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The flow dependency of Tie2 expression in endotoxemia
Kurniati N.F.d, Jongman R.M., Vom Hagen F., Spokes K.C.c, Moser J., Regan E.R.c, Krenning G., Moonen J.-R.A.J., Harmsen M.C., Struys M.M.R.F., Hammes H.-P., Zijlstra J.G., Aird W.C.c, Heeringa P., Molema G., Van Meurs M.
a Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Netherlands
b 5th Medical Clinic, University-Clinic Mannheim, University of Heidelberg, Germany
c Department of Medicine, Center for Vascular Biology Research, Harvard Medical School, United States
d School of Pharmacy, Institute of Technology Bandung, Indonesia
[vc_row][vc_column][vc_row_inner][vc_column_inner][vc_separator css=”.vc_custom_1624529070653{padding-top: 30px !important;padding-bottom: 30px !important;}”][/vc_column_inner][/vc_row_inner][vc_row_inner layout=”boxed”][vc_column_inner width=”3/4″ css=”.vc_custom_1624695412187{border-right-width: 1px !important;border-right-color: #dddddd !important;border-right-style: solid !important;border-radius: 1px !important;}”][vc_empty_space][megatron_heading title=”Abstract” size=”size-sm” text_align=”text-left”][vc_column_text]Rationale: Tie2 is predominantly expressed by endothelial cells and is involved in vascular integrity control during sepsis. Changes in Tie2 expression during sepsis development may contribute to microvascular dysfunction. Understanding the kinetics and molecular basis of these changes may assist in the development of therapeutic intervention to counteract microvascular dysfunction. Objective: To investigate the molecular mechanisms underlying the changes in Tie2 expression upon lipopolysaccharide (LPS) challenge. Methods and results: Studies were performed in LPS and pro-inflammatory cytokine challenged mice as well as in mice subjected to hemorrhagic shock, primary endothelial cells were used for in vitro experiments in static and flow conditions. Eight hours after LPS challenge, Tie2 mRNA loss was observed in all major organs, while loss of Tie2 protein was predominantly observed in lungs and kidneys, in the capillaries. A similar loss could be induced by secondary cytokines TNF-α and IL-1β. Ang2 protein administration did not affect Tie2 protein expression nor was Tie2 protein rescued in LPS-challenged Ang2-deficient mice, excluding a major role for Ang2 in Tie2 down regulation. In vitro, endothelial loss of Tie2 was observed upon lowering of shear stress, not upon LPS and TNF-α stimulation, suggesting that inflammation related haemodynamic changes play a major role in loss of Tie2 in vivo, as also hemorrhagic shock induced Tie2 mRNA loss. In vitro, this loss was partially counteracted by pre-incubation with a pharmacologically NF-kB inhibitor (BAY11-7082), an effect further substantiated in vivo by pre-treatment of mice with the NF-kB inhibitor prior to the inflammatory challenge. Conclusions: Microvascular bed specific loss of Tie2 mRNA and protein in vivo upon LPS, TNFα, IL-1β challenge, as well as in response to hemorrhagic shock, is likely an indirect effect caused by a change in endothelial shear stress. This loss of Tie2 mRNA, but not Tie2 protein, induced by TNFα exposure was shown to be controlled by NF-kB signaling. Drugs aiming at restoring vascular integrity in sepsis could focus on preventing the Tie2 loss. © 2013 Springer-Verlag Berlin Heidelberg and ESICM.[/vc_column_text][vc_empty_space][vc_separator css=”.vc_custom_1624528584150{padding-top: 25px !important;padding-bottom: 25px !important;}”][vc_empty_space][megatron_heading title=”Author keywords” size=”size-sm” text_align=”text-left”][vc_column_text][/vc_column_text][vc_empty_space][vc_separator css=”.vc_custom_1624528584150{padding-top: 25px !important;padding-bottom: 25px !important;}”][vc_empty_space][megatron_heading title=”Indexed keywords” size=”size-sm” text_align=”text-left”][vc_column_text]Endothelial Tie2,Flow,In vitro,In vivo,Lipopolysaccharide[/vc_column_text][vc_empty_space][vc_separator css=”.vc_custom_1624528584150{padding-top: 25px !important;padding-bottom: 25px !important;}”][vc_empty_space][megatron_heading title=”Funding details” size=”size-sm” text_align=”text-left”][vc_column_text]Acknowledgments We like to thank Peter J. Zwiers, Henk E. Moorlag, Martin Schipper, Martin C. Houwertjes and Nynke Dragt (UMCG, Groningen), and P.P.M.F.A. Mulder (School of Pharmacy, University of Groningen) for excellent technical assistance and Kayla Glatman for English editing. We also would like to thank Dr. Sanjabi Bahram (UMCG, Groningen) for performing the micro-array experiments and Dr. Simon C. Satchell for the generous gift of ciGEnC. This study was partially financially supported by a grant from the Genzyme Renal Innovation Program (GM) and ZONMW (VIDI grant-PH).[/vc_column_text][vc_empty_space][vc_separator css=”.vc_custom_1624528584150{padding-top: 25px !important;padding-bottom: 25px !important;}”][vc_empty_space][megatron_heading title=”DOI” size=”size-sm” text_align=”text-left”][vc_column_text]https://doi.org/10.1007/s00134-013-2899-7[/vc_column_text][/vc_column_inner][vc_column_inner width=”1/4″][vc_column_text]Widget Plumx[/vc_column_text][/vc_column_inner][/vc_row_inner][/vc_column][/vc_row][vc_row][vc_column][vc_separator css=”.vc_custom_1624528584150{padding-top: 25px !important;padding-bottom: 25px !important;}”][/vc_column][/vc_row]