Regulation of vascular smooth muscle cell proliferation by the protease MT4-MMP in developmental and adult arteriogenesis

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 12-03-2021

Detalles Bibliográficos
Autor: Sahún Español, Álvaro
Tipo de recurso: tesis doctoral
Fecha de publicación:2021
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/695933
Acceso en línea:http://hdl.handle.net/10486/695933
Access Level:acceso abierto
Palabra clave:Enfermedades vasculares isquémicas - Tratamiento - Flujo sanguíneo - Tesis doctorales
Biología y Biomedicina / Biología
id ES_b74245fd2a57009f68596be3cc3fbc81
oai_identifier_str oai:repositorio.uam.es:10486/695933
network_acronym_str ES
network_name_str España
repository_id_str
spelling Regulation of vascular smooth muscle cell proliferation by the protease MT4-MMP in developmental and adult arteriogenesisRegulación de la proliferación de células de musculo liso vascular por la proteasa MT4-MMP en arteriogenesis durante el desarrollo y en adultoSahún Español, ÁlvaroEnfermedades vasculares isquémicas - Tratamiento - Flujo sanguíneo - Tesis doctoralesBiología y Biomedicina / BiologíaTesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 12-03-2021Esta tesis tiene embargado el acceso al texto completo hasta el 12-09-2022Ischemic vascular diseases are characterized by the lack of blood flow, usually after arterial occlusion, leading to hypoxia and irreversible tissue damage. Currently considered a major clinical burden, new therapeutical strategies to confront them are highly needed. A detailed understanding of the formation of functional arterioles, both during physiological development (arterial morphogenesis) and in pathological adult settings (arteriogenesis), may pave the way for the efficient development of such therapies. Although proliferation of vascular smooth muscle cells (VSMCs) is crucial for arterioles to be formed, details about its regulation are still lacking. Our group previously showed that absence of MT4-MMP, a matrix metalloprotease highly expressed in VSMCs, led to enhanced VSMC proliferation in neonatal aorta. Hence, we investigated whether MT4-MMP genetic elimination may boost artery formation through an increase in VSMC proliferation both during physiological development (coronary arterial development) and in a pathological adult scenario (hindlimb ischemia). In the developing heart, we observed MT4-MMP expressed in epicardial-derived cells during early embryonic development and in the coronary VSMCs in postnatal stages (P8 neonates). Deletion of MT4-MMP resulted in enhanced VSMC proliferation and increased number of arterioles both in the developing postnatal heart and after cryoinjury performed in P1 neonates. In the adult setting, MT4-MMP expression was also detected in arterial VSMCs of the superficial adductor muscle. Both global and VSMC-specific MT4-MMP deletion led to enhanced blood flow recovery in the superficial adductor muscle, correlating with increased abundance of large remodeled arterioles, after permanent femoral artery ligation. In addition, in VSMC-specific MT4-MMP-deficient mice, the remodeled arterioles contained higher proportion of proliferating VSMCs. We investigated the underlying molecular mechanisms in vitro in VSMCs isolated from the aortic vessel wall. We first observed that MT4-MMP-deficient VSMCs presented a constitutive increased activation of the p38 MAPK that led to enhanced proliferation of VSMCs upon PDGF-BB stimulation. Moreover, this augmented basal p38 MAPK activation upregulated mitophagy flux in MT4-MMP-null VSMCs. Our findings point to MT4-MMP as a negative modulator of VSMC proliferation both during development and after hindlimb ischemia-triggered arteriogenesis. Specifically, MT4-MMP deletion provides an additional control of mitophagy through a p38-dependent pathway in VSMCs, an scenario that primes VSMCs and enables them to mount a boosted proliferative response increasing artery formation and ameliorating blood flow recovery upon hindlimb ischemiaGarcía Arroyo, AliciaDepartamento de BioquímicaFacultad de MedicinaCentro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)20212021-03-12doctoral thesishttp://purl.org/coar/resource_type/c_db06NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/doctoralThesisapplication/pdfhttp://hdl.handle.net/10486/695933reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/6959332026-06-23T12:46:27Z
dc.title.none.fl_str_mv Regulation of vascular smooth muscle cell proliferation by the protease MT4-MMP in developmental and adult arteriogenesis
Regulación de la proliferación de células de musculo liso vascular por la proteasa MT4-MMP en arteriogenesis durante el desarrollo y en adulto
title Regulation of vascular smooth muscle cell proliferation by the protease MT4-MMP in developmental and adult arteriogenesis
spellingShingle Regulation of vascular smooth muscle cell proliferation by the protease MT4-MMP in developmental and adult arteriogenesis
Sahún Español, Álvaro
Enfermedades vasculares isquémicas - Tratamiento - Flujo sanguíneo - Tesis doctorales
Biología y Biomedicina / Biología
title_short Regulation of vascular smooth muscle cell proliferation by the protease MT4-MMP in developmental and adult arteriogenesis
title_full Regulation of vascular smooth muscle cell proliferation by the protease MT4-MMP in developmental and adult arteriogenesis
title_fullStr Regulation of vascular smooth muscle cell proliferation by the protease MT4-MMP in developmental and adult arteriogenesis
title_full_unstemmed Regulation of vascular smooth muscle cell proliferation by the protease MT4-MMP in developmental and adult arteriogenesis
title_sort Regulation of vascular smooth muscle cell proliferation by the protease MT4-MMP in developmental and adult arteriogenesis
dc.creator.none.fl_str_mv Sahún Español, Álvaro
author Sahún Español, Álvaro
author_facet Sahún Español, Álvaro
author_role author
dc.contributor.none.fl_str_mv García Arroyo, Alicia
Departamento de Bioquímica
Facultad de Medicina
Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
dc.subject.none.fl_str_mv Enfermedades vasculares isquémicas - Tratamiento - Flujo sanguíneo - Tesis doctorales
Biología y Biomedicina / Biología
topic Enfermedades vasculares isquémicas - Tratamiento - Flujo sanguíneo - Tesis doctorales
Biología y Biomedicina / Biología
description Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 12-03-2021
publishDate 2021
dc.date.none.fl_str_mv 2021
2021-03-12
dc.type.none.fl_str_mv doctoral thesis
http://purl.org/coar/resource_type/c_db06
NA
http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv info:eu-repo/semantics/doctoralThesis
format doctoralThesis
dc.identifier.none.fl_str_mv http://hdl.handle.net/10486/695933
url http://hdl.handle.net/10486/695933
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
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
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869417514413326336
score 15,301629

Similares en LA Referencia