Genetic dissection of the Vav2-Rac1 signaling axis in vascular smooth muscle cells

Autores
Fabbiano, Salvatore; Menacho Márquez, Mauricio Ariel; Sevilla, María A.; Albarrán Juárez, Julián; Zheng, Yi; Offermanns, Stefan; Montero, María J.; Bustelo, Xosé R.
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Vascular smooth muscle cells (vSMCs) are key in the regulation of blood pressure and the engagement of vascular pathologies, such as hypertension, arterial remodeling, and neointima formation. The role of the Rac1 GTPase in these cells remains poorly characterized. To clarify this issue, we have utilized genetically engineered mice to manipulate the signaling output of Rac1 in these cells at will using inducible, Cre-loxP-mediated DNA recombination techniques. Here, we show that the expression of an active version of the Rac1 activator Vav2 exclusively in vSMCs leads to hypotension as well as the elimination of the hypertension induced by the systemic loss of wild-type Vav2. Conversely, the specific depletion of Rac1 in vSMCs causes defective nitric oxide vasodilation responses and hypertension. Rac1, but not Vav2, also is important for neointima formation but not for hypertension-driven vascular remodeling. These animals also have allowed us to dismiss etiological connections between hypertension and metabolic disease and, most importantly, identify pathophysiological programs that cooperate in the development and consolidation of hypertensive states caused by local vascular tone dysfunctions. Finally, our results suggest that the therapeutic inhibition of Rac1 will be associated with extensive cardiovascular system-related side effects and identify pharmacological avenues to circumvent them.
Fil: Fabbiano, Salvatore. Universidad de Salamanca; España
Fil: Menacho Márquez, Mauricio Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad de Salamanca; España
Fil: Sevilla, María A.. Universidad de Salamanca; España
Fil: Albarrán Juárez, Julián. Max-planck-instituts Für Herz- Und Lungenforschung; Alemania
Fil: Zheng, Yi. Cincinnati Children's Hospital Research Foundation; Estados Unidos
Fil: Offermanns, Stefan. Max-planck-instituts Für Herz- Und Lungenforschung; Alemania
Fil: Montero, María J.. Universidad de Salamanca; España
Fil: Bustelo, Xosé R.. Universidad de Salamanca; España
Materia
Rac1
Vav
GTPases
Signaling
vascular smooth muscle
Hypertension
Blood pressure
Nitric oxide, animal models
Nitric oxide
Animal models
Phosphodiesterase 5
Diabetes
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/95254
Acceder
id CONICETDig_2487aa0f2a120e8ee1ee447e80e305e8
oai_identifier_str oai:ri.conicet.gov.ar:11336/95254
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Genetic dissection of the Vav2-Rac1 signaling axis in vascular smooth muscle cellsFabbiano, SalvatoreMenacho Márquez, Mauricio ArielSevilla, María A.Albarrán Juárez, JuliánZheng, YiOffermanns, StefanMontero, María J.Bustelo, Xosé R.Rac1VavGTPasesSignalingvascular smooth muscleHypertensionBlood pressureNitric oxide, animal modelsNitric oxideAnimal modelsPhosphodiesterase 5Diabeteshttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Vascular smooth muscle cells (vSMCs) are key in the regulation of blood pressure and the engagement of vascular pathologies, such as hypertension, arterial remodeling, and neointima formation. The role of the Rac1 GTPase in these cells remains poorly characterized. To clarify this issue, we have utilized genetically engineered mice to manipulate the signaling output of Rac1 in these cells at will using inducible, Cre-loxP-mediated DNA recombination techniques. Here, we show that the expression of an active version of the Rac1 activator Vav2 exclusively in vSMCs leads to hypotension as well as the elimination of the hypertension induced by the systemic loss of wild-type Vav2. Conversely, the specific depletion of Rac1 in vSMCs causes defective nitric oxide vasodilation responses and hypertension. Rac1, but not Vav2, also is important for neointima formation but not for hypertension-driven vascular remodeling. These animals also have allowed us to dismiss etiological connections between hypertension and metabolic disease and, most importantly, identify pathophysiological programs that cooperate in the development and consolidation of hypertensive states caused by local vascular tone dysfunctions. Finally, our results suggest that the therapeutic inhibition of Rac1 will be associated with extensive cardiovascular system-related side effects and identify pharmacological avenues to circumvent them.Fil: Fabbiano, Salvatore. Universidad de Salamanca; EspañaFil: Menacho Márquez, Mauricio Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad de Salamanca; EspañaFil: Sevilla, María A.. Universidad de Salamanca; EspañaFil: Albarrán Juárez, Julián. Max-planck-instituts Für Herz- Und Lungenforschung; AlemaniaFil: Zheng, Yi. Cincinnati Children's Hospital Research Foundation; Estados UnidosFil: Offermanns, Stefan. Max-planck-instituts Für Herz- Und Lungenforschung; AlemaniaFil: Montero, María J.. Universidad de Salamanca; EspañaFil: Bustelo, Xosé R.. Universidad de Salamanca; EspañaAmerican Society for Microbiology2014-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/95254Fabbiano, Salvatore; Menacho Márquez, Mauricio Ariel; Sevilla, María A.; Albarrán Juárez, Julián; Zheng, Yi; et al.; Genetic dissection of the Vav2-Rac1 signaling axis in vascular smooth muscle cells; American Society for Microbiology; Molecular and Cellular Biology; 34; 24; 10-2014; 4404-44190270-7306CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://journals.asm.org/doi/10.1128/MCB.01066-14info:eu-repo/semantics/altIdentifier/doi/10.1128/MCB.01066-14info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:35:58Zoai:ri.conicet.gov.ar:11336/95254instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:35:58.97CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Genetic dissection of the Vav2-Rac1 signaling axis in vascular smooth muscle cells
title Genetic dissection of the Vav2-Rac1 signaling axis in vascular smooth muscle cells
spellingShingle Genetic dissection of the Vav2-Rac1 signaling axis in vascular smooth muscle cells
Fabbiano, Salvatore
Rac1
Vav
GTPases
Signaling
vascular smooth muscle
Hypertension
Blood pressure
Nitric oxide, animal models
Nitric oxide
Animal models
Phosphodiesterase 5
Diabetes
title_short Genetic dissection of the Vav2-Rac1 signaling axis in vascular smooth muscle cells
title_full Genetic dissection of the Vav2-Rac1 signaling axis in vascular smooth muscle cells
title_fullStr Genetic dissection of the Vav2-Rac1 signaling axis in vascular smooth muscle cells
title_full_unstemmed Genetic dissection of the Vav2-Rac1 signaling axis in vascular smooth muscle cells
title_sort Genetic dissection of the Vav2-Rac1 signaling axis in vascular smooth muscle cells
dc.creator.none.fl_str_mv Fabbiano, Salvatore
Menacho Márquez, Mauricio Ariel
Sevilla, María A.
Albarrán Juárez, Julián
Zheng, Yi
Offermanns, Stefan
Montero, María J.
Bustelo, Xosé R.
author Fabbiano, Salvatore
author_facet Fabbiano, Salvatore
Menacho Márquez, Mauricio Ariel
Sevilla, María A.
Albarrán Juárez, Julián
Zheng, Yi
Offermanns, Stefan
Montero, María J.
Bustelo, Xosé R.
author_role author
author2 Menacho Márquez, Mauricio Ariel
Sevilla, María A.
Albarrán Juárez, Julián
Zheng, Yi
Offermanns, Stefan
Montero, María J.
Bustelo, Xosé R.
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Rac1
Vav
GTPases
Signaling
vascular smooth muscle
Hypertension
Blood pressure
Nitric oxide, animal models
Nitric oxide
Animal models
Phosphodiesterase 5
Diabetes
topic Rac1
Vav
GTPases
Signaling
vascular smooth muscle
Hypertension
Blood pressure
Nitric oxide, animal models
Nitric oxide
Animal models
Phosphodiesterase 5
Diabetes
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Vascular smooth muscle cells (vSMCs) are key in the regulation of blood pressure and the engagement of vascular pathologies, such as hypertension, arterial remodeling, and neointima formation. The role of the Rac1 GTPase in these cells remains poorly characterized. To clarify this issue, we have utilized genetically engineered mice to manipulate the signaling output of Rac1 in these cells at will using inducible, Cre-loxP-mediated DNA recombination techniques. Here, we show that the expression of an active version of the Rac1 activator Vav2 exclusively in vSMCs leads to hypotension as well as the elimination of the hypertension induced by the systemic loss of wild-type Vav2. Conversely, the specific depletion of Rac1 in vSMCs causes defective nitric oxide vasodilation responses and hypertension. Rac1, but not Vav2, also is important for neointima formation but not for hypertension-driven vascular remodeling. These animals also have allowed us to dismiss etiological connections between hypertension and metabolic disease and, most importantly, identify pathophysiological programs that cooperate in the development and consolidation of hypertensive states caused by local vascular tone dysfunctions. Finally, our results suggest that the therapeutic inhibition of Rac1 will be associated with extensive cardiovascular system-related side effects and identify pharmacological avenues to circumvent them.
Fil: Fabbiano, Salvatore. Universidad de Salamanca; España
Fil: Menacho Márquez, Mauricio Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad de Salamanca; España
Fil: Sevilla, María A.. Universidad de Salamanca; España
Fil: Albarrán Juárez, Julián. Max-planck-instituts Für Herz- Und Lungenforschung; Alemania
Fil: Zheng, Yi. Cincinnati Children's Hospital Research Foundation; Estados Unidos
Fil: Offermanns, Stefan. Max-planck-instituts Für Herz- Und Lungenforschung; Alemania
Fil: Montero, María J.. Universidad de Salamanca; España
Fil: Bustelo, Xosé R.. Universidad de Salamanca; España
description Vascular smooth muscle cells (vSMCs) are key in the regulation of blood pressure and the engagement of vascular pathologies, such as hypertension, arterial remodeling, and neointima formation. The role of the Rac1 GTPase in these cells remains poorly characterized. To clarify this issue, we have utilized genetically engineered mice to manipulate the signaling output of Rac1 in these cells at will using inducible, Cre-loxP-mediated DNA recombination techniques. Here, we show that the expression of an active version of the Rac1 activator Vav2 exclusively in vSMCs leads to hypotension as well as the elimination of the hypertension induced by the systemic loss of wild-type Vav2. Conversely, the specific depletion of Rac1 in vSMCs causes defective nitric oxide vasodilation responses and hypertension. Rac1, but not Vav2, also is important for neointima formation but not for hypertension-driven vascular remodeling. These animals also have allowed us to dismiss etiological connections between hypertension and metabolic disease and, most importantly, identify pathophysiological programs that cooperate in the development and consolidation of hypertensive states caused by local vascular tone dysfunctions. Finally, our results suggest that the therapeutic inhibition of Rac1 will be associated with extensive cardiovascular system-related side effects and identify pharmacological avenues to circumvent them.
publishDate 2014
dc.date.none.fl_str_mv 2014-10
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/95254
Fabbiano, Salvatore; Menacho Márquez, Mauricio Ariel; Sevilla, María A.; Albarrán Juárez, Julián; Zheng, Yi; et al.; Genetic dissection of the Vav2-Rac1 signaling axis in vascular smooth muscle cells; American Society for Microbiology; Molecular and Cellular Biology; 34; 24; 10-2014; 4404-4419
0270-7306
CONICET Digital
CONICET
url http://hdl.handle.net/11336/95254
identifier_str_mv Fabbiano, Salvatore; Menacho Márquez, Mauricio Ariel; Sevilla, María A.; Albarrán Juárez, Julián; Zheng, Yi; et al.; Genetic dissection of the Vav2-Rac1 signaling axis in vascular smooth muscle cells; American Society for Microbiology; Molecular and Cellular Biology; 34; 24; 10-2014; 4404-4419
0270-7306
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://journals.asm.org/doi/10.1128/MCB.01066-14
info:eu-repo/semantics/altIdentifier/doi/10.1128/MCB.01066-14
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society for Microbiology
publisher.none.fl_str_mv American Society for Microbiology
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1846781998169849856
score 12.982451

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