Fibrous Caps in Atherosclerosis Form by Notch-Dependent Mechanisms Common to Arterial Media Development.

Atheromatous fibrous caps are produced by smooth muscle cells (SMCs) that are recruited to the subendothelial space. We tested whether the recruitment mechanisms are the same as in embryonic artery development, which relies prominently on Notch signaling to form the subendothelial medial SMC layers....

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Autores: Martos-Rodríguez, Carlos J, Albarrán-Juárez, Julián, Morales-Cano, Daniel, Caballero, Ainoa, MacGrogan, Donal, de la Pompa, Jose Luis, Carramolino, Laura, Bentzon, Jacob F
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/15379
Acceso en línea:http://hdl.handle.net/20.500.12105/15379
Access Level:acceso abierto
Palabra clave:Plaque, Atherosclerotic
Actins
Animals
Arteries
Atherosclerosis
Cell Lineage
Cells, Cultured
Disease Progression
Fibrosis
Humans
Immunoglobulin J Recombination Signal Sequence-Binding Protein
Jagged-1 Protein
Male
Mice, Inbred C57BL
Mice, Knockout
Muscle, Smooth, Vascular
Myocytes, Smooth Muscle
Phenotype
Rats
Receptors, Notch
Signal Transduction
Tunica Media
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oai_identifier_str oai:repisalud.isciii.es:20.500.12105/15379
network_acronym_str ES
network_name_str España
repository_id_str
spelling Fibrous Caps in Atherosclerosis Form by Notch-Dependent Mechanisms Common to Arterial Media Development.Martos-Rodríguez, Carlos JAlbarrán-Juárez, JuliánMorales-Cano, DanielCaballero, AinoaMacGrogan, Donalde la Pompa, Jose LuisCarramolino, LauraBentzon, Jacob FPlaque, AtheroscleroticActinsAnimalsArteriesAtherosclerosisCell LineageCells, CulturedDisease ProgressionFibrosisHumansImmunoglobulin J Recombination Signal Sequence-Binding ProteinJagged-1 ProteinMaleMice, Inbred C57BLMice, KnockoutMuscle, Smooth, VascularMyocytes, Smooth MusclePhenotypeRatsReceptors, NotchSignal TransductionTunica MediaAtheromatous fibrous caps are produced by smooth muscle cells (SMCs) that are recruited to the subendothelial space. We tested whether the recruitment mechanisms are the same as in embryonic artery development, which relies prominently on Notch signaling to form the subendothelial medial SMC layers. Notch elements were expressed in regions of fibrous cap in human and mouse plaques. To assess the causal role of Notch signaling in cap formation, we studied atherosclerosis in mice where the Notch pathway was inactivated in SMCs by conditional knockout of the essential effector transcription factor RBPJ (recombination signal-binding protein for immunoglobulin kappa J region). The recruitment of cap SMCs was significantly reduced without major effects on plaque size. Lineage tracing revealed the accumulation of SMC-derived plaque cells in the cap region was unaltered but that Notch-defective cells failed to re-acquire the SMC phenotype in the cap. Conversely, to analyze whether the loss of Notch signaling is required for SMC-derived cells to accumulate in atherogenesis, we studied atherosclerosis in mice with constitutive activation of Notch signaling in SMCs achieved by conditional expression of the Notch intracellular domain. Forced Notch signaling inhibited the ability of medial SMCs to contribute to plaque cells, including both cap SMCs and osteochondrogenic cells, and significantly reduced atherosclerosis development. Sequential loss and gain of Notch signaling is needed to build the cap SMC population. The shared mechanisms with embryonic arterial media assembly suggest that the cap forms as a neo-media that restores the connection between endothelium and subendothelial SMCs, transiently disrupted in early atherogenesis.American Heart Association (AHA)Ministerio de Ciencia e Innovación (España)Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)Novo Nordisk FoundationInstituto de Salud Carlos IIIFundación ProCNICMinisterio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)20222022-12-2220212021-09-0120212021-09-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/15379reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/153792026-06-12T12:43:37Z
dc.title.none.fl_str_mv Fibrous Caps in Atherosclerosis Form by Notch-Dependent Mechanisms Common to Arterial Media Development.
title Fibrous Caps in Atherosclerosis Form by Notch-Dependent Mechanisms Common to Arterial Media Development.
spellingShingle Fibrous Caps in Atherosclerosis Form by Notch-Dependent Mechanisms Common to Arterial Media Development.
Martos-Rodríguez, Carlos J
Plaque, Atherosclerotic
Actins
Animals
Arteries
Atherosclerosis
Cell Lineage
Cells, Cultured
Disease Progression
Fibrosis
Humans
Immunoglobulin J Recombination Signal Sequence-Binding Protein
Jagged-1 Protein
Male
Mice, Inbred C57BL
Mice, Knockout
Muscle, Smooth, Vascular
Myocytes, Smooth Muscle
Phenotype
Rats
Receptors, Notch
Signal Transduction
Tunica Media
title_short Fibrous Caps in Atherosclerosis Form by Notch-Dependent Mechanisms Common to Arterial Media Development.
title_full Fibrous Caps in Atherosclerosis Form by Notch-Dependent Mechanisms Common to Arterial Media Development.
title_fullStr Fibrous Caps in Atherosclerosis Form by Notch-Dependent Mechanisms Common to Arterial Media Development.
title_full_unstemmed Fibrous Caps in Atherosclerosis Form by Notch-Dependent Mechanisms Common to Arterial Media Development.
title_sort Fibrous Caps in Atherosclerosis Form by Notch-Dependent Mechanisms Common to Arterial Media Development.
dc.creator.none.fl_str_mv Martos-Rodríguez, Carlos J
Albarrán-Juárez, Julián
Morales-Cano, Daniel
Caballero, Ainoa
MacGrogan, Donal
de la Pompa, Jose Luis
Carramolino, Laura
Bentzon, Jacob F
author Martos-Rodríguez, Carlos J
author_facet Martos-Rodríguez, Carlos J
Albarrán-Juárez, Julián
Morales-Cano, Daniel
Caballero, Ainoa
MacGrogan, Donal
de la Pompa, Jose Luis
Carramolino, Laura
Bentzon, Jacob F
author_role author
author2 Albarrán-Juárez, Julián
Morales-Cano, Daniel
Caballero, Ainoa
MacGrogan, Donal
de la Pompa, Jose Luis
Carramolino, Laura
Bentzon, Jacob F
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia e Innovación (España)
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Novo Nordisk Foundation
Instituto de Salud Carlos III
Fundación ProCNIC
Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)
dc.subject.none.fl_str_mv Plaque, Atherosclerotic
Actins
Animals
Arteries
Atherosclerosis
Cell Lineage
Cells, Cultured
Disease Progression
Fibrosis
Humans
Immunoglobulin J Recombination Signal Sequence-Binding Protein
Jagged-1 Protein
Male
Mice, Inbred C57BL
Mice, Knockout
Muscle, Smooth, Vascular
Myocytes, Smooth Muscle
Phenotype
Rats
Receptors, Notch
Signal Transduction
Tunica Media
topic Plaque, Atherosclerotic
Actins
Animals
Arteries
Atherosclerosis
Cell Lineage
Cells, Cultured
Disease Progression
Fibrosis
Humans
Immunoglobulin J Recombination Signal Sequence-Binding Protein
Jagged-1 Protein
Male
Mice, Inbred C57BL
Mice, Knockout
Muscle, Smooth, Vascular
Myocytes, Smooth Muscle
Phenotype
Rats
Receptors, Notch
Signal Transduction
Tunica Media
description Atheromatous fibrous caps are produced by smooth muscle cells (SMCs) that are recruited to the subendothelial space. We tested whether the recruitment mechanisms are the same as in embryonic artery development, which relies prominently on Notch signaling to form the subendothelial medial SMC layers. Notch elements were expressed in regions of fibrous cap in human and mouse plaques. To assess the causal role of Notch signaling in cap formation, we studied atherosclerosis in mice where the Notch pathway was inactivated in SMCs by conditional knockout of the essential effector transcription factor RBPJ (recombination signal-binding protein for immunoglobulin kappa J region). The recruitment of cap SMCs was significantly reduced without major effects on plaque size. Lineage tracing revealed the accumulation of SMC-derived plaque cells in the cap region was unaltered but that Notch-defective cells failed to re-acquire the SMC phenotype in the cap. Conversely, to analyze whether the loss of Notch signaling is required for SMC-derived cells to accumulate in atherogenesis, we studied atherosclerosis in mice with constitutive activation of Notch signaling in SMCs achieved by conditional expression of the Notch intracellular domain. Forced Notch signaling inhibited the ability of medial SMCs to contribute to plaque cells, including both cap SMCs and osteochondrogenic cells, and significantly reduced atherosclerosis development. Sequential loss and gain of Notch signaling is needed to build the cap SMC population. The shared mechanisms with embryonic arterial media assembly suggest that the cap forms as a neo-media that restores the connection between endothelium and subendothelial SMCs, transiently disrupted in early atherogenesis.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021-09-01
2021
2021-09-01
2022
2022-12-22
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/15379
url http://hdl.handle.net/20.500.12105/15379
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv American Heart Association (AHA)
publisher.none.fl_str_mv American Heart Association (AHA)
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869425349688819713
score 15.812429

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