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Conditional deficiency of Rho‐associated kinases disrupts endothelial cell junctions and impairs respiratory function in adult mice

Authors :
Takahiro Akamine
Takeshi Terabayashi
Takako Sasaki
Riku Hayashi
Ichitaro Abe
Fumihiro Hirayama
Shin‐ichi Nureki
Masahito Ikawa
Haruhiko Miyata
Akinori Tokunaga
Takashi Kobayashi
Katsuhiro Hanada
Dean Thumkeo
Shuh Narumiya
Toshimasa Ishizaki
Source :
FEBS Open Bio, Vol 14, Iss 6, Pp 906-921 (2024)
Publication Year :
2024
Publisher :
Wiley, 2024.

Abstract

The Ras homology (Rho) family of GTPases serves various functions, including promotion of cell migration, adhesion, and transcription, through activation of effector molecule targets. One such pair of effectors, the Rho‐associated coiled‐coil kinases (ROCK1 and ROCK2), induce reorganization of actin cytoskeleton and focal adhesion through substrate phosphorylation. Studies on ROCK knockout mice have confirmed that ROCK proteins are essential for embryonic development, but their physiological functions in adult mice remain unknown. In this study, we aimed to examine the roles of ROCK1 and ROCK2 proteins in normal adult mice. Tamoxifen (TAM)‐inducible ROCK1 and ROCK2 single and double knockout mice (ROCK1flox/flox and/or ROCK2flox/flox;Ubc‐CreERT2) were generated and administered a 5‐day course of TAM. No deaths occurred in either of the single knockout strains, whereas all of the ROCK1/ROCK2 double conditional knockout mice (DcKO) had died by Day 11 following the TAM course. DcKO mice exhibited increased lung tissue vascular permeability, thickening of alveolar walls, and a decrease in percutaneous oxygen saturation compared with noninducible ROCK1/ROCK2 double‐floxed control mice. On Day 3 post‐TAM, there was a decrease in phalloidin staining in the lungs in DcKO mice. On Day 5 post‐TAM, immunohistochemical analysis also revealed reduced staining for vascular endothelial (VE)‐cadherin, β‐catenin, and p120‐catenin at cell–cell contact sites in vascular endothelial cells in DcKO mice. Additionally, VE‐cadherin/β‐catenin complexes were decreased in DcKO mice, indicating that ROCK proteins play a crucial role in maintaining lung function by regulating cell–cell adhesion.

Details

Language :
English
ISSN :
22115463
Volume :
14
Issue :
6
Database :
Directory of Open Access Journals
Journal :
FEBS Open Bio
Publication Type :
Academic Journal
Accession number :
edsdoj.55c8cc91eaf9494c8af4f125e026844e
Document Type :
article
Full Text :
https://doi.org/10.1002/2211-5463.13802