A noncanonical role for Jagged1 in endothelial mechanotransduction

Rodriguez, Freddy Suarez; Virtanen, Noora; Kiviluoto, Elmeri; H., Rob C.; Zhao, Feihu; C., Carlijn V.; J., Oscar M.; Sahlgren, Cecilia M.

doi:10.1111/febs.70466

Journal article 37 views 6 downloads

A noncanonical role for Jagged1 in endothelial mechanotransduction

Freddy Suarez Rodriguez

, Noora Virtanen, Elmeri Kiviluoto, Rob C. H. Driessen, Feihu Zhao

, Carlijn V. C. Bouten, Oscar M. J. A. Stassen, Cecilia M. Sahlgren

The FEBS Journal

Swansea University Author: Feihu Zhao

PDF | Version of Record

Copyright: 2026 The Author(s). This is an open access article under the terms of the Creative Commons Attribution License.
Download (7.88MB)

Check full text

DOI (Published version): 10.1111/febs.70466

Abstract

The Notch signaling pathway plays a crucial role in regulating endothelial biology. Notch signaling is sensitive to hemodynamic forces and governs mechanically driven cardiovascular development, physiology, and remodeling. However, the mechanisms by which mechanical forces integrate with the Notch p...

Full description

Published in:	The FEBS Journal
ISSN:	1742-464X
Published:	2026
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa71485

first_indexed	2026-02-23T15:11:13Z
last_indexed	2026-02-24T05:33:35Z
id	cronfa71485
recordtype	SURis
fullrecord	<?xml version="1.0"?><rfc1807><datestamp>2026-02-23T15:17:50.2475000</datestamp><bib-version>v2</bib-version><id>71485</id><entry>2026-02-23</entry><title>A noncanonical role for Jagged1 in endothelial mechanotransduction</title><swanseaauthors><author><sid>1c6e79b6edd08c88a8d17a241cd78630</sid><ORCID>0000-0003-0515-6808</ORCID><firstname>Feihu</firstname><surname>Zhao</surname><name>Feihu Zhao</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2026-02-23</date><deptcode>EAAS</deptcode><abstract>The Notch signaling pathway plays a crucial role in regulating endothelial biology. Notch signaling is sensitive to hemodynamic forces and governs mechanically driven cardiovascular development, physiology, and remodeling. However, the mechanisms by which mechanical forces integrate with the Notch pathway remain largely unknown. Here, we uncover a noncanonical role for the Notch ligand protein jagged-1 (Jagged1) in regulating the activity of mechanosensitive kinases in endothelial cells. We show that shear stress induces expression and relocalization of Jagged1 to cell junctions downstream of flow. Jagged1 expression under stress demonstrates magnitude dependence, and peaks at 0.8–1 Pa without impacting the Notch-activation potential of Jagged1. Jagged1 also regulates the activity of mechanosensitive kinases. Deletion of Jagged1 reduces the activity of vascular endothelial growth factor receptor 2 (VEGFR2) and mitogen-activated protein kinase (ERK) in vitro and diminished ERK activity in zebrafish embryos without affecting canonical Notch signaling. Furthermore, direct physical stimulation of Jagged1 using antibody-conjugated beads triggers the activation of VEGFR2 and ERK, mediated by Jagged1-induced proto-oncogene tyrosine-protein kinase Src activation. Taken together, we demonstrate a previously unknown noncanonical role for Jagged1 as a regulator of the activity of pathways involved in endothelial mechanotransduction.</abstract><type>Journal Article</type><journal>The FEBS Journal</journal><volume>0</volume><journalNumber/><paginationStart/><paginationEnd/><publisher/><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>1742-464X</issnPrint><issnElectronic/><keywords>endothelial cells; hemodynamic forces;jagged1; mechanotransduction; notch signaling</keywords><publishedDay>23</publishedDay><publishedMonth>2</publishedMonth><publishedYear>2026</publishedYear><publishedDate>2026-02-23</publishedDate><doi>10.1111/febs.70466</doi><url/><notes/><college>COLLEGE NANME</college><department>Engineering and Applied Sciences School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>EAAS</DepartmentCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><funders>European Research Council (ERC) ERC-CoGNo 771168 (ForceMorph). European Research Council(ERC) ERC-SynG No 101167065 (Making Blood). Research Council of Finland, Center of Excellence,decision number #374179 (CoEIMMENs). ResearchCouncil of Finland, decision number #316882(SPACE). Research Council of Finland, decision num-ber #330411 (SignalSheets). Research Council of Fin-land, decision number #336355 (Solutions for Healthat ˚Abo Akademi University). Research Council of Fin-land, decision number #337531 and #357911(InFLAMES Flagship Program). Abo Akademi Uni-versity Foundation’s Centers of Excellence in CellularMechanostasis (CellMech) and Bioelectronic Activa-tion of Cell Functions (BACE).</funders><projectreference/><lastEdited>2026-02-23T15:17:50.2475000</lastEdited><Created>2026-02-23T14:56:56.4640644</Created><path><level id="1">Faculty of Science and Engineering</level><level id="2">School of Engineering and Applied Sciences - Biomedical Engineering</level></path><authors><author><firstname>Freddy Suarez</firstname><surname>Rodriguez</surname><orcid>0000-0002-3556-1997</orcid><order>1</order></author><author><firstname>Noora</firstname><surname>Virtanen</surname><order>2</order></author><author><firstname>Elmeri</firstname><surname>Kiviluoto</surname><order>3</order></author><author><firstname>Rob C. H.</firstname><surname>Driessen</surname><order>4</order></author><author><firstname>Feihu</firstname><surname>Zhao</surname><orcid>0000-0003-0515-6808</orcid><order>5</order></author><author><firstname>Carlijn V. C.</firstname><surname>Bouten</surname><order>6</order></author><author><firstname>Oscar M. J. A.</firstname><surname>Stassen</surname><order>7</order></author><author><firstname>Cecilia M.</firstname><surname>Sahlgren</surname><orcid>0000-0003-3350-4937</orcid><order>8</order></author></authors><documents><document><filename>71485__36286__3c8fbb215d104ec6b0ed5ef3308191bb.pdf</filename><originalFilename>71485.VoR.pdf</originalFilename><uploaded>2026-02-23T15:09:51.9674729</uploaded><type>Output</type><contentLength>8263978</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>Copyright: 2026 The Author(s). This is an open access article under the terms of the Creative Commons Attribution License.</documentNotes><copyrightCorrect>true</copyrightCorrect><language>Eng</language><licence>http://creativecommons.org/licenses/by/4.0/</licence></document></documents><OutputDurs/></rfc1807>
spelling	2026-02-23T15:17:50.2475000 v2 71485 2026-02-23 A noncanonical role for Jagged1 in endothelial mechanotransduction 1c6e79b6edd08c88a8d17a241cd78630 0000-0003-0515-6808 Feihu Zhao Feihu Zhao true false 2026-02-23 EAAS The Notch signaling pathway plays a crucial role in regulating endothelial biology. Notch signaling is sensitive to hemodynamic forces and governs mechanically driven cardiovascular development, physiology, and remodeling. However, the mechanisms by which mechanical forces integrate with the Notch pathway remain largely unknown. Here, we uncover a noncanonical role for the Notch ligand protein jagged-1 (Jagged1) in regulating the activity of mechanosensitive kinases in endothelial cells. We show that shear stress induces expression and relocalization of Jagged1 to cell junctions downstream of flow. Jagged1 expression under stress demonstrates magnitude dependence, and peaks at 0.8–1 Pa without impacting the Notch-activation potential of Jagged1. Jagged1 also regulates the activity of mechanosensitive kinases. Deletion of Jagged1 reduces the activity of vascular endothelial growth factor receptor 2 (VEGFR2) and mitogen-activated protein kinase (ERK) in vitro and diminished ERK activity in zebrafish embryos without affecting canonical Notch signaling. Furthermore, direct physical stimulation of Jagged1 using antibody-conjugated beads triggers the activation of VEGFR2 and ERK, mediated by Jagged1-induced proto-oncogene tyrosine-protein kinase Src activation. Taken together, we demonstrate a previously unknown noncanonical role for Jagged1 as a regulator of the activity of pathways involved in endothelial mechanotransduction. Journal Article The FEBS Journal 0 1742-464X endothelial cells; hemodynamic forces;jagged1; mechanotransduction; notch signaling 23 2 2026 2026-02-23 10.1111/febs.70466 COLLEGE NANME Engineering and Applied Sciences School COLLEGE CODE EAAS Swansea University Another institution paid the OA fee European Research Council (ERC) ERC-CoGNo 771168 (ForceMorph). European Research Council(ERC) ERC-SynG No 101167065 (Making Blood). Research Council of Finland, Center of Excellence,decision number #374179 (CoEIMMENs). ResearchCouncil of Finland, decision number #316882(SPACE). Research Council of Finland, decision num-ber #330411 (SignalSheets). Research Council of Fin-land, decision number #336355 (Solutions for Healthat ˚Abo Akademi University). Research Council of Fin-land, decision number #337531 and #357911(InFLAMES Flagship Program). Abo Akademi Uni-versity Foundation’s Centers of Excellence in CellularMechanostasis (CellMech) and Bioelectronic Activa-tion of Cell Functions (BACE). 2026-02-23T15:17:50.2475000 2026-02-23T14:56:56.4640644 Faculty of Science and Engineering School of Engineering and Applied Sciences - Biomedical Engineering Freddy Suarez Rodriguez 0000-0002-3556-1997 1 Noora Virtanen 2 Elmeri Kiviluoto 3 Rob C. H. Driessen 4 Feihu Zhao 0000-0003-0515-6808 5 Carlijn V. C. Bouten 6 Oscar M. J. A. Stassen 7 Cecilia M. Sahlgren 0000-0003-3350-4937 8 71485__36286__3c8fbb215d104ec6b0ed5ef3308191bb.pdf 71485.VoR.pdf 2026-02-23T15:09:51.9674729 Output 8263978 application/pdf Version of Record true Copyright: 2026 The Author(s). This is an open access article under the terms of the Creative Commons Attribution License. true Eng http://creativecommons.org/licenses/by/4.0/
title	A noncanonical role for Jagged1 in endothelial mechanotransduction
spellingShingle	A noncanonical role for Jagged1 in endothelial mechanotransduction Feihu Zhao
title_short	A noncanonical role for Jagged1 in endothelial mechanotransduction
title_full	A noncanonical role for Jagged1 in endothelial mechanotransduction
title_fullStr	A noncanonical role for Jagged1 in endothelial mechanotransduction
title_full_unstemmed	A noncanonical role for Jagged1 in endothelial mechanotransduction
title_sort	A noncanonical role for Jagged1 in endothelial mechanotransduction
author_id_str_mv	1c6e79b6edd08c88a8d17a241cd78630
author_id_fullname_str_mv	1c6e79b6edd08c88a8d17a241cd78630_***_Feihu Zhao
author	Feihu Zhao
author2	Freddy Suarez Rodriguez Noora Virtanen Elmeri Kiviluoto Rob C. H. Driessen Feihu Zhao Carlijn V. C. Bouten Oscar M. J. A. Stassen Cecilia M. Sahlgren
format	Journal article
container_title	The FEBS Journal
container_volume	0
publishDate	2026
institution	Swansea University
issn	1742-464X
doi_str_mv	10.1111/febs.70466
college_str	Faculty of Science and Engineering
hierarchytype
hierarchy_top_id	facultyofscienceandengineering
hierarchy_top_title	Faculty of Science and Engineering
hierarchy_parent_id	facultyofscienceandengineering
hierarchy_parent_title	Faculty of Science and Engineering
department_str	School of Engineering and Applied Sciences - Biomedical Engineering{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Biomedical Engineering
document_store_str	1
active_str	0
description	The Notch signaling pathway plays a crucial role in regulating endothelial biology. Notch signaling is sensitive to hemodynamic forces and governs mechanically driven cardiovascular development, physiology, and remodeling. However, the mechanisms by which mechanical forces integrate with the Notch pathway remain largely unknown. Here, we uncover a noncanonical role for the Notch ligand protein jagged-1 (Jagged1) in regulating the activity of mechanosensitive kinases in endothelial cells. We show that shear stress induces expression and relocalization of Jagged1 to cell junctions downstream of flow. Jagged1 expression under stress demonstrates magnitude dependence, and peaks at 0.8–1 Pa without impacting the Notch-activation potential of Jagged1. Jagged1 also regulates the activity of mechanosensitive kinases. Deletion of Jagged1 reduces the activity of vascular endothelial growth factor receptor 2 (VEGFR2) and mitogen-activated protein kinase (ERK) in vitro and diminished ERK activity in zebrafish embryos without affecting canonical Notch signaling. Furthermore, direct physical stimulation of Jagged1 using antibody-conjugated beads triggers the activation of VEGFR2 and ERK, mediated by Jagged1-induced proto-oncogene tyrosine-protein kinase Src activation. Taken together, we demonstrate a previously unknown noncanonical role for Jagged1 as a regulator of the activity of pathways involved in endothelial mechanotransduction.
published_date	2026-02-23T05:32:49Z
_version_	1858708302170423296
score	11.098499

A noncanonical role for Jagged1 in endothelial mechanotransduction

Similar Items