Publicação
Phosphoinositide 3-Kinase-Regulated pericyte maturation governs vascular remodeling
| Resumo: | Background: 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. |
|---|---|
| Autores principais: | Figueiredo, Ana |
| Outros Autores: | Villacampa, Pilar; Diéguez-Hurtado, Rodrigo; José Lozano, Juan; Kobialka, Piotr; Cortazar, Ana Rosa; Martinez-Romero, Anabel; Angulo-Urarte, Ana; Franco, Claudio; Claret, Marc; Aransay, Ana Maria; Adams, Ralf H.; Carracedo, Arkaitz; Graupera, Mariona |
| Assunto: | Angiogenesis, physiological Pericytes Phosphoinositide 3-kinase Signal transduction |
| Ano: | 2020 |
| País: | Portugal |
| Tipo de documento: | artigo |
| Tipo de acesso: | acesso restrito |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| _version_ | 1866810587653079040 |
|---|---|
| author | Figueiredo, Ana |
| author2 | Villacampa, Pilar Diéguez-Hurtado, Rodrigo José Lozano, Juan Kobialka, Piotr Cortazar, Ana Rosa Martinez-Romero, Anabel Angulo-Urarte, Ana Franco, Claudio Claret, Marc Aransay, Ana Maria Adams, Ralf H. Carracedo, Arkaitz Graupera, Mariona |
| author2_role | author author author author author author author author author author author author author |
| author_facet | Figueiredo, Ana Villacampa, Pilar Diéguez-Hurtado, Rodrigo José Lozano, Juan Kobialka, Piotr Cortazar, Ana Rosa Martinez-Romero, Anabel Angulo-Urarte, Ana Franco, Claudio Claret, Marc Aransay, Ana Maria Adams, Ralf H. Carracedo, Arkaitz Graupera, Mariona |
| author_role | author |
| contributor_name_str_mv | Repositório Científico de Acesso Aberto da ULisboa |
| country_str | PT |
| creators_json_txt | [{\"Person.name\":\"Figueiredo, Ana\",\"Person.identifier.orcid\":\"0000-0003-3499-9871\"},{\"Person.name\":\"Villacampa, Pilar\"},{\"Person.name\":\"Diéguez-Hurtado, Rodrigo\"},{\"Person.name\":\"José Lozano, Juan\"},{\"Person.name\":\"Kobialka, Piotr\"},{\"Person.name\":\"Cortazar, Ana Rosa\"},{\"Person.name\":\"Martinez-Romero, Anabel\"},{\"Person.name\":\"Angulo-Urarte, Ana\"},{\"Person.name\":\"Franco, Claudio\",\"Person.identifier.orcid\":\"0000-0002-2861-3883\"},{\"Person.name\":\"Claret, Marc\"},{\"Person.name\":\"Aransay, Ana Maria\",\"Person.identifier.orcid\":\"0000-0002-8271-612X\"},{\"Person.name\":\"Adams, Ralf H.\"},{\"Person.name\":\"Carracedo, Arkaitz\"},{\"Person.name\":\"Graupera, Mariona\"}] |
| datacite.contributors.contributor.contributorName.fl_str_mv | Repositório Científico de Acesso Aberto da ULisboa |
| datacite.creators.creator.creatorName.fl_str_mv | Figueiredo, Ana Villacampa, Pilar Diéguez-Hurtado, Rodrigo José Lozano, Juan Kobialka, Piotr Cortazar, Ana Rosa Martinez-Romero, Anabel Angulo-Urarte, Ana Franco, Claudio Claret, Marc Aransay, Ana Maria Adams, Ralf H. Carracedo, Arkaitz Graupera, Mariona |
| datacite.date.Accepted.fl_str_mv | 2020-08-18T00:00:00Z |
| datacite.date.available.fl_str_mv | 2021-07-23T11:14:13Z |
| datacite.date.embargoed.fl_str_mv | 2021-07-23T11:14:13Z |
| datacite.rights.fl_str_mv | http://purl.org/coar/access_right/c_16ec |
| datacite.subjects.subject.fl_str_mv | Angiogenesis, physiological Pericytes Phosphoinositide 3-kinase Signal transduction |
| datacite.titles.title.fl_str_mv | Phosphoinositide 3-Kinase-Regulated pericyte maturation governs vascular remodeling |
| dc.contributor.none.fl_str_mv | Repositório Científico de Acesso Aberto da ULisboa |
| dc.creator.none.fl_str_mv | Figueiredo, Ana Villacampa, Pilar Diéguez-Hurtado, Rodrigo José Lozano, Juan Kobialka, Piotr Cortazar, Ana Rosa Martinez-Romero, Anabel Angulo-Urarte, Ana Franco, Claudio Claret, Marc Aransay, Ana Maria Adams, Ralf H. Carracedo, Arkaitz Graupera, Mariona |
| dc.date.Accepted.fl_str_mv | 2020-08-18T00:00:00Z |
| dc.date.available.fl_str_mv | 2021-07-23T11:14:13Z |
| dc.date.embargoed.fl_str_mv | 2021-07-23T11:14:13Z |
| dc.format.none.fl_str_mv | application/pdf |
| dc.identifier.none.fl_str_mv | http://hdl.handle.net/10451/49078 |
| dc.language.none.fl_str_mv | eng |
| dc.publisher.none.fl_str_mv | American Heart Association, Inc. |
| dc.rights.none.fl_str_mv | http://purl.org/coar/access_right/c_16ec |
| dc.subject.none.fl_str_mv | Angiogenesis, physiological Pericytes Phosphoinositide 3-kinase Signal transduction |
| dc.title.fl_str_mv | Phosphoinositide 3-Kinase-Regulated pericyte maturation governs vascular remodeling |
| dc.type.none.fl_str_mv | http://purl.org/coar/resource_type/c_6501 |
| description | Background: 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. |
| dirty | 0 |
| eu_rights_str_mv | restrictedAccess |
| format | article |
| fulltext.url.fl_str_mv | https://repositorio.ulisboa.pt/bitstreams/c6fe407c-1172-44b2-9cfe-e960cc2e7ff1/download |
| funding.funder.alternateName_str_mv | EC |
| funding.funder.identifier_str_mv | http://doi.org/10.13039/501100008530 |
| funding.funder.name_str_mv | European Commission |
| funding.name_str_mv | H2020 |
| id | ul_7d4e5cbb3a059e095df0e7ad9d3930d5 |
| identifier.url.fl_str_mv | http://hdl.handle.net/10451/49078 |
| instacron_str | ul |
| institution | Universidade de Lisboa |
| instname_str | Universidade de Lisboa |
| language | eng |
| network_acronym_str | ul |
| network_name_str | Repositório da Universidade de Lisboa |
| oai_identifier_str | oai:repositorio.ulisboa.pt:10451/49078 |
| organization_str_mv | urn:organizationAcronym:ul |
| person_str_mv | Figueiredo, Ana Figueiredo, Ana https://www.ciencia-id.pt/861B-2032-C580 861B-2032-C580 http://orcid.org/0000-0003-3499-9871 0000-0003-3499-9871 Villacampa, Pilar Diéguez-Hurtado, Rodrigo José Lozano, Juan Kobialka, Piotr Cortazar, Ana Rosa Martinez-Romero, Anabel Angulo-Urarte, Ana Franco, Claudio Franco, Claudio https://www.ciencia-id.pt/F012-B7D6-AE72 F012-B7D6-AE72 http://orcid.org/0000-0002-2861-3883 0000-0002-2861-3883 Claret, Marc Aransay, Ana Maria Aransay, Ana Maria http://orcid.org/0000-0002-8271-612X 0000-0002-8271-612X Adams, Ralf H. Carracedo, Arkaitz Graupera, Mariona |
| publishDate | 2020 |
| publisher.none.fl_str_mv | American Heart Association, Inc. |
| reponame_str | Repositório da Universidade de Lisboa |
| repository_id_str | urn:repositoryAcronym:ul |
| service_str_mv | urn:repositoryAcronym:ul |
| spelling | engAmerican Heart Association, Inc.pt_PTBackground: 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.application/pdfpt_PTPhosphoinositide 3-Kinase-Regulated pericyte maturation governs vascular remodelingPersonalFigueiredo, AnaDSpacehttp://dspace.org/items/8dc70955-51ce-45fa-b173-b236eba21681DSpacehttp://dspace.org/items/8dc70955-51ce-45fa-b173-b236eba21681Martins Figueiredo FonsecaAna RaquelCiência IDhttps://www.ciencia-id.pt861B-2032-C580ORCIDhttp://orcid.org0000-0003-3499-9871Villacampa, PilarDiéguez-Hurtado, RodrigoJosé Lozano, JuanKobialka, PiotrCortazar, Ana RosaMartinez-Romero, AnabelAngulo-Urarte, AnaPersonalFranco, ClaudioDSpacehttp://dspace.org/items/633fb0a6-1f81-4d35-98ca-b4cfd838d81eDSpacehttp://dspace.org/items/633fb0a6-1f81-4d35-98ca-b4cfd838d81eFrancoClaudioCiência IDhttps://www.ciencia-id.ptF012-B7D6-AE72ORCIDhttp://orcid.org0000-0002-2861-3883Scopus Author IDhttps://www.scopus.com24280736600Claret, MarcPersonalAransay, Ana MariaDSpacehttp://dspace.org/items/9ae0b1a0-3de0-477e-a83f-6710dbb86feaDSpacehttp://dspace.org/items/9ae0b1a0-3de0-477e-a83f-6710dbb86feaAransayAna MariaORCIDhttp://orcid.org0000-0002-8271-612XResearcher IDhttps://www.researcherid.comF-8086-2011Adams, Ralf H.Carracedo, ArkaitzGraupera, MarionaHostingInstitutionOrganizationalRepositório Científico de Acesso Aberto da ULisboae-mailmailto:repositorio@reitoria.ulisboa.ptrepositorio@reitoria.ulisboa.ptISSNIsPartOf0009-7322DOIIsPartOf10.1161/CIRCULATIONAHA.119.0423542021-07-23T11:14:13Z2020-08-182020-08-18T00:00:00ZHandlehttp://hdl.handle.net/10451/49078http://purl.org/coar/access_right/c_16ecrestricted accessAngiogenesis, physiologicalPericytesPhosphoinositide 3-kinaseSignal transduction6309276 bytesEuropean CommissionDeciphering PI3K biology in health and diseaseH2020Crossref Funder IDhttp://doi.org/10.13039/501100008530literaturehttp://purl.org/coar/resource_type/c_6501journal articlehttp://purl.org/coar/access_right/c_16ecapplication/pdffulltexthttps://repositorio.ulisboa.pt/bitstreams/c6fe407c-1172-44b2-9cfe-e960cc2e7ff1/downloadCirculation1427688704 |
| spellingShingle | Phosphoinositide 3-Kinase-Regulated pericyte maturation governs vascular remodeling Figueiredo, Ana Angiogenesis, physiological Pericytes Phosphoinositide 3-kinase Signal transduction |
| status | SINGLETON |
| subject.fl_str_mv | Angiogenesis, physiological Pericytes Phosphoinositide 3-kinase Signal transduction |
| title | Phosphoinositide 3-Kinase-Regulated pericyte maturation governs vascular remodeling |
| title_full | Phosphoinositide 3-Kinase-Regulated pericyte maturation governs vascular remodeling |
| title_fullStr | Phosphoinositide 3-Kinase-Regulated pericyte maturation governs vascular remodeling |
| title_full_unstemmed | Phosphoinositide 3-Kinase-Regulated pericyte maturation governs vascular remodeling |
| title_short | Phosphoinositide 3-Kinase-Regulated pericyte maturation governs vascular remodeling |
| title_sort | Phosphoinositide 3-Kinase-Regulated pericyte maturation governs vascular remodeling |
| topic | Angiogenesis, physiological Pericytes Phosphoinositide 3-kinase Signal transduction |
| topic_facet | Angiogenesis, physiological Pericytes Phosphoinositide 3-kinase Signal transduction |
| url | http://hdl.handle.net/10451/49078 |
| visible | 1 |