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Phosphoinositide 3-Kinase-Regulated pericyte maturation governs vascular remodeling

2020-08-18Journal article Restricted access
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dc.contributor.authorFigueiredo, Ana
dc.contributor.authorVillacampa, Pilar
dc.contributor.authorDiéguez-Hurtado, Rodrigo
dc.contributor.authorJosé Lozano, Juan
dc.contributor.authorKobialka, Piotr
dc.contributor.authorCortazar, Ana Rosa
dc.contributor.authorMartinez-Romero, Anabel
dc.contributor.authorAngulo-Urarte, Ana
dc.contributor.authorFranco, Claudio
dc.contributor.authorClaret, Marc
dc.contributor.authorAransay, Ana Maria
dc.contributor.authorAdams, Ralf H.
dc.contributor.authorCarracedo, Arkaitz
dc.contributor.authorGraupera, Mariona
dc.date.accessioned2021-07-23T11:14:13Z
dc.date.available2021-07-23T11:14:13Z
dc.date.issued2020-08-18
dc.description© 2020 American Heart Association, Inc.pt_PT
dc.description.abstractBackground: Pericytes regulate vessel stabilization and function, and their loss is associated with diseases such as diabetic retinopathy or cancer. Despite their physiological importance, pericyte function and molecular regulation during angiogenesis remain poorly understood. Methods: To decipher the transcriptomic programs of pericytes during angiogenesis, we crossed Pdgfrb(BAC)-CreERT2 mice into RiboTagflox/flox mice. Pericyte morphological changes were assessed in mural cell-specific R26-mTmG reporter mice, in which low doses of tamoxifen allowed labeling of single-cell pericytes at high resolution. To study the role of phosphoinositide 3-kinase (PI3K) signaling in pericyte biology during angiogenesis, we used genetic mouse models that allow selective inactivation of PI3Kα and PI3Kβ isoforms and their negative regulator phosphate and tensin homolog deleted on chromosome 10 (PTEN) in mural cells. Results: At the onset of angiogenesis, pericytes exhibit molecular traits of cell proliferation and activated PI3K signaling, whereas during vascular remodeling, pericytes upregulate genes involved in mature pericyte cell function, together with a remarkable decrease in PI3K signaling. Immature pericytes showed stellate shape and high proliferation, and mature pericytes were quiescent and elongated. Unexpectedly, we demonstrate that PI3Kβ, but not PI3Kα, regulates pericyte proliferation and maturation during vessel formation. Genetic PI3Kβ inactivation in pericytes triggered early pericyte maturation. Conversely, unleashing PI3K signaling by means of PTEN deletion delayed pericyte maturation. Pericyte maturation was necessary to undergo vessel remodeling during angiogenesis. Conclusions: Our results identify new molecular and morphological traits associated with pericyte maturation and uncover PI3Kβ activity as a checkpoint to ensure appropriate vessel formation. In turn, our results may open new therapeutic opportunities to regulate angiogenesis in pathological processes through the manipulation of pericyte PI3Kβ activity.pt_PT
dc.description.sponsorshipDr Graupera’s laboratory is supported by the research grants SAF2017-89116R-P from Ministerio de Ciencia (Spain) cofunded by European Regional Developmental Fund (ERDF), a Way to Build Europe; by the Catalan government through the project 2017-SGR; by La Caixa Foundation (HR18-00120); by la Asociación Española contra el Cancer (AECC)-Grupos Traslacionales (GCTRA18006CARR); by la Fundación BBVA (Beca Leonardo a Investigadores y Creadores Culturales 2017); and by the People Program (Marie Curie Actions; grant agreement 317250) of the European Union’s Seventh Framework Program FP7/2007 to 2013/, and the Marie Skłodowska-Curie (grant agreement 675392) of the European Union’s Horizon 2020 research. Dr Carracedo’s laboratory is supported by the Basque Department of Industry, Tourism and Trade (Elkartek) and the Department of Education (IKERTALDE IT1106-16), the Ministerio de Ciencia (SAF2016-79381-R [FEDER/EU], Severo Ochoa Excellence Accreditation SEV-2016-0644; Excellence Networks SAF2016-81975-REDT), European Training Networks Project (H2020-MSCA-ITN-308 2016 721532), the AECC (IDEAS175CARR, GCTRA18006CARR), La Caixa Foundation (HR17-00094), and the European Research Council (StG 336343, PoC 754627, CoG 819242). Centro de Investigación Biomédica en Red Cáncer (CIBERONC) was cofunded with FEDER funds and funded by Instituto de Salud Carlos III. Dr Aransay’s laboratory is supported by the Basque Department of Industry, Tourism and Trade (Elkartek) and the Severo Ochoa Excellence Accreditation SEV-2016-0644. Dr Franco was supported by European Research Council (StG 679368), the H2020-Twinning grant (692322), the Fundação para a Ciência e a Tecnologia funding (grants IF/00412/2012; EXPL-BEX-BCM-2258-2013; PRECISE-LISBOA-01-0145-FEDER-016394), and a grant from the Fondation Leducq (17CVD03). Personal support was from Marie-Curie ITN Actions (Dr Figueiredo and Kobialka), Juan de la Cierva (IJCI-2015-23455, Dr Villacampa), and CIBERONC (A. Martinez-Romero).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCirculation. 2020 Aug 18;142(7):688-704pt_PT
dc.identifier.doi10.1161/CIRCULATIONAHA.119.042354pt_PT
dc.identifier.eissn1524-4539
dc.identifier.issn0009-7322
dc.identifier.urihttp://hdl.handle.net/10451/49078
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmerican Heart Association, Inc.pt_PT
dc.relationEXPL-BEX-BCM-2258-2013pt_PT
dc.relationDeciphering PI3K biology in health and disease
dc.relation.publisherversionhttps://www.ahajournals.org/journal/circpt_PT
dc.subjectAngiogenesis, physiologicalpt_PT
dc.subjectPericytespt_PT
dc.subjectPhosphoinositide 3-kinasept_PT
dc.subjectSignal transductionpt_PT
dc.titlePhosphoinositide 3-Kinase-Regulated pericyte maturation governs vascular remodelingpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleDeciphering PI3K biology in health and disease
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/675392/EU
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/Investigador FCT/IF%2F00412%2F2012%2FCP0163%2FCT0007/PT
oaire.citation.endPage704pt_PT
oaire.citation.issue7pt_PT
oaire.citation.startPage688pt_PT
oaire.citation.titleCirculationpt_PT
oaire.citation.volume142pt_PT
oaire.fundingStreamH2020
oaire.fundingStreamInvestigador FCT
person.familyNameMartins Figueiredo Fonseca
person.familyNameFranco
person.familyNameAransay
person.givenNameAna Raquel
person.givenNameClaudio
person.givenNameAna Maria
person.identifierD-8117-2015
person.identifier.ciencia-id861B-2032-C580
person.identifier.ciencia-idF012-B7D6-AE72
person.identifier.orcid0000-0003-3499-9871
person.identifier.orcid0000-0002-2861-3883
person.identifier.orcid0000-0002-8271-612X
person.identifier.ridF-8086-2011
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
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