Development of a recombinant Ang1 variant with enhanced Tie2 binding and its application to attenuate sepsis in mice
The angiopoietin (Ang)-Tie axis, critical for endothelial cell function and vascular development, is a promising therapeutic target for treating vascular disorders and inflammatory conditions like sepsis. This study aimed to enhance the binding affinity of recombinant Ang1 variants to the Tie2 and e...
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| Veröffentlicht in: | Science advances 2025-01, Vol.11 (3), p.eads1796 |
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| creator | Wang, Rui Li, Hao Xie, Zhinuo Huang, Meijuan Xu, Peng Yuan, Cai Li, Jinyu Flaumenhaft, Robert Huang, Mingdong Jiang, Longguang |
| description | The angiopoietin (Ang)-Tie axis, critical for endothelial cell function and vascular development, is a promising therapeutic target for treating vascular disorders and inflammatory conditions like sepsis. This study aimed to enhance the binding affinity of recombinant Ang1 variants to the Tie2 and explore their therapeutic potential. Structural insights from the Ang1-Tie2 complex enabled the identification of key residues within the Ang1 receptor binding domain (RBD) critical for Tie2 interaction. Molecular dynamics simulations revealed that Met
Arg (M436R) and Ala
Asp (A451D) could improve Ang1's Tie2 binding affinity. One variant, Ang1-RBD
, demonstrated a 100-fold increase compared to the wild type. Cellular assays revealed that Ang1
enhanced Tie2 phosphorylation, promoting endothelial cell migration and tube formation. In vivo, this variant effectively reduced inflammatory cytokines and attenuated organ damage in septic mice. These findings highlight Ang1
as a promising therapeutic candidate for vascular diseases, offering notable clinical potential for mitigating sepsis-related vascular dysfunction. |
| doi_str_mv | 10.1126/sciadv.ads1796 |
| format | Article |
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Arg (M436R) and Ala
Asp (A451D) could improve Ang1's Tie2 binding affinity. One variant, Ang1-RBD
, demonstrated a 100-fold increase compared to the wild type. Cellular assays revealed that Ang1
enhanced Tie2 phosphorylation, promoting endothelial cell migration and tube formation. In vivo, this variant effectively reduced inflammatory cytokines and attenuated organ damage in septic mice. These findings highlight Ang1
as a promising therapeutic candidate for vascular diseases, offering notable clinical potential for mitigating sepsis-related vascular dysfunction.</description><identifier>ISSN: 2375-2548</identifier><identifier>EISSN: 2375-2548</identifier><identifier>DOI: 10.1126/sciadv.ads1796</identifier><identifier>PMID: 39813336</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Angiopoietin-1 - genetics ; Angiopoietin-1 - metabolism ; Animals ; Biomedicine and Life Sciences ; Cell Movement ; Disease Models, Animal ; Human Umbilical Vein Endothelial Cells ; Humans ; Immunology ; Male ; Mice ; Molecular Dynamics Simulation ; Phosphorylation ; Protein Binding ; Receptor, TIE-2 - chemistry ; Receptor, TIE-2 - genetics ; Receptor, TIE-2 - metabolism ; Recombinant Proteins - genetics ; Recombinant Proteins - metabolism ; SciAdv r-articles ; Sepsis - metabolism</subject><ispartof>Science advances, 2025-01, Vol.11 (3), p.eads1796</ispartof><rights>Copyright © 2025 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). 2025 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c236t-fa06f2351e0c7de200e8dc4db27732b1d783f0d91a8e156178862d776c2788723</cites><orcidid>0000-0001-8004-9688 ; 0000-0002-2536-9600 ; 0009-0007-0711-6080 ; 0000-0002-4734-3778 ; 0000-0002-8220-049X ; 0000-0001-6122-0259 ; 0000-0003-0085-9141 ; 0000-0003-3968-7279 ; 0009-0008-1050-0099</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/PMC11734714/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734714/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39813336$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Rui</creatorcontrib><creatorcontrib>Li, Hao</creatorcontrib><creatorcontrib>Xie, Zhinuo</creatorcontrib><creatorcontrib>Huang, Meijuan</creatorcontrib><creatorcontrib>Xu, Peng</creatorcontrib><creatorcontrib>Yuan, Cai</creatorcontrib><creatorcontrib>Li, Jinyu</creatorcontrib><creatorcontrib>Flaumenhaft, Robert</creatorcontrib><creatorcontrib>Huang, Mingdong</creatorcontrib><creatorcontrib>Jiang, Longguang</creatorcontrib><title>Development of a recombinant Ang1 variant with enhanced Tie2 binding and its application to attenuate sepsis in mice</title><title>Science advances</title><addtitle>Sci Adv</addtitle><description>The angiopoietin (Ang)-Tie axis, critical for endothelial cell function and vascular development, is a promising therapeutic target for treating vascular disorders and inflammatory conditions like sepsis. This study aimed to enhance the binding affinity of recombinant Ang1 variants to the Tie2 and explore their therapeutic potential. Structural insights from the Ang1-Tie2 complex enabled the identification of key residues within the Ang1 receptor binding domain (RBD) critical for Tie2 interaction. Molecular dynamics simulations revealed that Met
Arg (M436R) and Ala
Asp (A451D) could improve Ang1's Tie2 binding affinity. One variant, Ang1-RBD
, demonstrated a 100-fold increase compared to the wild type. Cellular assays revealed that Ang1
enhanced Tie2 phosphorylation, promoting endothelial cell migration and tube formation. In vivo, this variant effectively reduced inflammatory cytokines and attenuated organ damage in septic mice. These findings highlight Ang1
as a promising therapeutic candidate for vascular diseases, offering notable clinical potential for mitigating sepsis-related vascular dysfunction.</description><subject>Angiopoietin-1 - genetics</subject><subject>Angiopoietin-1 - metabolism</subject><subject>Animals</subject><subject>Biomedicine and Life Sciences</subject><subject>Cell Movement</subject><subject>Disease Models, Animal</subject><subject>Human Umbilical Vein Endothelial Cells</subject><subject>Humans</subject><subject>Immunology</subject><subject>Male</subject><subject>Mice</subject><subject>Molecular Dynamics Simulation</subject><subject>Phosphorylation</subject><subject>Protein Binding</subject><subject>Receptor, TIE-2 - chemistry</subject><subject>Receptor, TIE-2 - genetics</subject><subject>Receptor, TIE-2 - metabolism</subject><subject>Recombinant Proteins - genetics</subject><subject>Recombinant Proteins - metabolism</subject><subject>SciAdv r-articles</subject><subject>Sepsis - metabolism</subject><issn>2375-2548</issn><issn>2375-2548</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1PGzEQtSqqgijXHisfuSR47LW9OVUIaKmE1As9WxN7NnG1a2_XThD_vosSED3N15v3ZvQY-wJiCSDNVfERw36JoYBdmQ_sTCqrF1I37cm7_JRdlPJHCAGNMRpWn9ipWrWglDJnrN7Snvo8DpQqzx1HPpHPwzomnBvXaQN8j1N8KZ5i3XJKW0yeAn-MJPkMCzFtOKbAYy0cx7GPHmvMidfMsVZKO6zEC40lFh4TH6Knz-xjh32hi2M8Z7-_3z3e3C8efv34eXP9sPBSmbroUJhOKg0kvA0khaA2-CaspbVKriHYVnUirABbAm3Atq2RwVrj5Zxaqc7ZtwPvuFsPFPz844S9G6c44PTsMkb3_yTFrdvkvQOwqrHQzAyXR4Yp_91RqW6IxVPfY6K8K07NulpqrWGGLg9QP-VSJuredEC4F7vcwS53tGte-Pr-ujf4qznqH49clEA</recordid><startdate>20250117</startdate><enddate>20250117</enddate><creator>Wang, Rui</creator><creator>Li, Hao</creator><creator>Xie, Zhinuo</creator><creator>Huang, Meijuan</creator><creator>Xu, Peng</creator><creator>Yuan, Cai</creator><creator>Li, Jinyu</creator><creator>Flaumenhaft, Robert</creator><creator>Huang, Mingdong</creator><creator>Jiang, Longguang</creator><general>American Association for the Advancement of Science</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><orcidid>https://orcid.org/0000-0001-8004-9688</orcidid><orcidid>https://orcid.org/0000-0002-2536-9600</orcidid><orcidid>https://orcid.org/0009-0007-0711-6080</orcidid><orcidid>https://orcid.org/0000-0002-4734-3778</orcidid><orcidid>https://orcid.org/0000-0002-8220-049X</orcidid><orcidid>https://orcid.org/0000-0001-6122-0259</orcidid><orcidid>https://orcid.org/0000-0003-0085-9141</orcidid><orcidid>https://orcid.org/0000-0003-3968-7279</orcidid><orcidid>https://orcid.org/0009-0008-1050-0099</orcidid></search><sort><creationdate>20250117</creationdate><title>Development of a recombinant Ang1 variant with enhanced Tie2 binding and its application to attenuate sepsis in mice</title><author>Wang, Rui ; Li, Hao ; Xie, Zhinuo ; Huang, Meijuan ; Xu, Peng ; Yuan, Cai ; Li, Jinyu ; Flaumenhaft, Robert ; Huang, Mingdong ; Jiang, Longguang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c236t-fa06f2351e0c7de200e8dc4db27732b1d783f0d91a8e156178862d776c2788723</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><topic>Angiopoietin-1 - genetics</topic><topic>Angiopoietin-1 - metabolism</topic><topic>Animals</topic><topic>Biomedicine and Life Sciences</topic><topic>Cell Movement</topic><topic>Disease Models, Animal</topic><topic>Human Umbilical Vein Endothelial Cells</topic><topic>Humans</topic><topic>Immunology</topic><topic>Male</topic><topic>Mice</topic><topic>Molecular Dynamics Simulation</topic><topic>Phosphorylation</topic><topic>Protein Binding</topic><topic>Receptor, TIE-2 - chemistry</topic><topic>Receptor, TIE-2 - genetics</topic><topic>Receptor, TIE-2 - metabolism</topic><topic>Recombinant Proteins - genetics</topic><topic>Recombinant Proteins - metabolism</topic><topic>SciAdv r-articles</topic><topic>Sepsis - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Rui</creatorcontrib><creatorcontrib>Li, Hao</creatorcontrib><creatorcontrib>Xie, Zhinuo</creatorcontrib><creatorcontrib>Huang, Meijuan</creatorcontrib><creatorcontrib>Xu, Peng</creatorcontrib><creatorcontrib>Yuan, Cai</creatorcontrib><creatorcontrib>Li, Jinyu</creatorcontrib><creatorcontrib>Flaumenhaft, Robert</creatorcontrib><creatorcontrib>Huang, Mingdong</creatorcontrib><creatorcontrib>Jiang, Longguang</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>Science advances</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Rui</au><au>Li, Hao</au><au>Xie, Zhinuo</au><au>Huang, Meijuan</au><au>Xu, Peng</au><au>Yuan, Cai</au><au>Li, Jinyu</au><au>Flaumenhaft, Robert</au><au>Huang, Mingdong</au><au>Jiang, Longguang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Development of a recombinant Ang1 variant with enhanced Tie2 binding and its application to attenuate sepsis in mice</atitle><jtitle>Science advances</jtitle><addtitle>Sci Adv</addtitle><date>2025-01-17</date><risdate>2025</risdate><volume>11</volume><issue>3</issue><spage>eads1796</spage><pages>eads1796-</pages><issn>2375-2548</issn><eissn>2375-2548</eissn><abstract>The angiopoietin (Ang)-Tie axis, critical for endothelial cell function and vascular development, is a promising therapeutic target for treating vascular disorders and inflammatory conditions like sepsis. This study aimed to enhance the binding affinity of recombinant Ang1 variants to the Tie2 and explore their therapeutic potential. Structural insights from the Ang1-Tie2 complex enabled the identification of key residues within the Ang1 receptor binding domain (RBD) critical for Tie2 interaction. Molecular dynamics simulations revealed that Met
Arg (M436R) and Ala
Asp (A451D) could improve Ang1's Tie2 binding affinity. One variant, Ang1-RBD
, demonstrated a 100-fold increase compared to the wild type. Cellular assays revealed that Ang1
enhanced Tie2 phosphorylation, promoting endothelial cell migration and tube formation. In vivo, this variant effectively reduced inflammatory cytokines and attenuated organ damage in septic mice. These findings highlight Ang1
as a promising therapeutic candidate for vascular diseases, offering notable clinical potential for mitigating sepsis-related vascular dysfunction.</abstract><cop>United States</cop><pub>American Association for the Advancement of Science</pub><pmid>39813336</pmid><doi>10.1126/sciadv.ads1796</doi><orcidid>https://orcid.org/0000-0001-8004-9688</orcidid><orcidid>https://orcid.org/0000-0002-2536-9600</orcidid><orcidid>https://orcid.org/0009-0007-0711-6080</orcidid><orcidid>https://orcid.org/0000-0002-4734-3778</orcidid><orcidid>https://orcid.org/0000-0002-8220-049X</orcidid><orcidid>https://orcid.org/0000-0001-6122-0259</orcidid><orcidid>https://orcid.org/0000-0003-0085-9141</orcidid><orcidid>https://orcid.org/0000-0003-3968-7279</orcidid><orcidid>https://orcid.org/0009-0008-1050-0099</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Angiopoietin-1 - genetics Angiopoietin-1 - metabolism Animals Biomedicine and Life Sciences Cell Movement Disease Models, Animal Human Umbilical Vein Endothelial Cells Humans Immunology Male Mice Molecular Dynamics Simulation Phosphorylation Protein Binding Receptor, TIE-2 - chemistry Receptor, TIE-2 - genetics Receptor, TIE-2 - metabolism Recombinant Proteins - genetics Recombinant Proteins - metabolism SciAdv r-articles Sepsis - metabolism |
| title | Development of a recombinant Ang1 variant with enhanced Tie2 binding and its application to attenuate sepsis in mice |
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