Sun-Hwa Song1, Kyungjong Kim1, Eun-Kyung Jo1, Young-Wook Kim1, Jin-Sook Kwon1, Sun Sik Bae1, Jong-Hyuk Sung1, Sang Gyu Park1, Jee Taek Kim1, Wonhee Suh2. 1. 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.). 2. 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.
Abstract
OBJECTIVE: 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. APPROACH AND RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVE: 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. APPROACH AND RESULTS: 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. CONCLUSIONS: 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: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311