Annexin A2 is a Robo4 ligand that modulates ARF6 activation-associated cerebral trans-endothelial permeability
Blood–brain barrier (BBB) disruption in neurological disorders remains an intractable problem with limited therapeutic options. Here, we investigate whether the endothelial cell membrane protein annexin A2 (ANXA2) may play a role in reducing trans-endothelial permeability and maintaining cerebrovasc...
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| Veröffentlicht in: | Journal of cerebral blood flow and metabolism 2019-10, Vol.39 (10), p.2048-2060 |
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| container_title | Journal of cerebral blood flow and metabolism |
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| creator | Li, Wenlu Chen, Zhigang Yuan, Jing Yu, Zhanyang Cheng, Chongjie Zhao, Qiuchen Huang, Lena Hajjar, Katherine A Chen, Zhong Lo, Eng H Dai, Haibin Wang, Xiaoying |
| description | Blood–brain barrier (BBB) disruption in neurological disorders remains an intractable problem with limited therapeutic options. Here, we investigate whether the endothelial cell membrane protein annexin A2 (ANXA2) may play a role in reducing trans-endothelial permeability and maintaining cerebrovascular integrity after injury. Compared with wild-type mice, the expression of cerebral endothelial junctional proteins was reduced in E15.5 and adult ANXA2 knockout mice, along with increased leakage of small molecule tracers. In human brain endothelial cells that were damaged by hypoxia plus IL-1β, treatment with recombinant ANXA2 (rA2) rescued the expression of junctional proteins and decreased trans-endothelial permeability. These protective effects were mediated in part by interactions with F-actin and VE-cadherin, and the ability of rA2 to modulate signaling via the roundabout guidance receptor 4 (Robo4)-paxillin-ADP-ribosylation factor 6 (ARF6) pathway. Taken together, these observations suggest that ANXA2 may be associated with the maintenance of endothelial tightness after cerebrovascular injury. ANXA2-mediated pathways should be further explored as potential therapeutic targets for protecting the BBB in neurological disorders. |
| doi_str_mv | 10.1177/0271678X18777916 |
| format | Article |
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Here, we investigate whether the endothelial cell membrane protein annexin A2 (ANXA2) may play a role in reducing trans-endothelial permeability and maintaining cerebrovascular integrity after injury. Compared with wild-type mice, the expression of cerebral endothelial junctional proteins was reduced in E15.5 and adult ANXA2 knockout mice, along with increased leakage of small molecule tracers. In human brain endothelial cells that were damaged by hypoxia plus IL-1β, treatment with recombinant ANXA2 (rA2) rescued the expression of junctional proteins and decreased trans-endothelial permeability. These protective effects were mediated in part by interactions with F-actin and VE-cadherin, and the ability of rA2 to modulate signaling via the roundabout guidance receptor 4 (Robo4)-paxillin-ADP-ribosylation factor 6 (ARF6) pathway. Taken together, these observations suggest that ANXA2 may be associated with the maintenance of endothelial tightness after cerebrovascular injury. ANXA2-mediated pathways should be further explored as potential therapeutic targets for protecting the BBB in neurological disorders.</description><identifier>ISSN: 0271-678X</identifier><identifier>EISSN: 1559-7016</identifier><identifier>DOI: 10.1177/0271678X18777916</identifier><identifier>PMID: 29786451</identifier><language>eng</language><publisher>London, England: SAGE Publications</publisher><subject>ADP-Ribosylation Factors - metabolism ; Animals ; Annexin A2 - genetics ; Annexin A2 - metabolism ; Blood-Brain Barrier - metabolism ; Blood-Brain Barrier - pathology ; Capillary Permeability ; Cell Hypoxia ; Cell Line ; Endothelial Cells - metabolism ; Endothelial Cells - pathology ; Humans ; Mice ; Mice, Knockout ; Original ; Receptors, Cell Surface - metabolism</subject><ispartof>Journal of cerebral blood flow and metabolism, 2019-10, Vol.39 (10), p.2048-2060</ispartof><rights>The Author(s) 2018</rights><rights>The Author(s) 2018 2018 International Society for Cerebral Blood Flow and Metabolism</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c481t-dc0e7064d7046e3ca76fb6d7bfd35e9a7b7b7a832b57e5fcf2728f0f07b4aaa23</citedby><cites>FETCH-LOGICAL-c481t-dc0e7064d7046e3ca76fb6d7bfd35e9a7b7b7a832b57e5fcf2728f0f07b4aaa23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775579/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775579/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,725,778,782,883,21806,27911,27912,43608,43609,53778,53780</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29786451$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Wenlu</creatorcontrib><creatorcontrib>Chen, Zhigang</creatorcontrib><creatorcontrib>Yuan, Jing</creatorcontrib><creatorcontrib>Yu, Zhanyang</creatorcontrib><creatorcontrib>Cheng, Chongjie</creatorcontrib><creatorcontrib>Zhao, Qiuchen</creatorcontrib><creatorcontrib>Huang, Lena</creatorcontrib><creatorcontrib>Hajjar, Katherine A</creatorcontrib><creatorcontrib>Chen, Zhong</creatorcontrib><creatorcontrib>Lo, Eng H</creatorcontrib><creatorcontrib>Dai, Haibin</creatorcontrib><creatorcontrib>Wang, Xiaoying</creatorcontrib><title>Annexin A2 is a Robo4 ligand that modulates ARF6 activation-associated cerebral trans-endothelial permeability</title><title>Journal of cerebral blood flow and metabolism</title><addtitle>J Cereb Blood Flow Metab</addtitle><description>Blood–brain barrier (BBB) disruption in neurological disorders remains an intractable problem with limited therapeutic options. Here, we investigate whether the endothelial cell membrane protein annexin A2 (ANXA2) may play a role in reducing trans-endothelial permeability and maintaining cerebrovascular integrity after injury. Compared with wild-type mice, the expression of cerebral endothelial junctional proteins was reduced in E15.5 and adult ANXA2 knockout mice, along with increased leakage of small molecule tracers. In human brain endothelial cells that were damaged by hypoxia plus IL-1β, treatment with recombinant ANXA2 (rA2) rescued the expression of junctional proteins and decreased trans-endothelial permeability. These protective effects were mediated in part by interactions with F-actin and VE-cadherin, and the ability of rA2 to modulate signaling via the roundabout guidance receptor 4 (Robo4)-paxillin-ADP-ribosylation factor 6 (ARF6) pathway. Taken together, these observations suggest that ANXA2 may be associated with the maintenance of endothelial tightness after cerebrovascular injury. ANXA2-mediated pathways should be further explored as potential therapeutic targets for protecting the BBB in neurological disorders.</description><subject>ADP-Ribosylation Factors - metabolism</subject><subject>Animals</subject><subject>Annexin A2 - genetics</subject><subject>Annexin A2 - metabolism</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>Blood-Brain Barrier - pathology</subject><subject>Capillary Permeability</subject><subject>Cell Hypoxia</subject><subject>Cell Line</subject><subject>Endothelial Cells - metabolism</subject><subject>Endothelial Cells - pathology</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Original</subject><subject>Receptors, Cell Surface - metabolism</subject><issn>0271-678X</issn><issn>1559-7016</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1UcGKFDEQDaK44-rdk-TopTXp7qS6L8KwuCosCIuCt1BJV89k6U7GJL3s_r09zLqoIHUoqPfq1aMeY6-leCclwHtRg9TQ_ZAdAPRSP2EbqVRfgZD6Kdsc4eqIn7EXOd8IIbpGqefsrO6h062SGxa2IdCdD3xbc5858utoY8snv8Mw8LLHwuc4LBMWynx7fak5uuJvsfgYKsw5Or9CA3eUyCaceEkYckVhiGVPk18nB0ozofWTL_cv2bMRp0yvHvo5-3758dvF5-rq66cvF9uryrWdLNXgBIHQ7QCi1dQ4BD1aPYAdh0ZRj2DXwq6prQJSoxtrqLtRjAJsi4h1c84-nHQPi51pcBRWX5M5JD9jujcRvfkbCX5vdvHWaACloF8F3j4IpPhzoVzM7LOjacJAccmmFm0NSnS6W6niRHUp5pxofDwjhTnGZP6NaV1586e9x4XfuayE6kTIuCNzE5cU1nf9X_AXV0ydsw</recordid><startdate>20191001</startdate><enddate>20191001</enddate><creator>Li, Wenlu</creator><creator>Chen, Zhigang</creator><creator>Yuan, Jing</creator><creator>Yu, Zhanyang</creator><creator>Cheng, Chongjie</creator><creator>Zhao, Qiuchen</creator><creator>Huang, Lena</creator><creator>Hajjar, Katherine A</creator><creator>Chen, Zhong</creator><creator>Lo, Eng H</creator><creator>Dai, Haibin</creator><creator>Wang, Xiaoying</creator><general>SAGE Publications</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20191001</creationdate><title>Annexin A2 is a Robo4 ligand that modulates ARF6 activation-associated cerebral trans-endothelial permeability</title><author>Li, Wenlu ; Chen, Zhigang ; Yuan, Jing ; Yu, Zhanyang ; Cheng, Chongjie ; Zhao, Qiuchen ; Huang, Lena ; Hajjar, Katherine A ; Chen, Zhong ; Lo, Eng H ; Dai, Haibin ; Wang, Xiaoying</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c481t-dc0e7064d7046e3ca76fb6d7bfd35e9a7b7b7a832b57e5fcf2728f0f07b4aaa23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>ADP-Ribosylation Factors - metabolism</topic><topic>Animals</topic><topic>Annexin A2 - genetics</topic><topic>Annexin A2 - metabolism</topic><topic>Blood-Brain Barrier - metabolism</topic><topic>Blood-Brain Barrier - pathology</topic><topic>Capillary Permeability</topic><topic>Cell Hypoxia</topic><topic>Cell Line</topic><topic>Endothelial Cells - metabolism</topic><topic>Endothelial Cells - pathology</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Original</topic><topic>Receptors, Cell Surface - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Wenlu</creatorcontrib><creatorcontrib>Chen, Zhigang</creatorcontrib><creatorcontrib>Yuan, Jing</creatorcontrib><creatorcontrib>Yu, Zhanyang</creatorcontrib><creatorcontrib>Cheng, Chongjie</creatorcontrib><creatorcontrib>Zhao, Qiuchen</creatorcontrib><creatorcontrib>Huang, Lena</creatorcontrib><creatorcontrib>Hajjar, Katherine A</creatorcontrib><creatorcontrib>Chen, Zhong</creatorcontrib><creatorcontrib>Lo, Eng H</creatorcontrib><creatorcontrib>Dai, Haibin</creatorcontrib><creatorcontrib>Wang, Xiaoying</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of cerebral blood flow and metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Wenlu</au><au>Chen, Zhigang</au><au>Yuan, Jing</au><au>Yu, Zhanyang</au><au>Cheng, Chongjie</au><au>Zhao, Qiuchen</au><au>Huang, Lena</au><au>Hajjar, Katherine A</au><au>Chen, Zhong</au><au>Lo, Eng H</au><au>Dai, Haibin</au><au>Wang, Xiaoying</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Annexin A2 is a Robo4 ligand that modulates ARF6 activation-associated cerebral trans-endothelial permeability</atitle><jtitle>Journal of cerebral blood flow and metabolism</jtitle><addtitle>J Cereb Blood Flow Metab</addtitle><date>2019-10-01</date><risdate>2019</risdate><volume>39</volume><issue>10</issue><spage>2048</spage><epage>2060</epage><pages>2048-2060</pages><issn>0271-678X</issn><eissn>1559-7016</eissn><abstract>Blood–brain barrier (BBB) disruption in neurological disorders remains an intractable problem with limited therapeutic options. Here, we investigate whether the endothelial cell membrane protein annexin A2 (ANXA2) may play a role in reducing trans-endothelial permeability and maintaining cerebrovascular integrity after injury. Compared with wild-type mice, the expression of cerebral endothelial junctional proteins was reduced in E15.5 and adult ANXA2 knockout mice, along with increased leakage of small molecule tracers. In human brain endothelial cells that were damaged by hypoxia plus IL-1β, treatment with recombinant ANXA2 (rA2) rescued the expression of junctional proteins and decreased trans-endothelial permeability. These protective effects were mediated in part by interactions with F-actin and VE-cadherin, and the ability of rA2 to modulate signaling via the roundabout guidance receptor 4 (Robo4)-paxillin-ADP-ribosylation factor 6 (ARF6) pathway. Taken together, these observations suggest that ANXA2 may be associated with the maintenance of endothelial tightness after cerebrovascular injury. ANXA2-mediated pathways should be further explored as potential therapeutic targets for protecting the BBB in neurological disorders.</abstract><cop>London, England</cop><pub>SAGE Publications</pub><pmid>29786451</pmid><doi>10.1177/0271678X18777916</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; SAGE Complete A-Z List; PubMed Central |
| subjects | ADP-Ribosylation Factors - metabolism Animals Annexin A2 - genetics Annexin A2 - metabolism Blood-Brain Barrier - metabolism Blood-Brain Barrier - pathology Capillary Permeability Cell Hypoxia Cell Line Endothelial Cells - metabolism Endothelial Cells - pathology Humans Mice Mice, Knockout Original Receptors, Cell Surface - metabolism |
| title | Annexin A2 is a Robo4 ligand that modulates ARF6 activation-associated cerebral trans-endothelial permeability |
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