Fibroblast growth factor 12 is a novel regulator of vascular smooth muscle cell plasticity and fate

Sun Hwa Song, Kyungjong Kim, Eun Kyung Jo, Young Wook Kim, Jin Sook Kwon, Sun Sik Bae, Jong Hyuk Sung, Sang Gyu Park, Jee Taek Kim, Wonhee Suh

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1928-1936
Number of pages9
JournalArteriosclerosis, thrombosis, and vascular biology
Volume36
Issue number9
DOIs
Publication statusPublished - 2016 Sep 1

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Fibroblast Growth Factors
Vascular Smooth Muscle
Smooth Muscle Myocytes
Phenotype
Cell Lineage
Cell Differentiation
Atherosclerosis
Cell Transdifferentiation
Cell Plasticity
Serum Response Factor
Carotid Artery Injuries
Neointima
p38 Mitogen-Activated Protein Kinases
Hyperplasia
Down-Regulation
Fibroblasts
Cell Proliferation
Skin

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Song, Sun Hwa ; Kim, Kyungjong ; Jo, Eun Kyung ; Kim, Young Wook ; Kwon, Jin Sook ; Bae, Sun Sik ; Sung, Jong Hyuk ; Park, Sang Gyu ; Kim, Jee Taek ; Suh, Wonhee. / Fibroblast growth factor 12 is a novel regulator of vascular smooth muscle cell plasticity and fate. In: Arteriosclerosis, thrombosis, and vascular biology. 2016 ; Vol. 36, No. 9. pp. 1928-1936.
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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.",
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Fibroblast growth factor 12 is a novel regulator of vascular smooth muscle cell plasticity and fate. / Song, Sun Hwa; Kim, Kyungjong; Jo, Eun Kyung; Kim, Young Wook; Kwon, Jin Sook; Bae, Sun Sik; Sung, Jong Hyuk; Park, Sang Gyu; Kim, Jee Taek; Suh, Wonhee.

In: Arteriosclerosis, thrombosis, and vascular biology, Vol. 36, No. 9, 01.09.2016, p. 1928-1936.

Research output: Contribution to journalArticle

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AU - Song, Sun Hwa

AU - Kim, Kyungjong

AU - Jo, Eun Kyung

AU - Kim, Young Wook

AU - Kwon, Jin Sook

AU - Bae, Sun Sik

AU - Sung, Jong Hyuk

AU - Park, Sang Gyu

AU - Kim, Jee Taek

AU - Suh, Wonhee

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AB - 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.

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