Differences in the Thoracic Aorta by Region and Sex in a Murine Model of Marfan Syndrome

Marfan syndrome (MFS) is a hereditary disorder of the connective tissue that causes life-threatening aortic aneurysm, which initiates at the aortic root and can progress into the ascending portion. However, analysis of ascending aorta reactivity in animal models of MFS has remained elusive. Epidemio...

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Autores: Jiménez Altayó, Francesc|||0000-0002-9034-2041, Siegert, Anna-Maria, Bonorino, Fabio, Meirelles, Thayna, Barberà, Laura|||0000-0002-0883-657X, Dantas, A. P.|||0000-0001-8514-4094, Vila Calsina, Elisabet|||0000-0001-8817-9399, Egea, Gustavo|||0000-0001-5242-150X
Formato: artículo
Fecha de publicación:2017
País:España
Recursos:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:186388
Acesso em linha:https://ddd.uab.cat/record/186388
https://dx.doi.org/urn:doi:10.3389/fphys.2017.00933
Access Level:acceso abierto
Palavra-chave:Marfan syndrome
Aortic aneurysm
Sex differences
Gender medicine
Ascending thoracic aorta contraction
Cyclooxygenase
Nitric oxide synthase
Elastin fragmentation
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spelling Differences in the Thoracic Aorta by Region and Sex in a Murine Model of Marfan SyndromeJiménez Altayó, Francesc|||0000-0002-9034-2041Siegert, Anna-MariaBonorino, FabioMeirelles, ThaynaBarberà, Laura|||0000-0002-0883-657XDantas, A. P.|||0000-0001-8514-4094Vila Calsina, Elisabet|||0000-0001-8817-9399Egea, Gustavo|||0000-0001-5242-150XMarfan syndromeAortic aneurysmSex differencesGender medicineAscending thoracic aorta contractionCyclooxygenaseNitric oxide synthaseElastin fragmentationMarfan syndrome (MFS) is a hereditary disorder of the connective tissue that causes life-threatening aortic aneurysm, which initiates at the aortic root and can progress into the ascending portion. However, analysis of ascending aorta reactivity in animal models of MFS has remained elusive. Epidemiologic evidence suggests that although MFS is equally prevalent in men and women, men are at a higher risk of aortic complications than non-pregnant women. Nevertheless, there is no experimental evidence to support this hypothesis. The aim of this study was to explore whether there are regional and sex differences in the thoracic aorta function of mice heterozygous for the fibrillin 1 (Fbn1) allele encoding a missense mutation (Fbn1 C1039G/+), the most common class of mutation in MFS. Ascending and descending thoracic aorta reactivity was evaluated by wire myography. Ascending aorta mRNA and protein levels, and elastic fiber integrity were assessed by qRT-PCR, Western blotting, and Verhoeff-Van Gieson histological staining, respectively. MFS differently altered reactivity in the ascending and descending thoracic aorta by either increasing or decreasing phenylephrine contractions, respectively. When mice were separated by sex, contractions to phenylephrine increased progressively from 3 to 6 months of age in MFS ascending aortas of males, whereas contractions in females were unchanged. Endothelium-dependent relaxation was unaltered in the MFS ascending aorta of either sex; an effect related to augmented endothelium-dependent hyperpolarization-type dilations. In MFS males, the non-selective cyclooxygenase (COX) inhibitor indomethacin prevented the MFS-induced enhancement of phenylephrine contractions linked to increased COX-2 expression. In MFS mice of both sexes, the non-selective nitric oxide synthase inhibitor L-NAME revealed negative feedback of nitric oxide on phenylephrine contractions, which was associated with upregulation of eNOS in females. Finally, MFS ascending aortas showed a greater number of elastic fiber breaks than the wild-types, and males exhibited more breaks than females. These results show regional and sex differences in Fbn1 C1039G/+ mice thoracic aorta contractility and aortic media injuries. The presence of more pronounced aortic alterations in male mice provides experimental evidence to support that male MFS patients are at increased risk of suffering aortic complications. 22017-01-0120172017-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/186388https://dx.doi.org/urn:doi:10.3389/fphys.2017.00933reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengMinisterio de Ciencia e Innovación https://doi.org/10.13039/501100004837 SAF2005-64136-RMinisterio de Economía y Competitividad https://doi.org/10.13039/501100003329 SAF2014-56111-RAgència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2014/SGR-574open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:1863882026-06-06T12:50:31Z
dc.title.none.fl_str_mv Differences in the Thoracic Aorta by Region and Sex in a Murine Model of Marfan Syndrome
title Differences in the Thoracic Aorta by Region and Sex in a Murine Model of Marfan Syndrome
spellingShingle Differences in the Thoracic Aorta by Region and Sex in a Murine Model of Marfan Syndrome
Jiménez Altayó, Francesc|||0000-0002-9034-2041
Marfan syndrome
Aortic aneurysm
Sex differences
Gender medicine
Ascending thoracic aorta contraction
Cyclooxygenase
Nitric oxide synthase
Elastin fragmentation
title_short Differences in the Thoracic Aorta by Region and Sex in a Murine Model of Marfan Syndrome
title_full Differences in the Thoracic Aorta by Region and Sex in a Murine Model of Marfan Syndrome
title_fullStr Differences in the Thoracic Aorta by Region and Sex in a Murine Model of Marfan Syndrome
title_full_unstemmed Differences in the Thoracic Aorta by Region and Sex in a Murine Model of Marfan Syndrome
title_sort Differences in the Thoracic Aorta by Region and Sex in a Murine Model of Marfan Syndrome
dc.creator.none.fl_str_mv Jiménez Altayó, Francesc|||0000-0002-9034-2041
Siegert, Anna-Maria
Bonorino, Fabio
Meirelles, Thayna
Barberà, Laura|||0000-0002-0883-657X
Dantas, A. P.|||0000-0001-8514-4094
Vila Calsina, Elisabet|||0000-0001-8817-9399
Egea, Gustavo|||0000-0001-5242-150X
author Jiménez Altayó, Francesc|||0000-0002-9034-2041
author_facet Jiménez Altayó, Francesc|||0000-0002-9034-2041
Siegert, Anna-Maria
Bonorino, Fabio
Meirelles, Thayna
Barberà, Laura|||0000-0002-0883-657X
Dantas, A. P.|||0000-0001-8514-4094
Vila Calsina, Elisabet|||0000-0001-8817-9399
Egea, Gustavo|||0000-0001-5242-150X
author_role author
author2 Siegert, Anna-Maria
Bonorino, Fabio
Meirelles, Thayna
Barberà, Laura|||0000-0002-0883-657X
Dantas, A. P.|||0000-0001-8514-4094
Vila Calsina, Elisabet|||0000-0001-8817-9399
Egea, Gustavo|||0000-0001-5242-150X
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Marfan syndrome
Aortic aneurysm
Sex differences
Gender medicine
Ascending thoracic aorta contraction
Cyclooxygenase
Nitric oxide synthase
Elastin fragmentation
topic Marfan syndrome
Aortic aneurysm
Sex differences
Gender medicine
Ascending thoracic aorta contraction
Cyclooxygenase
Nitric oxide synthase
Elastin fragmentation
description Marfan syndrome (MFS) is a hereditary disorder of the connective tissue that causes life-threatening aortic aneurysm, which initiates at the aortic root and can progress into the ascending portion. However, analysis of ascending aorta reactivity in animal models of MFS has remained elusive. Epidemiologic evidence suggests that although MFS is equally prevalent in men and women, men are at a higher risk of aortic complications than non-pregnant women. Nevertheless, there is no experimental evidence to support this hypothesis. The aim of this study was to explore whether there are regional and sex differences in the thoracic aorta function of mice heterozygous for the fibrillin 1 (Fbn1) allele encoding a missense mutation (Fbn1 C1039G/+), the most common class of mutation in MFS. Ascending and descending thoracic aorta reactivity was evaluated by wire myography. Ascending aorta mRNA and protein levels, and elastic fiber integrity were assessed by qRT-PCR, Western blotting, and Verhoeff-Van Gieson histological staining, respectively. MFS differently altered reactivity in the ascending and descending thoracic aorta by either increasing or decreasing phenylephrine contractions, respectively. When mice were separated by sex, contractions to phenylephrine increased progressively from 3 to 6 months of age in MFS ascending aortas of males, whereas contractions in females were unchanged. Endothelium-dependent relaxation was unaltered in the MFS ascending aorta of either sex; an effect related to augmented endothelium-dependent hyperpolarization-type dilations. In MFS males, the non-selective cyclooxygenase (COX) inhibitor indomethacin prevented the MFS-induced enhancement of phenylephrine contractions linked to increased COX-2 expression. In MFS mice of both sexes, the non-selective nitric oxide synthase inhibitor L-NAME revealed negative feedback of nitric oxide on phenylephrine contractions, which was associated with upregulation of eNOS in females. Finally, MFS ascending aortas showed a greater number of elastic fiber breaks than the wild-types, and males exhibited more breaks than females. These results show regional and sex differences in Fbn1 C1039G/+ mice thoracic aorta contractility and aortic media injuries. The presence of more pronounced aortic alterations in male mice provides experimental evidence to support that male MFS patients are at increased risk of suffering aortic complications.
publishDate 2017
dc.date.none.fl_str_mv 2
2017-01-01
2017
2017-01-01
dc.type.none.fl_str_mv 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 https://ddd.uab.cat/record/186388
https://dx.doi.org/urn:doi:10.3389/fphys.2017.00933
url https://ddd.uab.cat/record/186388
https://dx.doi.org/urn:doi:10.3389/fphys.2017.00933
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Ministerio de Ciencia e Innovación https://doi.org/10.13039/501100004837 SAF2005-64136-R
Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 SAF2014-56111-R
Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2014/SGR-574
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://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
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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