Flow-dependent regulation of endothelial Tie2 by GATA3 in vivo.
Blood flow
Capillary leakage
Hypotension
Permeability
Shock
Vascular leakage
Journal
Intensive care medicine experimental
ISSN: 2197-425X
Titre abrégé: Intensive Care Med Exp
Pays: Germany
ID NLM: 101645149
Informations de publication
Date de publication:
02 Aug 2021
02 Aug 2021
Historique:
received:
09
04
2021
accepted:
24
06
2021
entrez:
2
8
2021
pubmed:
3
8
2021
medline:
3
8
2021
Statut:
epublish
Résumé
Reduced endothelial Tie2 expression occurs in diverse experimental models of critical illness, and experimental Tie2 suppression is sufficient to increase spontaneous vascular permeability. Looking for a common denominator among different critical illnesses that could drive the same Tie2 suppressive (thereby leak inducing) phenotype, we identified "circulatory shock" as a shared feature and postulated a flow-dependency of Tie2 gene expression in a GATA3 dependent manner. Here, we analyzed if this mechanism of flow-regulation of gene expression exists in vivo in the absence of inflammation. To experimentally mimic a shock-like situation, we developed a murine model of clonidine-induced hypotension by targeting a reduced mean arterial pressure (MAP) of approximately 50% over 4 h. We found that hypotension-induced reduction of flow in the absence of confounding disease factors (i.e., inflammation, injury, among others) is sufficient to suppress GATA3 and Tie2 transcription. Conditional endothelial-specific GATA3 knockdown (B6-Gata3 The data suggest that the GATA3-Tie2 signaling pathway might play a pivotal role in controlling vascular barrier function and that it is affected in diverse critical illnesses with shock as a consequence of a flow-regulated gene response. Targeting this novel mechanism might offer therapeutic opportunities to treat vascular leakage of diverse etiologies.
Sections du résumé
BACKGROUND
BACKGROUND
Reduced endothelial Tie2 expression occurs in diverse experimental models of critical illness, and experimental Tie2 suppression is sufficient to increase spontaneous vascular permeability. Looking for a common denominator among different critical illnesses that could drive the same Tie2 suppressive (thereby leak inducing) phenotype, we identified "circulatory shock" as a shared feature and postulated a flow-dependency of Tie2 gene expression in a GATA3 dependent manner. Here, we analyzed if this mechanism of flow-regulation of gene expression exists in vivo in the absence of inflammation.
RESULTS
RESULTS
To experimentally mimic a shock-like situation, we developed a murine model of clonidine-induced hypotension by targeting a reduced mean arterial pressure (MAP) of approximately 50% over 4 h. We found that hypotension-induced reduction of flow in the absence of confounding disease factors (i.e., inflammation, injury, among others) is sufficient to suppress GATA3 and Tie2 transcription. Conditional endothelial-specific GATA3 knockdown (B6-Gata3
CONCLUSIONS
CONCLUSIONS
The data suggest that the GATA3-Tie2 signaling pathway might play a pivotal role in controlling vascular barrier function and that it is affected in diverse critical illnesses with shock as a consequence of a flow-regulated gene response. Targeting this novel mechanism might offer therapeutic opportunities to treat vascular leakage of diverse etiologies.
Identifiants
pubmed: 34337671
doi: 10.1186/s40635-021-00402-x
pii: 10.1186/s40635-021-00402-x
pmc: PMC8326239
doi:
Types de publication
Journal Article
Langues
eng
Pagination
38Subventions
Organisme : Deutsche Forschungsgemeinschaft
ID : DA 1209/4-3
Informations de copyright
© 2021. The Author(s).
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