Stiffening Matrix Induces Age-Mediated Microvascular Phenotype Through Increased Cell Contractility and Destabilization of Adherens Junctions.
collagen
disease model
extracellular matrix mechanics
hydrogel
induced pluripotent stem cells
vascular aging
Journal
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
ISSN: 2198-3844
Titre abrégé: Adv Sci (Weinh)
Pays: Germany
ID NLM: 101664569
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
revised:
02
05
2022
received:
14
03
2022
pubmed:
4
6
2022
medline:
9
8
2022
entrez:
3
6
2022
Statut:
ppublish
Résumé
Aging is a major risk factor in microvascular dysfunction and disease development, but the underlying mechanism remains largely unknown. As a result, age-mediated changes in the mechanical properties of tissue collagen have gained interest as drivers of endothelial cell (EC) dysfunction. 3D culture models that mimic age-mediated changes in the microvasculature can facilitate mechanistic understanding. A fibrillar hydrogel capable of changing its stiffness after forming microvascular networks is established. This hydrogel model is used to form vascular networks from induced pluripotent stem cells under soft conditions that mimic young tissue mechanics. Then matrix stiffness is gradually increased, thus exposing the vascular networks to the aging-mimicry process in vitro. It is found that upon dynamic matrix stiffening, EC contractility is increased, resulting in the activation of focal adhesion kinase and subsequent dissociation of β-catenin from VE-Cadherin mediated adherens junctions, leading to the abruption of the vascular networks. Inhibiting cell contractility impedes the dissociation of β-catenin, thereby preventing the deconstruction of adherens junctions, thus partially rescuing the age-mediated vascular phenotype. The findings provide the first direct evidence of matrix's dynamic mechano-changes in compromising microvasculature with aging and highlight the importance of hydrogel systems to study tissue-level changes with aging in basic and translational studies.
Identifiants
pubmed: 35657074
doi: 10.1002/advs.202201483
pmc: PMC9353494
doi:
Substances chimiques
Hydrogels
0
beta Catenin
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2201483Subventions
Organisme : NCI NIH HHS
ID : U54 CA210173
Pays : United States
Organisme : National Science Foundation
ID : ECCS-2025064
Organisme : Air Force
ID : FA9550-20-1-0356
Organisme : NCI NIH HHS
ID : U54 CA210173-01
Pays : United States
Organisme : Translational Research Institute through NASA Cooperative
ID : NNX16AO69A
Organisme : Translational Research Institute through NASA Cooperative
ID : RAD0102
Organisme : Maryland Stem Cell Research Fund
ID : MSCRFF-5159
Organisme : NIGMS NIH HHS
ID : R01 GM134542
Pays : United States
Informations de copyright
© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.
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