Flow-dependent regulation of endothelial Tie2 by GATA3 in vivo

Intensive Care Medicine Experimental

Joerg Heineke¹  Klaus Stahl²  Thorben Pape³  Temitayo O. Idowu³  Valerie Etzrodt³  Hermann Haller³  Sascha David⁴ 

[1] Department of Cardiovascular Physiology, European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany;German Center for Cardiovascular Research (DZHK), Partner Site Heidelberg, Mannheim, Germany;Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany;Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany;Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany;Institute of Intensive Care Medicine, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland;

关键词: Vascular leakage;    Permeability;    Hypotension;    Shock;    Blood flow;    Capillary leakage;   

DOI  :  10.1186/s40635-021-00402-x

来源: Springer

【 摘 要 】

BackgroundReduced 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.ResultsTo 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-Gata3tm1-Jfz VE-Cadherin(PAC)-cerERT2) led to baseline Tie2 suppression inducing spontaneous vascular leak. On the contrary, the transient overexpression of GATA3 in the pulmonary endothelium (jet-PEI plasmid delivery platform) was sufficient to increase Tie2 at baseline and completely block its hypotension-induced acute drop. On the functional level, the Tie2 protection by GATA3 overexpression abrogated the development of pulmonary capillary leakage.ConclusionsThe 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.

【 授权许可】

CC BY