Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam, Korea (S.S.B.); College of Pharmacy, Yonsei University, Incheon, Korea (J.-H.S.); STEMORE Co. Ltd., Incheon, Korea (J.-H.S.); and College of Pharmacy, Ajou University, Suwon, Korea (S.G.P.).
authors.forename: Jong-Hyuk
authors.initials: JH
authors.lastname: Sung
authors.affiliation: From the College of Pharmacy (S.-H.S., K.K., E.-K.J., W.S.), Department of Ophthalmology, College of Medicine (J.T.K.), Chung-Ang University, Seoul, Korea; Division of Vascular Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (Y.-W.K.); Division of Cardiovascular and Rare Disease, Center for Biomedical Sciences, Korea National Institute of Health, Osong, Cheongju, Chungbuk, Korea (J.-S.K.); Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam, Korea (S.S.B.); College of Pharmacy, Yonsei University, Incheon, Korea (J.-H.S.); STEMORE Co. Ltd., Incheon, Korea (J.-H.S.); and College of Pharmacy, Ajou University, Suwon, Korea (S.G.P.).
authors.forename: Sang Gyu
authors.initials: SG
authors.lastname: Park
authors.affiliation: From the College of Pharmacy (S.-H.S., K.K., E.-K.J., W.S.), Department of Ophthalmology, College of Medicine (J.T.K.), Chung-Ang University, Seoul, Korea; Division of Vascular Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (Y.-W.K.); Division of Cardiovascular and Rare Disease, Center for Biomedical Sciences, Korea National Institute of Health, Osong, Cheongju, Chungbuk, Korea (J.-S.K.); Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam, Korea (S.S.B.); College of Pharmacy, Yonsei University, Incheon, Korea (J.-H.S.); STEMORE Co. Ltd., Incheon, Korea (J.-H.S.); and College of Pharmacy, Ajou University, Suwon, Korea (S.G.P.).
authors.forename: Jee Taek
authors.initials: JT
authors.lastname: Kim
authors.affiliation: From the College of Pharmacy (S.-H.S., K.K., E.-K.J., W.S.), Department of Ophthalmology, College of Medicine (J.T.K.), Chung-Ang University, Seoul, Korea; Division of Vascular Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (Y.-W.K.); Division of Cardiovascular and Rare Disease, Center for Biomedical Sciences, Korea National Institute of Health, Osong, Cheongju, Chungbuk, Korea (J.-S.K.); Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam, Korea (S.S.B.); College of Pharmacy, Yonsei University, Incheon, Korea (J.-H.S.); STEMORE Co. Ltd., Incheon, Korea (J.-H.S.); and College of Pharmacy, Ajou University, Suwon, Korea (S.G.P.). wsuh@cau.ac.kr.
authors.forename: Wonhee
authors.initials: W
authors.lastname: Suh
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D000077214:Becaplermin; D001665:Binding Sites; D002340:Carotid Artery Diseases / Q000378:metabolism* / Q000473:pathology; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017536:Carotid Artery, Common / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D000066670:Cell Plasticity / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D006965:Hyperplasia; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D058426:Neointima; D010641:Phenotype; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D011485:Protein Binding; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D014661:Vasoconstriction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; D001057:Apolipoproteins E; C486356:FGF12 protein, human; C108110:Fgf12 protein, mouse; D020574:Proto-Oncogene Proteins c-sis; C000604599:fibroblast growth factor 12, rat; D000077214:Becaplermin; D005346:Fibroblast Growth Factors; D058539:Phosphatidylinositol 3-Kinase; D048051:p38 Mitogen-Activated Protein Kinases
keywords: cell proliferation; cell transdifferentiation; muscle, smooth, vascular; myocytes, smooth muscle; neointima