Preexisting endothelial cells mediate cardiac neovascularization after injury
The mechanisms that promote the generation of new coronary vasculature during cardiac homeostasis and after injury remain a fundamental and clinically important area of study in the cardiovascular field. Recently, it was reported that mesenchymal-to-endothelial transition (MEndoT) contributes to sub...
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| Veröffentlicht in: | The Journal of clinical investigation 2017-08, Vol.127 (8), p.2968-2981 |
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| creator | He, Lingjuan Huang, Xiuzhen Kanisicak, Onur Li, Yi Wang, Yue Li, Yan Pu, Wenjuan Liu, Qiaozhen Zhang, Hui Tian, Xueying Zhao, Huan Liu, Xiuxiu Zhang, Shaohua Nie, Yu Hu, Shengshou Miao, Xiang Wang, Qing-Dong Wang, Fengchao Chen, Ting Xu, Qingbo Lui, Kathy O Molkentin, Jeffery D Zhou, Bin |
| description | The mechanisms that promote the generation of new coronary vasculature during cardiac homeostasis and after injury remain a fundamental and clinically important area of study in the cardiovascular field. Recently, it was reported that mesenchymal-to-endothelial transition (MEndoT) contributes to substantial numbers of coronary endothelial cells after myocardial infarction. Therefore, the MEndoT has been proposed as a paradigm mediating neovascularization and is considered a promising therapeutic target in cardiac regeneration. Here, we show that preexisting endothelial cells mainly beget new coronary vessels in the adult mouse heart, with essentially no contribution from other cell sources through cell-lineage transdifferentiation. Genetic-lineage tracing revealed that cardiac fibroblasts expand substantially after injury, but do not contribute to the formation of new coronary blood vessels, indicating no contribution of MEndoT to neovascularization. Moreover, genetic-lineage tracing with a pulse-chase labeling strategy also showed that essentially all new coronary vessels in the injured heart are derived from preexisting endothelial cells, but not from other cell lineages. These data indicate that therapeutic strategies for inducing neovascularization should not be based on targeting presumptive lineage transdifferentiation such as MEndoT. Instead, preexisting endothelial cells appear more likely to be the therapeutic target for promoting neovascularization and driving heart regeneration after injury. |
| doi_str_mv | 10.1172/JCI93868 |
| format | Article |
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Recently, it was reported that mesenchymal-to-endothelial transition (MEndoT) contributes to substantial numbers of coronary endothelial cells after myocardial infarction. Therefore, the MEndoT has been proposed as a paradigm mediating neovascularization and is considered a promising therapeutic target in cardiac regeneration. Here, we show that preexisting endothelial cells mainly beget new coronary vessels in the adult mouse heart, with essentially no contribution from other cell sources through cell-lineage transdifferentiation. Genetic-lineage tracing revealed that cardiac fibroblasts expand substantially after injury, but do not contribute to the formation of new coronary blood vessels, indicating no contribution of MEndoT to neovascularization. Moreover, genetic-lineage tracing with a pulse-chase labeling strategy also showed that essentially all new coronary vessels in the injured heart are derived from preexisting endothelial cells, but not from other cell lineages. These data indicate that therapeutic strategies for inducing neovascularization should not be based on targeting presumptive lineage transdifferentiation such as MEndoT. Instead, preexisting endothelial cells appear more likely to be the therapeutic target for promoting neovascularization and driving heart regeneration after injury.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI93868</identifier><identifier>PMID: 28650345</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Angiogenesis ; Animals ; Biomedical research ; Blood vessels ; Cardiomyocytes ; Cardiovascular disease ; Cell Lineage ; Coronary Circulation ; Coronary vessels ; Coronary Vessels - cytology ; Endothelial cells ; Endothelial Cells - cytology ; Endothelium ; Endothelium - metabolism ; Fatty acids ; Female ; Fibroblasts ; Health aspects ; Heart ; Heart - physiology ; Heart attacks ; Heart failure ; Heart Injuries - metabolism ; Homeostasis ; Male ; Mesenchyme ; Mesoderm - metabolism ; Mice ; Myocardial infarction ; Myocardial Infarction - metabolism ; Neovascularization ; Neovascularization, Pathologic ; Nitric oxide ; Proteins ; Recombination, Genetic ; Regeneration ; Rodents ; Studies ; Transgenes ; Vascularization</subject><ispartof>The Journal of clinical investigation, 2017-08, Vol.127 (8), p.2968-2981</ispartof><rights>COPYRIGHT 2017 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Aug 2017</rights><rights>Copyright © 2017, American Society for Clinical Investigation 2017 American Society for Clinical Investigation</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c709t-2a7e9c54fa3f865b0e91940cfa7d7e4032cb8ca81c26be21c2989e03086b26313</citedby><cites>FETCH-LOGICAL-c709t-2a7e9c54fa3f865b0e91940cfa7d7e4032cb8ca81c26be21c2989e03086b26313</cites><orcidid>0000-0002-8393-4874 ; 0000-0001-9570-4411</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/PMC5531398/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531398/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,724,777,781,882,27905,27906,53772,53774</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28650345$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>He, Lingjuan</creatorcontrib><creatorcontrib>Huang, Xiuzhen</creatorcontrib><creatorcontrib>Kanisicak, Onur</creatorcontrib><creatorcontrib>Li, Yi</creatorcontrib><creatorcontrib>Wang, Yue</creatorcontrib><creatorcontrib>Li, Yan</creatorcontrib><creatorcontrib>Pu, Wenjuan</creatorcontrib><creatorcontrib>Liu, Qiaozhen</creatorcontrib><creatorcontrib>Zhang, Hui</creatorcontrib><creatorcontrib>Tian, Xueying</creatorcontrib><creatorcontrib>Zhao, Huan</creatorcontrib><creatorcontrib>Liu, Xiuxiu</creatorcontrib><creatorcontrib>Zhang, Shaohua</creatorcontrib><creatorcontrib>Nie, Yu</creatorcontrib><creatorcontrib>Hu, Shengshou</creatorcontrib><creatorcontrib>Miao, Xiang</creatorcontrib><creatorcontrib>Wang, Qing-Dong</creatorcontrib><creatorcontrib>Wang, Fengchao</creatorcontrib><creatorcontrib>Chen, Ting</creatorcontrib><creatorcontrib>Xu, Qingbo</creatorcontrib><creatorcontrib>Lui, Kathy O</creatorcontrib><creatorcontrib>Molkentin, Jeffery D</creatorcontrib><creatorcontrib>Zhou, Bin</creatorcontrib><title>Preexisting endothelial cells mediate cardiac neovascularization after injury</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>The mechanisms that promote the generation of new coronary vasculature during cardiac homeostasis and after injury remain a fundamental and clinically important area of study in the cardiovascular field. Recently, it was reported that mesenchymal-to-endothelial transition (MEndoT) contributes to substantial numbers of coronary endothelial cells after myocardial infarction. Therefore, the MEndoT has been proposed as a paradigm mediating neovascularization and is considered a promising therapeutic target in cardiac regeneration. Here, we show that preexisting endothelial cells mainly beget new coronary vessels in the adult mouse heart, with essentially no contribution from other cell sources through cell-lineage transdifferentiation. Genetic-lineage tracing revealed that cardiac fibroblasts expand substantially after injury, but do not contribute to the formation of new coronary blood vessels, indicating no contribution of MEndoT to neovascularization. Moreover, genetic-lineage tracing with a pulse-chase labeling strategy also showed that essentially all new coronary vessels in the injured heart are derived from preexisting endothelial cells, but not from other cell lineages. These data indicate that therapeutic strategies for inducing neovascularization should not be based on targeting presumptive lineage transdifferentiation such as MEndoT. Instead, preexisting endothelial cells appear more likely to be the therapeutic target for promoting neovascularization and driving heart regeneration after injury.</description><subject>Angiogenesis</subject><subject>Animals</subject><subject>Biomedical research</subject><subject>Blood vessels</subject><subject>Cardiomyocytes</subject><subject>Cardiovascular disease</subject><subject>Cell Lineage</subject><subject>Coronary Circulation</subject><subject>Coronary vessels</subject><subject>Coronary Vessels - cytology</subject><subject>Endothelial cells</subject><subject>Endothelial Cells - cytology</subject><subject>Endothelium</subject><subject>Endothelium - metabolism</subject><subject>Fatty acids</subject><subject>Female</subject><subject>Fibroblasts</subject><subject>Health aspects</subject><subject>Heart</subject><subject>Heart - physiology</subject><subject>Heart attacks</subject><subject>Heart failure</subject><subject>Heart Injuries - metabolism</subject><subject>Homeostasis</subject><subject>Male</subject><subject>Mesenchyme</subject><subject>Mesoderm - metabolism</subject><subject>Mice</subject><subject>Myocardial infarction</subject><subject>Myocardial Infarction - metabolism</subject><subject>Neovascularization</subject><subject>Neovascularization, Pathologic</subject><subject>Nitric oxide</subject><subject>Proteins</subject><subject>Recombination, Genetic</subject><subject>Regeneration</subject><subject>Rodents</subject><subject>Studies</subject><subject>Transgenes</subject><subject>Vascularization</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqNkl1rFDEUhoModl0Ff4EMCKIXU_MxH8mNUBarK5WKX7chkz2zmyWb1CRT2v56M7itHdkLycUJyXPevOfkIPSc4GNCWvr202IpGG_4AzQjdc1LThl_iGYYU1KKlvEj9CTGLcakqurqMTqivKkxq-oZ-vwlAFyZmIxbF-BWPm3AGmULDdbGYgcroxIUWoW80YUDf6miHqwK5kYl412h-gShMG47hOun6FGvbIRn-zhHP07ff198LM_OPywXJ2elbrFIJVUtCF1XvWJ9dtJhEERUWPeqXbVQYUZ1x7XiRNOmA5qD4AIww7zpaMMIm6N3f3Qvhi5b1OBSUFZeBLNT4Vp6ZeT0xpmNXPtLWdc5W_As8HovEPyvAWKSOxPHklWucIiSCMI4o7gd0Zf_oFs_BJfLyxQV2SzFzV9qrSxI43qf39WjqDypMeEMi9zxOSoPUGtwkE16B73JxxP--ACf1wp2Rh9MeDNJyEyCq7RWQ4xy-e3r_7PnP6fsq3vsBpRNm-jtME5AnIL7xurgYwzQ330KwXKcVXk7qxl9cf8T78Db4WS_Ab2739w</recordid><startdate>20170801</startdate><enddate>20170801</enddate><creator>He, Lingjuan</creator><creator>Huang, Xiuzhen</creator><creator>Kanisicak, Onur</creator><creator>Li, Yi</creator><creator>Wang, Yue</creator><creator>Li, Yan</creator><creator>Pu, Wenjuan</creator><creator>Liu, Qiaozhen</creator><creator>Zhang, Hui</creator><creator>Tian, Xueying</creator><creator>Zhao, Huan</creator><creator>Liu, Xiuxiu</creator><creator>Zhang, Shaohua</creator><creator>Nie, Yu</creator><creator>Hu, Shengshou</creator><creator>Miao, Xiang</creator><creator>Wang, Qing-Dong</creator><creator>Wang, Fengchao</creator><creator>Chen, Ting</creator><creator>Xu, Qingbo</creator><creator>Lui, Kathy O</creator><creator>Molkentin, Jeffery D</creator><creator>Zhou, Bin</creator><general>American Society for Clinical Investigation</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</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>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>S0X</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8393-4874</orcidid><orcidid>https://orcid.org/0000-0001-9570-4411</orcidid></search><sort><creationdate>20170801</creationdate><title>Preexisting endothelial cells mediate cardiac neovascularization after injury</title><author>He, Lingjuan ; Huang, Xiuzhen ; Kanisicak, Onur ; Li, Yi ; Wang, Yue ; Li, Yan ; Pu, Wenjuan ; Liu, Qiaozhen ; Zhang, Hui ; Tian, Xueying ; Zhao, Huan ; Liu, Xiuxiu ; Zhang, Shaohua ; Nie, Yu ; Hu, Shengshou ; Miao, Xiang ; Wang, Qing-Dong ; Wang, Fengchao ; Chen, Ting ; Xu, Qingbo ; Lui, Kathy O ; Molkentin, Jeffery D ; Zhou, Bin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c709t-2a7e9c54fa3f865b0e91940cfa7d7e4032cb8ca81c26be21c2989e03086b26313</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Angiogenesis</topic><topic>Animals</topic><topic>Biomedical research</topic><topic>Blood vessels</topic><topic>Cardiomyocytes</topic><topic>Cardiovascular disease</topic><topic>Cell Lineage</topic><topic>Coronary Circulation</topic><topic>Coronary vessels</topic><topic>Coronary Vessels - cytology</topic><topic>Endothelial cells</topic><topic>Endothelial Cells - cytology</topic><topic>Endothelium</topic><topic>Endothelium - metabolism</topic><topic>Fatty acids</topic><topic>Female</topic><topic>Fibroblasts</topic><topic>Health aspects</topic><topic>Heart</topic><topic>Heart - physiology</topic><topic>Heart attacks</topic><topic>Heart failure</topic><topic>Heart Injuries - metabolism</topic><topic>Homeostasis</topic><topic>Male</topic><topic>Mesenchyme</topic><topic>Mesoderm - metabolism</topic><topic>Mice</topic><topic>Myocardial infarction</topic><topic>Myocardial Infarction - metabolism</topic><topic>Neovascularization</topic><topic>Neovascularization, Pathologic</topic><topic>Nitric oxide</topic><topic>Proteins</topic><topic>Recombination, Genetic</topic><topic>Regeneration</topic><topic>Rodents</topic><topic>Studies</topic><topic>Transgenes</topic><topic>Vascularization</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>He, Lingjuan</creatorcontrib><creatorcontrib>Huang, Xiuzhen</creatorcontrib><creatorcontrib>Kanisicak, Onur</creatorcontrib><creatorcontrib>Li, Yi</creatorcontrib><creatorcontrib>Wang, Yue</creatorcontrib><creatorcontrib>Li, Yan</creatorcontrib><creatorcontrib>Pu, Wenjuan</creatorcontrib><creatorcontrib>Liu, Qiaozhen</creatorcontrib><creatorcontrib>Zhang, Hui</creatorcontrib><creatorcontrib>Tian, Xueying</creatorcontrib><creatorcontrib>Zhao, Huan</creatorcontrib><creatorcontrib>Liu, Xiuxiu</creatorcontrib><creatorcontrib>Zhang, Shaohua</creatorcontrib><creatorcontrib>Nie, Yu</creatorcontrib><creatorcontrib>Hu, Shengshou</creatorcontrib><creatorcontrib>Miao, Xiang</creatorcontrib><creatorcontrib>Wang, Qing-Dong</creatorcontrib><creatorcontrib>Wang, Fengchao</creatorcontrib><creatorcontrib>Chen, Ting</creatorcontrib><creatorcontrib>Xu, Qingbo</creatorcontrib><creatorcontrib>Lui, Kathy O</creatorcontrib><creatorcontrib>Molkentin, Jeffery D</creatorcontrib><creatorcontrib>Zhou, Bin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</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>eLibrary</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</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>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</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 China</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>He, Lingjuan</au><au>Huang, Xiuzhen</au><au>Kanisicak, Onur</au><au>Li, Yi</au><au>Wang, Yue</au><au>Li, Yan</au><au>Pu, Wenjuan</au><au>Liu, Qiaozhen</au><au>Zhang, Hui</au><au>Tian, Xueying</au><au>Zhao, Huan</au><au>Liu, Xiuxiu</au><au>Zhang, Shaohua</au><au>Nie, Yu</au><au>Hu, Shengshou</au><au>Miao, Xiang</au><au>Wang, Qing-Dong</au><au>Wang, Fengchao</au><au>Chen, Ting</au><au>Xu, Qingbo</au><au>Lui, Kathy O</au><au>Molkentin, Jeffery D</au><au>Zhou, Bin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Preexisting endothelial cells mediate cardiac neovascularization after injury</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2017-08-01</date><risdate>2017</risdate><volume>127</volume><issue>8</issue><spage>2968</spage><epage>2981</epage><pages>2968-2981</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>The mechanisms that promote the generation of new coronary vasculature during cardiac homeostasis and after injury remain a fundamental and clinically important area of study in the cardiovascular field. Recently, it was reported that mesenchymal-to-endothelial transition (MEndoT) contributes to substantial numbers of coronary endothelial cells after myocardial infarction. Therefore, the MEndoT has been proposed as a paradigm mediating neovascularization and is considered a promising therapeutic target in cardiac regeneration. Here, we show that preexisting endothelial cells mainly beget new coronary vessels in the adult mouse heart, with essentially no contribution from other cell sources through cell-lineage transdifferentiation. Genetic-lineage tracing revealed that cardiac fibroblasts expand substantially after injury, but do not contribute to the formation of new coronary blood vessels, indicating no contribution of MEndoT to neovascularization. Moreover, genetic-lineage tracing with a pulse-chase labeling strategy also showed that essentially all new coronary vessels in the injured heart are derived from preexisting endothelial cells, but not from other cell lineages. These data indicate that therapeutic strategies for inducing neovascularization should not be based on targeting presumptive lineage transdifferentiation such as MEndoT. Instead, preexisting endothelial cells appear more likely to be the therapeutic target for promoting neovascularization and driving heart regeneration after injury.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>28650345</pmid><doi>10.1172/JCI93868</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-8393-4874</orcidid><orcidid>https://orcid.org/0000-0001-9570-4411</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Journals@Ovid Ovid Autoload; PubMed Central; Alma/SFX Local Collection |
| subjects | Angiogenesis Animals Biomedical research Blood vessels Cardiomyocytes Cardiovascular disease Cell Lineage Coronary Circulation Coronary vessels Coronary Vessels - cytology Endothelial cells Endothelial Cells - cytology Endothelium Endothelium - metabolism Fatty acids Female Fibroblasts Health aspects Heart Heart - physiology Heart attacks Heart failure Heart Injuries - metabolism Homeostasis Male Mesenchyme Mesoderm - metabolism Mice Myocardial infarction Myocardial Infarction - metabolism Neovascularization Neovascularization, Pathologic Nitric oxide Proteins Recombination, Genetic Regeneration Rodents Studies Transgenes Vascularization |
| title | Preexisting endothelial cells mediate cardiac neovascularization after injury |
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