Repository logo
 
Publication

Defective flow-migration coupling causes arteriovenous malformations in hereditary hemorrhagic telangiectasia

2021Journal article Unknown
Simple item page
dc.contributor.authorPark, Hyojin
dc.contributor.authorFurtado, Jessica
dc.contributor.authorPoulet, Mathilde
dc.contributor.authorChung, Minhwan
dc.contributor.authorYun, Sanguk
dc.contributor.authorLee, Sungwoon
dc.contributor.authorSessa, William C.
dc.contributor.authorFranco, Claudio
dc.contributor.authorSchwartz, Martin A.
dc.contributor.authorEichmann, Anne
dc.date.accessioned2021-09-20T14:47:59Z
dc.date.available2021-09-20T14:47:59Z
dc.date.issued2021
dc.description© 2021 American Heart Association, Inc.pt_PT
dc.description.abstractBackground: Activin receptor-like kinase 1 (ALK1) is an endothelial transmembrane serine threonine kinase receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. Loss-of-function mutations in the ALK1 gene cause type 2 hereditary hemorrhagic telangiectasia, a devastating disorder that leads to arteriovenous malformations. Here, we show that ALK1 controls endothelial cell polarization against the direction of blood flow and flow-induced endothelial migration from veins through capillaries into arterioles. Methods: Using Cre lines that recombine in different subsets of arterial, capillary-venous, or endothelial tip cells, we show that capillary-venous Alk1 deletion was sufficient to induce arteriovenous malformation formation in the postnatal retina. Results: ALK1 deletion impaired capillary-venous endothelial cell polarization against the direction of blood flow in vivo and in vitro. Mechanistically, ALK1-deficient cells exhibited increased integrin signaling interaction with vascular endothelial growth factor receptor 2, which enhanced downstream YAP/TAZ nuclear translocation. Pharmacologic inhibition of integrin or YAP/TAZ signaling rescued flow migration coupling and prevented vascular malformations in Alk1-deficient mice. Conclusions: Our study reveals ALK1 as an essential driver of flow-induced endothelial cell migration and identifies loss of flow-migration coupling as a driver of arteriovenous malformation formation in hereditary hemorrhagic telangiectasia disease. Integrin-YAP/TAZ signaling blockers are new potential targets to prevent vascular malformations in patients with hereditary hemorrhagic telangiectasia.pt_PT
dc.description.sponsorshipThis work was supported by grants from the Leducq Foundation (TNE ATTRACT to Drs Eichmann and Franco) and the US National Institutes of Health (P30 EY026878 and R01EY025979 to Dr Eichmann and R01 HL135582 to Dr Schwartz). Dr Franco was supported by European Research Council starting grant (679368) and Fundação para a Ciência e a Tecnologia funding (CEECIND/02589/2018).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCirculation. 2021 Sep 7;144(10):805-822pt_PT
dc.identifier.doi10.1161/CIRCULATIONAHA.120.053047pt_PT
dc.identifier.eissn1524-4539
dc.identifier.issn0009-7322
dc.identifier.urihttp://hdl.handle.net/10451/49547
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmerican Heart Association, Inc.pt_PT
dc.relationPRINCIPLES OF AXIAL POLARITY-DRIVEN VASCULAR PATTERNING
dc.relation.publisherversionhttps://www.ahajournals.org/journal/circpt_PT
dc.subjectArteriovenous malformationspt_PT
dc.subjectCell movementpt_PT
dc.subjectTelangiectasiapt_PT
dc.subjectHereditary hemorrhagicpt_PT
dc.subjectVascular endothelial growth factor Apt_PT
dc.titleDefective flow-migration coupling causes arteriovenous malformations in hereditary hemorrhagic telangiectasiapt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitlePRINCIPLES OF AXIAL POLARITY-DRIVEN VASCULAR PATTERNING
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/679368/EU
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/CEEC IND 2018/6767/PT
oaire.citation.endPage822pt_PT
oaire.citation.issue10pt_PT
oaire.citation.startPage805pt_PT
oaire.citation.titleCirculationpt_PT
oaire.citation.volume144pt_PT
oaire.fundingStreamH2020
oaire.fundingStreamCEEC IND 2018
person.familyNameFranco
person.givenNameClaudio
person.identifierD-8117-2015
person.identifier.ciencia-idF012-B7D6-AE72
person.identifier.orcid0000-0002-2861-3883
person.identifier.scopus-author-id24280736600
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameEuropean Commission
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication633fb0a6-1f81-4d35-98ca-b4cfd838d81e
relation.isAuthorOfPublication.latestForDiscovery633fb0a6-1f81-4d35-98ca-b4cfd838d81e
relation.isProjectOfPublication5b819576-166d-4a04-9a0e-d37f9af3ec67
relation.isProjectOfPublication34ca0820-a544-4675-a3e2-e2b3504e9f2e
relation.isProjectOfPublication.latestForDiscovery34ca0820-a544-4675-a3e2-e2b3504e9f2e

Files

Original bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
Defective_migration.pdf
Size:
9.76 MB
Format:
Adobe Portable Document Format
Download

Collections

IMM - Artigos em Revistas Internacionais
Load more