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Gla rich protein (GRP) mediates vascular smooth muscle cell (VSMC) osteogenic differentiation, extracellular vesicle (EV) calcification propensity, and immunomodulatory properties

2024-11-19Journal article Open access
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dc.contributor.authorMaia, Teresa M.
dc.contributor.authorMacedo, Anjos L.
dc.contributor.authorMatos, António P.
dc.contributor.authorNeves, José
dc.contributor.authorViegas, Carla
dc.contributor.authorCamilo Carreira, Joana Sofia
dc.contributor.authorSimes, Dina
dc.date.accessioned2024-12-27T19:53:05Z
dc.date.available2024-12-27T19:53:05Z
dc.date.issued2024-11-19
dc.description.abstractVascular calcification (VC) is a complex process involving vascular smooth muscle cell (VSMC) osteogenic differentiation, inflammation, and extracellular vesicle (EV) calcification and communication networks. Gla rich protein (GRP) is a calcification inhibitor involved in most of these processes. However, the molecular mechanism of GRP in VC and the specific characteristics, cargo, and functionality of calcifying EVs require further elucidation. Here, we use a combination of human ex vivo aortic fragments and primary vascular smooth muscle cell (VSMC) models to obtain new information on GRP function in VC and EVs released by VSMCs. We demonstrate that GRP inhibits VSMC osteogenic differentiation through downregulation of bone-related proteins and upregulation of mineralization inhibitors, with decreased mineral crystallinity in EVs deposited into the tissue extracellular matrix (ECM). EVs isolated by ultracentrifugation at 30K and 100K from the cell media (CM) and deposited in the ECM from control (CTR) and mineralizing (MM) VSMCs were biochemically, physically, and proteomically characterized. Four different EV populations were identified with shared markers commonly present in all EVs but with unique protein cargo and specific molecular profiles. Comparative proteomics identified several regulated proteins specifically loaded into MM EV populations associated with multiple processes involved in VC. Functional analysis demonstrated that 30K and 100K ECM-MM EVs with higher calcium and lower GRP levels induced macrophage inflammation. Our findings reinforce the functional relevance of GRP in multiple VC processes and suggest that ECM EVs released under calcification stress function as a new signaling axis on the calcification-inflammation cycle.eng
dc.description.sponsorshipDL57/2016/CP1361/CT0006; 2022.12777.BD; 072583; EXPL/BTM-TEC/0990/2021
dc.identifier.doi10.3390/ijms252212406
dc.identifier.issn1422-0067
dc.identifier.urihttp://hdl.handle.net/10400.1/26543
dc.language.isoeng
dc.peerreviewedyes
dc.publisherMDPI
dc.relationAlgarve Centre for Marine Sciences
dc.relationCentre for Marine and Environmental Research
dc.relationApplied Molecular Biosciences Unit
dc.relationInstitute for Health and Bioeconomy
dc.relationAlgarve Centre for Marine Sciences
dc.relation.ispartofInternational Journal of Molecular Sciences
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectVascular calcification
dc.subjectExtracellular vesicles
dc.subjectInflammation
dc.subjectGla rich protein
dc.titleGla rich protein (GRP) mediates vascular smooth muscle cell (VSMC) osteogenic differentiation, extracellular vesicle (EV) calcification propensity, and immunomodulatory propertieseng
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleAlgarve Centre for Marine Sciences
oaire.awardTitleCentre for Marine and Environmental Research
oaire.awardTitleApplied Molecular Biosciences Unit
oaire.awardTitleInstitute for Health and Bioeconomy
oaire.awardTitleAlgarve Centre for Marine Sciences
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04326%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/LA%2FP%2F0101%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04378%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/LA%2FP%2F0140%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04326%2F2020/PT
oaire.citation.issue22
oaire.citation.startPage12406
oaire.citation.titleInternational Journal of Molecular Sciences
oaire.citation.volume25
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85
person.familyNameViegas
person.familyNameCamilo Carreira
person.familyNameSimes
person.givenNameCarla
person.givenNameJoana Sofia
person.givenNameDina
person.identifier.ciencia-idC414-F596-EEC6
person.identifier.ciencia-id3E11-5576-C40B
person.identifier.orcid0000-0002-5765-3665
person.identifier.orcid0000-0003-3048-8820
person.identifier.orcid0000-0002-5145-4753
person.identifier.ridN-6695-2014
person.identifier.ridN-2789-2014
person.identifier.scopus-author-id8656310300
person.identifier.scopus-author-id7201884723
project.funder.identifierhttp://doi.org/10.13039/501100001871
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project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
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