VSMC-specific EP4 deletion exacerbates angiotensin II-induced aortic dissection by increasing vascular inflammation and blood pressure
Prostaglandin E2 (PGE2) plays an important role in vascular homeostasis. Its receptor, E-prostanoid receptor 4 (EP4) is essential for physiological remodeling of the ductus arteriosus (DA). However, the role of EP4 in pathological vascular remodeling remains largely unknown. We found that chronic an...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2019-04, Vol.116 (17), p.8457-8462 |
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| creator | Xu, Hu Du, Shengnan Fang, Bingying Li, Chaojie Jia, Xiao Zheng, Senfeng Wang, Sailun Li, Qingwei Su, Wen Wang, Nanping Zheng, Feng Chen, Lihong Zhang, Xiaoyan Gustafsson, Jan-Åke Guan, Youfei |
| description | Prostaglandin E2 (PGE2) plays an important role in vascular homeostasis. Its receptor, E-prostanoid receptor 4 (EP4) is essential for physiological remodeling of the ductus arteriosus (DA). However, the role of EP4 in pathological vascular remodeling remains largely unknown. We found that chronic angiotensin II (AngII) infusion of mice with vascular smooth muscle cell (VSMC)-specific EP4 gene knockout (VSMC-EP4−/−) frequently developed aortic dissection (AD) with severe elastic fiber degradation and VSMC dedifferentiation. AngII-infused VSMC-EP4−/− mice also displayed more profound vascular inflammation with increased monocyte chemoattractant protein-1 (MCP-1) expression, macrophage infiltration, matrix metalloproteinase-2 and -9 (MMP2/9) levels, NADPH oxidase 1 (NOX1) activity, and reactive oxygen species production. In addition, VSMC-EP4−/− mice exhibited higher blood pressure under basal and AngII-infused conditions. Ex vivo and in vitro studies further revealed that VSMC-specific EP4 gene deficiency significantly increased AngII-elicited vasoconstriction of the mesenteric artery, likely by stimulating intracellular calcium release in VSMCs. Furthermore, EP4 gene ablation and EP4 blockade in cultured VSMCs were associated with a significant increase in MCP-1 and NOX1 expression and a marked reduction in α-SM actin (α-SMA), SM22α, and SM differentiation marker genes myosin heavy chain (SMMHC) levels and serum response factor (SRF) transcriptional activity. To summarize, the present study demonstrates that VSMC EP4 is critical for vascular homeostasis, and its dysfunction exacerbates AngII-induced pathological vascular remodeling. EP4 may therefore represent a potential therapeutic target for the treatment of AD. |
| doi_str_mv | 10.1073/pnas.1902119116 |
| format | Article |
| fullrecord | <record><control><sourceid>jstor_swepu</sourceid><recordid>TN_cdi_swepub_primary_oai_swepub_ki_se_480725</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><jstor_id>26703526</jstor_id><sourcerecordid>26703526</sourcerecordid><originalsourceid>FETCH-LOGICAL-c597t-bfc4791258d0b8a9c20ea326a23e2a27d4b24733f9f6d14541b15c40f3853bcd3</originalsourceid><addsrcrecordid>eNp1kktv1DAUhS0EotPCmhUoEptu0vqVON4goVGBkYpA4rG1HPtm8JDYwU4K_QP8bjyd6ZQisbLl-53je-2D0DOCzwgW7Hz0Op0RiSkhkpD6AVoQLElZc4kfogXGVJQNp_wIHae0wRjLqsGP0RHDkjc1Jwv0--un98syjWBc50xx8ZEXFnqYXPAF_NIGYqsnSIX2axcm8Mn5YrUqnbezAVvoEKcssy4lMDei9rpw3kTQmVwXVzqZudcxn3W9HgZ9w2hvi7YPwRZjhJTmCE_Qo073CZ7u1xP05c3F5-W78vLD29Xy9WVpKimmsu0MF5LQqrG4bbQ0FINmtNaUAdVUWN5SLhjrZFdbwitOWlIZjjvWVKw1lp2gcuebfsI4t2qMbtDxWgXt1P7oe96B4g0WtMq8_C8_xmDvRLdCwrGoiJAsa1_ttBkYwBrwU9T9fYt7Fe--qXW4UnX-G1HjbHC6N4jhxwxpUoNLBvpeewhzUpRiXss85bbPl_-gmzBHn58yUzR31HCxNTzfUSaGlCJ0h2YIVts8qW2e1F2esuLF3zMc-NsAZeD5DtikKcRDndb5uorW7A_vctRn</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2220758470</pqid></control><display><type>article</type><title>VSMC-specific EP4 deletion exacerbates angiotensin II-induced aortic dissection by increasing vascular inflammation and blood pressure</title><source>MEDLINE</source><source>SWEPUB Freely available online</source><source>JSTOR Archive Collection A-Z Listing</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><source>Free Full-Text Journals in Chemistry</source><creator>Xu, Hu ; Du, Shengnan ; Fang, Bingying ; Li, Chaojie ; Jia, Xiao ; Zheng, Senfeng ; Wang, Sailun ; Li, Qingwei ; Su, Wen ; Wang, Nanping ; Zheng, Feng ; Chen, Lihong ; Zhang, Xiaoyan ; Gustafsson, Jan-Åke ; Guan, Youfei</creator><creatorcontrib>Xu, Hu ; Du, Shengnan ; Fang, Bingying ; Li, Chaojie ; Jia, Xiao ; Zheng, Senfeng ; Wang, Sailun ; Li, Qingwei ; Su, Wen ; Wang, Nanping ; Zheng, Feng ; Chen, Lihong ; Zhang, Xiaoyan ; Gustafsson, Jan-Åke ; Guan, Youfei</creatorcontrib><description>Prostaglandin E2 (PGE2) plays an important role in vascular homeostasis. Its receptor, E-prostanoid receptor 4 (EP4) is essential for physiological remodeling of the ductus arteriosus (DA). However, the role of EP4 in pathological vascular remodeling remains largely unknown. We found that chronic angiotensin II (AngII) infusion of mice with vascular smooth muscle cell (VSMC)-specific EP4 gene knockout (VSMC-EP4−/−) frequently developed aortic dissection (AD) with severe elastic fiber degradation and VSMC dedifferentiation. AngII-infused VSMC-EP4−/− mice also displayed more profound vascular inflammation with increased monocyte chemoattractant protein-1 (MCP-1) expression, macrophage infiltration, matrix metalloproteinase-2 and -9 (MMP2/9) levels, NADPH oxidase 1 (NOX1) activity, and reactive oxygen species production. In addition, VSMC-EP4−/− mice exhibited higher blood pressure under basal and AngII-infused conditions. Ex vivo and in vitro studies further revealed that VSMC-specific EP4 gene deficiency significantly increased AngII-elicited vasoconstriction of the mesenteric artery, likely by stimulating intracellular calcium release in VSMCs. Furthermore, EP4 gene ablation and EP4 blockade in cultured VSMCs were associated with a significant increase in MCP-1 and NOX1 expression and a marked reduction in α-SM actin (α-SMA), SM22α, and SM differentiation marker genes myosin heavy chain (SMMHC) levels and serum response factor (SRF) transcriptional activity. To summarize, the present study demonstrates that VSMC EP4 is critical for vascular homeostasis, and its dysfunction exacerbates AngII-induced pathological vascular remodeling. EP4 may therefore represent a potential therapeutic target for the treatment of AD.</description><identifier>ISSN: 0027-8424</identifier><identifier>ISSN: 1091-6490</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1902119116</identifier><identifier>PMID: 30948641</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Ablation ; Actin ; Aneurysm, Dissecting - metabolism ; Angiotensin ; Angiotensin II ; Angiotensin II - metabolism ; Animals ; Aorta ; Aorta - chemistry ; Aorta - metabolism ; Aortic Aneurysm - metabolism ; Aortic dissection ; Biological Sciences ; Blood pressure ; Blood Pressure - physiology ; Calcium (intracellular) ; Clonal deletion ; Dinoprostone - metabolism ; Dissection ; Female ; Gelatinase A ; Homeostasis ; Hypertension - metabolism ; Infiltration ; Inflammation - metabolism ; Macrophages ; Male ; Matrix metalloproteinase ; Matrix metalloproteinases ; Medicin och hälsovetenskap ; Metalloproteinase ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Monocyte chemoattractant protein ; Monocyte chemoattractant protein 1 ; Monocytes ; Muscle, Smooth, Vascular - metabolism ; Muscles ; Myosin ; NAD(P)H oxidase ; Prostaglandin E2 ; Reactive oxygen species ; Receptors, Prostaglandin E, EP4 Subtype - genetics ; Receptors, Prostaglandin E, EP4 Subtype - metabolism ; Rodents ; Serum response factor ; Smooth muscle ; Therapeutic applications ; Vascular Remodeling - genetics ; Vasoconstriction</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2019-04, Vol.116 (17), p.8457-8462</ispartof><rights>Copyright National Academy of Sciences Apr 23, 2019</rights><rights>2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c597t-bfc4791258d0b8a9c20ea326a23e2a27d4b24733f9f6d14541b15c40f3853bcd3</citedby><cites>FETCH-LOGICAL-c597t-bfc4791258d0b8a9c20ea326a23e2a27d4b24733f9f6d14541b15c40f3853bcd3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26703526$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26703526$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,315,553,728,781,785,804,886,27929,27930,53796,53798,58022,58255</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30948641$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:140751793$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Xu, Hu</creatorcontrib><creatorcontrib>Du, Shengnan</creatorcontrib><creatorcontrib>Fang, Bingying</creatorcontrib><creatorcontrib>Li, Chaojie</creatorcontrib><creatorcontrib>Jia, Xiao</creatorcontrib><creatorcontrib>Zheng, Senfeng</creatorcontrib><creatorcontrib>Wang, Sailun</creatorcontrib><creatorcontrib>Li, Qingwei</creatorcontrib><creatorcontrib>Su, Wen</creatorcontrib><creatorcontrib>Wang, Nanping</creatorcontrib><creatorcontrib>Zheng, Feng</creatorcontrib><creatorcontrib>Chen, Lihong</creatorcontrib><creatorcontrib>Zhang, Xiaoyan</creatorcontrib><creatorcontrib>Gustafsson, Jan-Åke</creatorcontrib><creatorcontrib>Guan, Youfei</creatorcontrib><title>VSMC-specific EP4 deletion exacerbates angiotensin II-induced aortic dissection by increasing vascular inflammation and blood pressure</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Prostaglandin E2 (PGE2) plays an important role in vascular homeostasis. Its receptor, E-prostanoid receptor 4 (EP4) is essential for physiological remodeling of the ductus arteriosus (DA). However, the role of EP4 in pathological vascular remodeling remains largely unknown. We found that chronic angiotensin II (AngII) infusion of mice with vascular smooth muscle cell (VSMC)-specific EP4 gene knockout (VSMC-EP4−/−) frequently developed aortic dissection (AD) with severe elastic fiber degradation and VSMC dedifferentiation. AngII-infused VSMC-EP4−/− mice also displayed more profound vascular inflammation with increased monocyte chemoattractant protein-1 (MCP-1) expression, macrophage infiltration, matrix metalloproteinase-2 and -9 (MMP2/9) levels, NADPH oxidase 1 (NOX1) activity, and reactive oxygen species production. In addition, VSMC-EP4−/− mice exhibited higher blood pressure under basal and AngII-infused conditions. Ex vivo and in vitro studies further revealed that VSMC-specific EP4 gene deficiency significantly increased AngII-elicited vasoconstriction of the mesenteric artery, likely by stimulating intracellular calcium release in VSMCs. Furthermore, EP4 gene ablation and EP4 blockade in cultured VSMCs were associated with a significant increase in MCP-1 and NOX1 expression and a marked reduction in α-SM actin (α-SMA), SM22α, and SM differentiation marker genes myosin heavy chain (SMMHC) levels and serum response factor (SRF) transcriptional activity. To summarize, the present study demonstrates that VSMC EP4 is critical for vascular homeostasis, and its dysfunction exacerbates AngII-induced pathological vascular remodeling. EP4 may therefore represent a potential therapeutic target for the treatment of AD.</description><subject>Ablation</subject><subject>Actin</subject><subject>Aneurysm, Dissecting - metabolism</subject><subject>Angiotensin</subject><subject>Angiotensin II</subject><subject>Angiotensin II - metabolism</subject><subject>Animals</subject><subject>Aorta</subject><subject>Aorta - chemistry</subject><subject>Aorta - metabolism</subject><subject>Aortic Aneurysm - metabolism</subject><subject>Aortic dissection</subject><subject>Biological Sciences</subject><subject>Blood pressure</subject><subject>Blood Pressure - physiology</subject><subject>Calcium (intracellular)</subject><subject>Clonal deletion</subject><subject>Dinoprostone - metabolism</subject><subject>Dissection</subject><subject>Female</subject><subject>Gelatinase A</subject><subject>Homeostasis</subject><subject>Hypertension - metabolism</subject><subject>Infiltration</subject><subject>Inflammation - metabolism</subject><subject>Macrophages</subject><subject>Male</subject><subject>Matrix metalloproteinase</subject><subject>Matrix metalloproteinases</subject><subject>Medicin och hälsovetenskap</subject><subject>Metalloproteinase</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Monocyte chemoattractant protein</subject><subject>Monocyte chemoattractant protein 1</subject><subject>Monocytes</subject><subject>Muscle, Smooth, Vascular - metabolism</subject><subject>Muscles</subject><subject>Myosin</subject><subject>NAD(P)H oxidase</subject><subject>Prostaglandin E2</subject><subject>Reactive oxygen species</subject><subject>Receptors, Prostaglandin E, EP4 Subtype - genetics</subject><subject>Receptors, Prostaglandin E, EP4 Subtype - metabolism</subject><subject>Rodents</subject><subject>Serum response factor</subject><subject>Smooth muscle</subject><subject>Therapeutic applications</subject><subject>Vascular Remodeling - genetics</subject><subject>Vasoconstriction</subject><issn>0027-8424</issn><issn>1091-6490</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>D8T</sourceid><recordid>eNp1kktv1DAUhS0EotPCmhUoEptu0vqVON4goVGBkYpA4rG1HPtm8JDYwU4K_QP8bjyd6ZQisbLl-53je-2D0DOCzwgW7Hz0Op0RiSkhkpD6AVoQLElZc4kfogXGVJQNp_wIHae0wRjLqsGP0RHDkjc1Jwv0--un98syjWBc50xx8ZEXFnqYXPAF_NIGYqsnSIX2axcm8Mn5YrUqnbezAVvoEKcssy4lMDei9rpw3kTQmVwXVzqZudcxn3W9HgZ9w2hvi7YPwRZjhJTmCE_Qo073CZ7u1xP05c3F5-W78vLD29Xy9WVpKimmsu0MF5LQqrG4bbQ0FINmtNaUAdVUWN5SLhjrZFdbwitOWlIZjjvWVKw1lp2gcuebfsI4t2qMbtDxWgXt1P7oe96B4g0WtMq8_C8_xmDvRLdCwrGoiJAsa1_ttBkYwBrwU9T9fYt7Fe--qXW4UnX-G1HjbHC6N4jhxwxpUoNLBvpeewhzUpRiXss85bbPl_-gmzBHn58yUzR31HCxNTzfUSaGlCJ0h2YIVts8qW2e1F2esuLF3zMc-NsAZeD5DtikKcRDndb5uorW7A_vctRn</recordid><startdate>20190423</startdate><enddate>20190423</enddate><creator>Xu, Hu</creator><creator>Du, Shengnan</creator><creator>Fang, Bingying</creator><creator>Li, Chaojie</creator><creator>Jia, Xiao</creator><creator>Zheng, Senfeng</creator><creator>Wang, Sailun</creator><creator>Li, Qingwei</creator><creator>Su, Wen</creator><creator>Wang, Nanping</creator><creator>Zheng, Feng</creator><creator>Chen, Lihong</creator><creator>Zhang, Xiaoyan</creator><creator>Gustafsson, Jan-Åke</creator><creator>Guan, Youfei</creator><general>National Academy of Sciences</general><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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>ZZAVC</scope></search><sort><creationdate>20190423</creationdate><title>VSMC-specific EP4 deletion exacerbates angiotensin II-induced aortic dissection by increasing vascular inflammation and blood pressure</title><author>Xu, Hu ; Du, Shengnan ; Fang, Bingying ; Li, Chaojie ; Jia, Xiao ; Zheng, Senfeng ; Wang, Sailun ; Li, Qingwei ; Su, Wen ; Wang, Nanping ; Zheng, Feng ; Chen, Lihong ; Zhang, Xiaoyan ; Gustafsson, Jan-Åke ; Guan, Youfei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c597t-bfc4791258d0b8a9c20ea326a23e2a27d4b24733f9f6d14541b15c40f3853bcd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Ablation</topic><topic>Actin</topic><topic>Aneurysm, Dissecting - metabolism</topic><topic>Angiotensin</topic><topic>Angiotensin II</topic><topic>Angiotensin II - metabolism</topic><topic>Animals</topic><topic>Aorta</topic><topic>Aorta - chemistry</topic><topic>Aorta - metabolism</topic><topic>Aortic Aneurysm - metabolism</topic><topic>Aortic dissection</topic><topic>Biological Sciences</topic><topic>Blood pressure</topic><topic>Blood Pressure - physiology</topic><topic>Calcium (intracellular)</topic><topic>Clonal deletion</topic><topic>Dinoprostone - metabolism</topic><topic>Dissection</topic><topic>Female</topic><topic>Gelatinase A</topic><topic>Homeostasis</topic><topic>Hypertension - metabolism</topic><topic>Infiltration</topic><topic>Inflammation - metabolism</topic><topic>Macrophages</topic><topic>Male</topic><topic>Matrix metalloproteinase</topic><topic>Matrix metalloproteinases</topic><topic>Medicin och hälsovetenskap</topic><topic>Metalloproteinase</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Monocyte chemoattractant protein</topic><topic>Monocyte chemoattractant protein 1</topic><topic>Monocytes</topic><topic>Muscle, Smooth, Vascular - metabolism</topic><topic>Muscles</topic><topic>Myosin</topic><topic>NAD(P)H oxidase</topic><topic>Prostaglandin E2</topic><topic>Reactive oxygen species</topic><topic>Receptors, Prostaglandin E, EP4 Subtype - genetics</topic><topic>Receptors, Prostaglandin E, EP4 Subtype - metabolism</topic><topic>Rodents</topic><topic>Serum response factor</topic><topic>Smooth muscle</topic><topic>Therapeutic applications</topic><topic>Vascular Remodeling - genetics</topic><topic>Vasoconstriction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Xu, Hu</creatorcontrib><creatorcontrib>Du, Shengnan</creatorcontrib><creatorcontrib>Fang, Bingying</creatorcontrib><creatorcontrib>Li, Chaojie</creatorcontrib><creatorcontrib>Jia, Xiao</creatorcontrib><creatorcontrib>Zheng, Senfeng</creatorcontrib><creatorcontrib>Wang, Sailun</creatorcontrib><creatorcontrib>Li, Qingwei</creatorcontrib><creatorcontrib>Su, Wen</creatorcontrib><creatorcontrib>Wang, Nanping</creatorcontrib><creatorcontrib>Zheng, Feng</creatorcontrib><creatorcontrib>Chen, Lihong</creatorcontrib><creatorcontrib>Zhang, Xiaoyan</creatorcontrib><creatorcontrib>Gustafsson, Jan-Åke</creatorcontrib><creatorcontrib>Guan, Youfei</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Xu, Hu</au><au>Du, Shengnan</au><au>Fang, Bingying</au><au>Li, Chaojie</au><au>Jia, Xiao</au><au>Zheng, Senfeng</au><au>Wang, Sailun</au><au>Li, Qingwei</au><au>Su, Wen</au><au>Wang, Nanping</au><au>Zheng, Feng</au><au>Chen, Lihong</au><au>Zhang, Xiaoyan</au><au>Gustafsson, Jan-Åke</au><au>Guan, Youfei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>VSMC-specific EP4 deletion exacerbates angiotensin II-induced aortic dissection by increasing vascular inflammation and blood pressure</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2019-04-23</date><risdate>2019</risdate><volume>116</volume><issue>17</issue><spage>8457</spage><epage>8462</epage><pages>8457-8462</pages><issn>0027-8424</issn><issn>1091-6490</issn><eissn>1091-6490</eissn><abstract>Prostaglandin E2 (PGE2) plays an important role in vascular homeostasis. Its receptor, E-prostanoid receptor 4 (EP4) is essential for physiological remodeling of the ductus arteriosus (DA). However, the role of EP4 in pathological vascular remodeling remains largely unknown. We found that chronic angiotensin II (AngII) infusion of mice with vascular smooth muscle cell (VSMC)-specific EP4 gene knockout (VSMC-EP4−/−) frequently developed aortic dissection (AD) with severe elastic fiber degradation and VSMC dedifferentiation. AngII-infused VSMC-EP4−/− mice also displayed more profound vascular inflammation with increased monocyte chemoattractant protein-1 (MCP-1) expression, macrophage infiltration, matrix metalloproteinase-2 and -9 (MMP2/9) levels, NADPH oxidase 1 (NOX1) activity, and reactive oxygen species production. In addition, VSMC-EP4−/− mice exhibited higher blood pressure under basal and AngII-infused conditions. Ex vivo and in vitro studies further revealed that VSMC-specific EP4 gene deficiency significantly increased AngII-elicited vasoconstriction of the mesenteric artery, likely by stimulating intracellular calcium release in VSMCs. Furthermore, EP4 gene ablation and EP4 blockade in cultured VSMCs were associated with a significant increase in MCP-1 and NOX1 expression and a marked reduction in α-SM actin (α-SMA), SM22α, and SM differentiation marker genes myosin heavy chain (SMMHC) levels and serum response factor (SRF) transcriptional activity. To summarize, the present study demonstrates that VSMC EP4 is critical for vascular homeostasis, and its dysfunction exacerbates AngII-induced pathological vascular remodeling. EP4 may therefore represent a potential therapeutic target for the treatment of AD.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>30948641</pmid><doi>10.1073/pnas.1902119116</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| issn | 0027-8424 1091-6490 1091-6490 |
| language | eng |
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| source | MEDLINE; SWEPUB Freely available online; JSTOR Archive Collection A-Z Listing; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Ablation Actin Aneurysm, Dissecting - metabolism Angiotensin Angiotensin II Angiotensin II - metabolism Animals Aorta Aorta - chemistry Aorta - metabolism Aortic Aneurysm - metabolism Aortic dissection Biological Sciences Blood pressure Blood Pressure - physiology Calcium (intracellular) Clonal deletion Dinoprostone - metabolism Dissection Female Gelatinase A Homeostasis Hypertension - metabolism Infiltration Inflammation - metabolism Macrophages Male Matrix metalloproteinase Matrix metalloproteinases Medicin och hälsovetenskap Metalloproteinase Mice Mice, Inbred C57BL Mice, Knockout Monocyte chemoattractant protein Monocyte chemoattractant protein 1 Monocytes Muscle, Smooth, Vascular - metabolism Muscles Myosin NAD(P)H oxidase Prostaglandin E2 Reactive oxygen species Receptors, Prostaglandin E, EP4 Subtype - genetics Receptors, Prostaglandin E, EP4 Subtype - metabolism Rodents Serum response factor Smooth muscle Therapeutic applications Vascular Remodeling - genetics Vasoconstriction |
| title | VSMC-specific EP4 deletion exacerbates angiotensin II-induced aortic dissection by increasing vascular inflammation and blood pressure |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-13T10%3A08%3A42IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-jstor_swepu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=VSMC-specific%20EP4%20deletion%20exacerbates%20angiotensin%20II-induced%20aortic%20dissection%20by%20increasing%20vascular%20inflammation%20and%20blood%20pressure&rft.jtitle=Proceedings%20of%20the%20National%20Academy%20of%20Sciences%20-%20PNAS&rft.au=Xu,%20Hu&rft.date=2019-04-23&rft.volume=116&rft.issue=17&rft.spage=8457&rft.epage=8462&rft.pages=8457-8462&rft.issn=0027-8424&rft.eissn=1091-6490&rft_id=info:doi/10.1073/pnas.1902119116&rft_dat=%3Cjstor_swepu%3E26703526%3C/jstor_swepu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2220758470&rft_id=info:pmid/30948641&rft_jstor_id=26703526&rfr_iscdi=true |