Abstract
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.
Highlights
Reduced endothelial Tie2 expression occurs in diverse experimental models of critical illness, and experimental Tie2 suppression is sufficient to increase spontaneous vascular permeability
The data suggest that the GATA Binding Protein 3 (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
Murine model of persistent hypotension To study the effect of low microcirculatory flow on endothelial Tie2 regulation in vivo in the absence of an inflammatory milieu, we developed a clonidine induced murine model of prolonged hypotension over 4 h
Summary
Reduced endothelial Tie expression occurs in diverse experimental models of critical illness, and experimental Tie suppression is sufficient to increase spontaneous vascular permeability. Looking for a common denominator among different critical illnesses that could drive the same Tie suppressive (thereby leak inducing) phenotype, we identified “circulatory shock” as a shared feature and postulated a flowdependency of Tie gene expression in a GATA3 dependent manner. Pulmonary Tie expression is rapidly suppressed in many experimental models of critical illness, such as sepsis, hemorrhagic shock, anthrax, malaria and even mesenteric ischemia [6,7,8]. Given that some endothelial genes are on the transcriptional level flow-regulated, we hypothesized that shock and accompanied decreased microvascular flow could count for acute changes in Tie transcription and associated vascular leak. Van Meurs et al have proposed such a mechanism in the context of hemorrhagic shock [5, 9]
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