Deletion of the FHL2 gene attenuates intima‐media thickening in a partially ligated carotid artery ligated mouse model
The four and a half LIM domain protein 2 (FHL2) is a member of the four and a half LIM domain (FHL) gene family, and it is associated with cholesterol‐enriched diet‐promoted atherosclerosis. However, the effect of FHL2 protein on vascular remodelling in response to hemodynamic alterations remains un...
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| Veröffentlicht in: | Journal of cellular and molecular medicine 2020-01, Vol.24 (1), p.160-173 |
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| creator | Chen, Chi‐Yu Tsai, Hsiao‐Ya Tsai, Shih‐Hung Chu, Pao‐Hsien Huang, Po‐Hsun Chen, Jaw‐Wen Lin, Shing‐Jong |
| description | The four and a half LIM domain protein 2 (FHL2) is a member of the four and a half LIM domain (FHL) gene family, and it is associated with cholesterol‐enriched diet‐promoted atherosclerosis. However, the effect of FHL2 protein on vascular remodelling in response to hemodynamic alterations remains unclear. Here, we investigated the role of FHL2 in a model of restricted blood flow‐induced atherosclerosis. To promote neointimal hyperplasia in vivo, we subjected FHL2+/+ and FHL2−/− mice to partial ligation of the left carotid artery (LCA). The expression of p‐ERK and p‐AKT was decreased in FHL2−/− mice. FHL2 bound to AKT regulated AKT phosphorylation and led to Rac1‐GTP inactivation. FHL2 silencing in human aortic smooth muscle cells down‐regulated the PDGF‐induced phosphorylation of ERK and AKT. Furthermore, FHL2 silencing reduced cytoskeleton conformational changes and caused cell cycle arrest. We concluded that FHL2 is essential for the regulation of arterial smooth muscle cell function. FHL2 modulates proliferation and migration via mitogen‐activated protein kinase (MAPK) and PI3K‐AKT signalling, leading to arterial wall thickening and thus neointimal hyperplasia. |
| doi_str_mv | 10.1111/jcmm.14687 |
| format | Article |
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However, the effect of FHL2 protein on vascular remodelling in response to hemodynamic alterations remains unclear. Here, we investigated the role of FHL2 in a model of restricted blood flow‐induced atherosclerosis. To promote neointimal hyperplasia in vivo, we subjected FHL2+/+ and FHL2−/− mice to partial ligation of the left carotid artery (LCA). The expression of p‐ERK and p‐AKT was decreased in FHL2−/− mice. FHL2 bound to AKT regulated AKT phosphorylation and led to Rac1‐GTP inactivation. FHL2 silencing in human aortic smooth muscle cells down‐regulated the PDGF‐induced phosphorylation of ERK and AKT. Furthermore, FHL2 silencing reduced cytoskeleton conformational changes and caused cell cycle arrest. We concluded that FHL2 is essential for the regulation of arterial smooth muscle cell function. FHL2 modulates proliferation and migration via mitogen‐activated protein kinase (MAPK) and PI3K‐AKT signalling, leading to arterial wall thickening and thus neointimal hyperplasia.</description><identifier>ISSN: 1582-1838</identifier><identifier>EISSN: 1582-4934</identifier><identifier>DOI: 10.1111/jcmm.14687</identifier><identifier>PMID: 31714683</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>1-Phosphatidylinositol 3-kinase ; AKT protein ; Angioplasty ; Animals ; Aorta ; Arteriosclerosis ; Atherosclerosis ; Atherosclerosis - etiology ; Atherosclerosis - metabolism ; Atherosclerosis - pathology ; Atherosclerosis - prevention & control ; Biotechnology ; Blood flow ; Carotid arteries ; Carotid Arteries - pathology ; Carotid Arteries - surgery ; Carotid artery ; carotid artery ligation ; Carotid Intima-Media Thickness ; Cell adhesion & migration ; Cell cycle ; Cell growth ; Cell Movement ; Cell Proliferation ; Cells, Cultured ; Cholesterol ; Clonal deletion ; Cytoskeleton ; Extracellular signal-regulated kinase ; FHL2 ; FHL2 protein ; Gene Deletion ; Guanosine triphosphate ; Hemodynamics ; Hyperplasia ; Inactivation ; Kinases ; Laboratory animals ; LIM-Homeodomain Proteins - physiology ; MAP kinase ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Muscle Proteins - physiology ; Muscle, Smooth, Vascular - metabolism ; Muscle, Smooth, Vascular - pathology ; Muscles ; neointimal hyperplasia ; Original ; Phosphorylation ; Platelet-derived growth factor ; Protein kinase ; Proteins ; Rac1 protein ; Signal Transduction ; Smooth muscle ; smooth muscle cell ; Software ; Stains & staining ; Transcription Factors - physiology ; Veins & arteries</subject><ispartof>Journal of cellular and molecular medicine, 2020-01, Vol.24 (1), p.160-173</ispartof><rights>2019 The Authors. published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.</rights><rights>2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.</rights><rights>2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4767-fabd7afcc7c3265da5fca7acb68c1bb60fa2d3916ab477c78aebcfcd2c1a30ef3</citedby><cites>FETCH-LOGICAL-c4767-fabd7afcc7c3265da5fca7acb68c1bb60fa2d3916ab477c78aebcfcd2c1a30ef3</cites><orcidid>0000-0003-1584-6749 ; 0000-0003-1245-0888</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933399/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933399/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,1417,11562,27924,27925,45574,45575,46052,46476,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31714683$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Chi‐Yu</creatorcontrib><creatorcontrib>Tsai, Hsiao‐Ya</creatorcontrib><creatorcontrib>Tsai, Shih‐Hung</creatorcontrib><creatorcontrib>Chu, Pao‐Hsien</creatorcontrib><creatorcontrib>Huang, Po‐Hsun</creatorcontrib><creatorcontrib>Chen, Jaw‐Wen</creatorcontrib><creatorcontrib>Lin, Shing‐Jong</creatorcontrib><title>Deletion of the FHL2 gene attenuates intima‐media thickening in a partially ligated carotid artery ligated mouse model</title><title>Journal of cellular and molecular medicine</title><addtitle>J Cell Mol Med</addtitle><description>The four and a half LIM domain protein 2 (FHL2) is a member of the four and a half LIM domain (FHL) gene family, and it is associated with cholesterol‐enriched diet‐promoted atherosclerosis. However, the effect of FHL2 protein on vascular remodelling in response to hemodynamic alterations remains unclear. Here, we investigated the role of FHL2 in a model of restricted blood flow‐induced atherosclerosis. To promote neointimal hyperplasia in vivo, we subjected FHL2+/+ and FHL2−/− mice to partial ligation of the left carotid artery (LCA). The expression of p‐ERK and p‐AKT was decreased in FHL2−/− mice. FHL2 bound to AKT regulated AKT phosphorylation and led to Rac1‐GTP inactivation. FHL2 silencing in human aortic smooth muscle cells down‐regulated the PDGF‐induced phosphorylation of ERK and AKT. Furthermore, FHL2 silencing reduced cytoskeleton conformational changes and caused cell cycle arrest. We concluded that FHL2 is essential for the regulation of arterial smooth muscle cell function. FHL2 modulates proliferation and migration via mitogen‐activated protein kinase (MAPK) and PI3K‐AKT signalling, leading to arterial wall thickening and thus neointimal hyperplasia.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>AKT protein</subject><subject>Angioplasty</subject><subject>Animals</subject><subject>Aorta</subject><subject>Arteriosclerosis</subject><subject>Atherosclerosis</subject><subject>Atherosclerosis - etiology</subject><subject>Atherosclerosis - metabolism</subject><subject>Atherosclerosis - pathology</subject><subject>Atherosclerosis - prevention & control</subject><subject>Biotechnology</subject><subject>Blood flow</subject><subject>Carotid arteries</subject><subject>Carotid Arteries - pathology</subject><subject>Carotid Arteries - surgery</subject><subject>Carotid artery</subject><subject>carotid artery ligation</subject><subject>Carotid Intima-Media Thickness</subject><subject>Cell adhesion & migration</subject><subject>Cell cycle</subject><subject>Cell growth</subject><subject>Cell Movement</subject><subject>Cell Proliferation</subject><subject>Cells, Cultured</subject><subject>Cholesterol</subject><subject>Clonal deletion</subject><subject>Cytoskeleton</subject><subject>Extracellular signal-regulated kinase</subject><subject>FHL2</subject><subject>FHL2 protein</subject><subject>Gene Deletion</subject><subject>Guanosine triphosphate</subject><subject>Hemodynamics</subject><subject>Hyperplasia</subject><subject>Inactivation</subject><subject>Kinases</subject><subject>Laboratory animals</subject><subject>LIM-Homeodomain Proteins - physiology</subject><subject>MAP kinase</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Muscle Proteins - physiology</subject><subject>Muscle, Smooth, Vascular - metabolism</subject><subject>Muscle, Smooth, Vascular - pathology</subject><subject>Muscles</subject><subject>neointimal hyperplasia</subject><subject>Original</subject><subject>Phosphorylation</subject><subject>Platelet-derived growth factor</subject><subject>Protein kinase</subject><subject>Proteins</subject><subject>Rac1 protein</subject><subject>Signal Transduction</subject><subject>Smooth muscle</subject><subject>smooth muscle cell</subject><subject>Software</subject><subject>Stains & staining</subject><subject>Transcription Factors - physiology</subject><subject>Veins & arteries</subject><issn>1582-1838</issn><issn>1582-4934</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kc9u1DAQxiMEoqVw4QGQJS6o0pY4k9jJBQltW1q0FRc4WxNnvPXiOIvjQPfGI_CMPAne7lL-HOqDbXl-83k-fVn2nOcnPK3XK933J7wUtXyQHfKqLmZlA-XD_Z3XUB9kT8ZxlecgODSPswPgcsvDYXZzSo6iHTwbDIvXxM4vFgVbkieGMZKfMNLIrI-2x5_ff_TUWUyc1Z_JW79MFYZsjSFadG7DnF2mho5pDEO0HUsFCn-e-2EaKe0duafZI4NupGf78yj7dH72cX4xW3x4dzl_u5jpUgo5M9h2Eo3WUkMhqg4ro1GibkWteduK3GDRQcMFtqWUWtZIrTa6KzRHyMnAUfZmp7ue2jS9Jh8DOrUOyVDYqAGt-rfi7bVaDl-VaACgaZLAq71AGL5MNEbV21GTc-gp2VEF8DIHEKJK6Mv_0NUwBZ_sqaIqqroGqMt7KYBcAge-_fZ4R-kwjGMgczcyz9U2drWNXd3GnuAXf5u8Q3_nnAC-A75ZR5t7pNT7-dXVTvQXBBe8BQ</recordid><startdate>202001</startdate><enddate>202001</enddate><creator>Chen, Chi‐Yu</creator><creator>Tsai, Hsiao‐Ya</creator><creator>Tsai, Shih‐Hung</creator><creator>Chu, Pao‐Hsien</creator><creator>Huang, Po‐Hsun</creator><creator>Chen, Jaw‐Wen</creator><creator>Lin, Shing‐Jong</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-1584-6749</orcidid><orcidid>https://orcid.org/0000-0003-1245-0888</orcidid></search><sort><creationdate>202001</creationdate><title>Deletion of the FHL2 gene attenuates intima‐media thickening in a partially ligated carotid artery ligated mouse model</title><author>Chen, Chi‐Yu ; Tsai, Hsiao‐Ya ; Tsai, Shih‐Hung ; Chu, Pao‐Hsien ; Huang, Po‐Hsun ; Chen, Jaw‐Wen ; Lin, Shing‐Jong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4767-fabd7afcc7c3265da5fca7acb68c1bb60fa2d3916ab477c78aebcfcd2c1a30ef3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>AKT protein</topic><topic>Angioplasty</topic><topic>Animals</topic><topic>Aorta</topic><topic>Arteriosclerosis</topic><topic>Atherosclerosis</topic><topic>Atherosclerosis - etiology</topic><topic>Atherosclerosis - metabolism</topic><topic>Atherosclerosis - pathology</topic><topic>Atherosclerosis - prevention & control</topic><topic>Biotechnology</topic><topic>Blood flow</topic><topic>Carotid arteries</topic><topic>Carotid Arteries - pathology</topic><topic>Carotid Arteries - surgery</topic><topic>Carotid artery</topic><topic>carotid artery ligation</topic><topic>Carotid Intima-Media Thickness</topic><topic>Cell adhesion & migration</topic><topic>Cell cycle</topic><topic>Cell growth</topic><topic>Cell Movement</topic><topic>Cell Proliferation</topic><topic>Cells, Cultured</topic><topic>Cholesterol</topic><topic>Clonal deletion</topic><topic>Cytoskeleton</topic><topic>Extracellular signal-regulated kinase</topic><topic>FHL2</topic><topic>FHL2 protein</topic><topic>Gene Deletion</topic><topic>Guanosine triphosphate</topic><topic>Hemodynamics</topic><topic>Hyperplasia</topic><topic>Inactivation</topic><topic>Kinases</topic><topic>Laboratory animals</topic><topic>LIM-Homeodomain Proteins - physiology</topic><topic>MAP kinase</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Muscle Proteins - physiology</topic><topic>Muscle, Smooth, Vascular - metabolism</topic><topic>Muscle, Smooth, Vascular - pathology</topic><topic>Muscles</topic><topic>neointimal hyperplasia</topic><topic>Original</topic><topic>Phosphorylation</topic><topic>Platelet-derived growth factor</topic><topic>Protein kinase</topic><topic>Proteins</topic><topic>Rac1 protein</topic><topic>Signal Transduction</topic><topic>Smooth muscle</topic><topic>smooth muscle cell</topic><topic>Software</topic><topic>Stains & staining</topic><topic>Transcription Factors - physiology</topic><topic>Veins & arteries</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Chi‐Yu</creatorcontrib><creatorcontrib>Tsai, Hsiao‐Ya</creatorcontrib><creatorcontrib>Tsai, Shih‐Hung</creatorcontrib><creatorcontrib>Chu, Pao‐Hsien</creatorcontrib><creatorcontrib>Huang, Po‐Hsun</creatorcontrib><creatorcontrib>Chen, Jaw‐Wen</creatorcontrib><creatorcontrib>Lin, Shing‐Jong</creatorcontrib><collection>Wiley-Blackwell Open Access Titles</collection><collection>Wiley Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of cellular and molecular medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Chi‐Yu</au><au>Tsai, Hsiao‐Ya</au><au>Tsai, Shih‐Hung</au><au>Chu, Pao‐Hsien</au><au>Huang, Po‐Hsun</au><au>Chen, Jaw‐Wen</au><au>Lin, Shing‐Jong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Deletion of the FHL2 gene attenuates intima‐media thickening in a partially ligated carotid artery ligated mouse model</atitle><jtitle>Journal of cellular and molecular medicine</jtitle><addtitle>J Cell Mol Med</addtitle><date>2020-01</date><risdate>2020</risdate><volume>24</volume><issue>1</issue><spage>160</spage><epage>173</epage><pages>160-173</pages><issn>1582-1838</issn><eissn>1582-4934</eissn><abstract>The four and a half LIM domain protein 2 (FHL2) is a member of the four and a half LIM domain (FHL) gene family, and it is associated with cholesterol‐enriched diet‐promoted atherosclerosis. However, the effect of FHL2 protein on vascular remodelling in response to hemodynamic alterations remains unclear. Here, we investigated the role of FHL2 in a model of restricted blood flow‐induced atherosclerosis. To promote neointimal hyperplasia in vivo, we subjected FHL2+/+ and FHL2−/− mice to partial ligation of the left carotid artery (LCA). The expression of p‐ERK and p‐AKT was decreased in FHL2−/− mice. FHL2 bound to AKT regulated AKT phosphorylation and led to Rac1‐GTP inactivation. FHL2 silencing in human aortic smooth muscle cells down‐regulated the PDGF‐induced phosphorylation of ERK and AKT. Furthermore, FHL2 silencing reduced cytoskeleton conformational changes and caused cell cycle arrest. We concluded that FHL2 is essential for the regulation of arterial smooth muscle cell function. FHL2 modulates proliferation and migration via mitogen‐activated protein kinase (MAPK) and PI3K‐AKT signalling, leading to arterial wall thickening and thus neointimal hyperplasia.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>31714683</pmid><doi>10.1111/jcmm.14687</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0003-1584-6749</orcidid><orcidid>https://orcid.org/0000-0003-1245-0888</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 1-Phosphatidylinositol 3-kinase AKT protein Angioplasty Animals Aorta Arteriosclerosis Atherosclerosis Atherosclerosis - etiology Atherosclerosis - metabolism Atherosclerosis - pathology Atherosclerosis - prevention & control Biotechnology Blood flow Carotid arteries Carotid Arteries - pathology Carotid Arteries - surgery Carotid artery carotid artery ligation Carotid Intima-Media Thickness Cell adhesion & migration Cell cycle Cell growth Cell Movement Cell Proliferation Cells, Cultured Cholesterol Clonal deletion Cytoskeleton Extracellular signal-regulated kinase FHL2 FHL2 protein Gene Deletion Guanosine triphosphate Hemodynamics Hyperplasia Inactivation Kinases Laboratory animals LIM-Homeodomain Proteins - physiology MAP kinase Mice Mice, Inbred C57BL Mice, Knockout Muscle Proteins - physiology Muscle, Smooth, Vascular - metabolism Muscle, Smooth, Vascular - pathology Muscles neointimal hyperplasia Original Phosphorylation Platelet-derived growth factor Protein kinase Proteins Rac1 protein Signal Transduction Smooth muscle smooth muscle cell Software Stains & staining Transcription Factors - physiology Veins & arteries |
| title | Deletion of the FHL2 gene attenuates intima‐media thickening in a partially ligated carotid artery ligated mouse model |
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