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Sepsis downregulates aortic Notch signaling to produce vascular hyporeactivity in mice

Inhibition of Notch signaling in macrophages is known to reduce inflammation, however, its role in regulating vascular hyporeactivity in sepsis is unknown. Thus we aimed to evaluate the effect of sepsis on vascular Notch signaling. Polymicrobial sepsis was induced by caecal ligation and puncture (CL...

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Autores principales: Singh, Vandana, Akash, Raut, Chaudhary, Gaurav, Singh, Rajneesh, Choudhury, Soumen, Shukla, Amit, Prabhu, Shyama N., Gangwar, Neeraj, Garg, Satish K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8861011/
https://www.ncbi.nlm.nih.gov/pubmed/35190630
http://dx.doi.org/10.1038/s41598-022-06949-3
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author Singh, Vandana
Akash, Raut
Chaudhary, Gaurav
Singh, Rajneesh
Choudhury, Soumen
Shukla, Amit
Prabhu, Shyama N.
Gangwar, Neeraj
Garg, Satish K.
author_facet Singh, Vandana
Akash, Raut
Chaudhary, Gaurav
Singh, Rajneesh
Choudhury, Soumen
Shukla, Amit
Prabhu, Shyama N.
Gangwar, Neeraj
Garg, Satish K.
author_sort Singh, Vandana
collection PubMed
description Inhibition of Notch signaling in macrophages is known to reduce inflammation, however, its role in regulating vascular hyporeactivity in sepsis is unknown. Thus we aimed to evaluate the effect of sepsis on vascular Notch signaling. Polymicrobial sepsis was induced by caecal ligation and puncture (CLP) in mice. mRNA expressions of Notch receptors (Notch1,3) and ligands (Jag1, Dll4), and downstream effector genes (Hey1, MLCK, MYPT1) were assessed by RT-qPCR. Protein level of activated Notch (NICD) was assessed by Western blot and immuno-histochemistry. Isometric tension in isolated aortic rings was measured by wire myography.CLP down-regulated aortic expression of Notch3, Jag1 and Dll4 as compared to control mice. Additionally, the protein level of NICD was found to be lesser in aortic tissue sections from CLP mice. Expression of Hey1 and MLCK were attenuated whereas MYPT1 expression was increased in septic mouse aorta. DAPT pretreatment did not improve CLP-induced vascular hyporeactivity to NA, CaCl(2) and high K(+) (80 mM), rather significantly attenuated the aortic response to these vasoconstrictors in control mice. Treatment with 1400 W reversed attenuated Notch3 (but not Jag1 and MLCK) expression in septic mouse aorta. In conclusion, sepsis significantly attenuated the Notch (especially Notch3) signaling in mouse aorta along with reduction in contractile gene expression and vasoconstriction response. Further, iNOS/NO pathway was involved in sepsis-induced down-regulation of Notch3 receptor. Thus systemic inhibition of Notch signaling during sepsis may have serious impact on sepsis-induced vascular hyporeactivity.
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spelling pubmed-88610112022-02-22 Sepsis downregulates aortic Notch signaling to produce vascular hyporeactivity in mice Singh, Vandana Akash, Raut Chaudhary, Gaurav Singh, Rajneesh Choudhury, Soumen Shukla, Amit Prabhu, Shyama N. Gangwar, Neeraj Garg, Satish K. Sci Rep Article Inhibition of Notch signaling in macrophages is known to reduce inflammation, however, its role in regulating vascular hyporeactivity in sepsis is unknown. Thus we aimed to evaluate the effect of sepsis on vascular Notch signaling. Polymicrobial sepsis was induced by caecal ligation and puncture (CLP) in mice. mRNA expressions of Notch receptors (Notch1,3) and ligands (Jag1, Dll4), and downstream effector genes (Hey1, MLCK, MYPT1) were assessed by RT-qPCR. Protein level of activated Notch (NICD) was assessed by Western blot and immuno-histochemistry. Isometric tension in isolated aortic rings was measured by wire myography.CLP down-regulated aortic expression of Notch3, Jag1 and Dll4 as compared to control mice. Additionally, the protein level of NICD was found to be lesser in aortic tissue sections from CLP mice. Expression of Hey1 and MLCK were attenuated whereas MYPT1 expression was increased in septic mouse aorta. DAPT pretreatment did not improve CLP-induced vascular hyporeactivity to NA, CaCl(2) and high K(+) (80 mM), rather significantly attenuated the aortic response to these vasoconstrictors in control mice. Treatment with 1400 W reversed attenuated Notch3 (but not Jag1 and MLCK) expression in septic mouse aorta. In conclusion, sepsis significantly attenuated the Notch (especially Notch3) signaling in mouse aorta along with reduction in contractile gene expression and vasoconstriction response. Further, iNOS/NO pathway was involved in sepsis-induced down-regulation of Notch3 receptor. Thus systemic inhibition of Notch signaling during sepsis may have serious impact on sepsis-induced vascular hyporeactivity. Nature Publishing Group UK 2022-02-21 /pmc/articles/PMC8861011/ /pubmed/35190630 http://dx.doi.org/10.1038/s41598-022-06949-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Singh, Vandana
Akash, Raut
Chaudhary, Gaurav
Singh, Rajneesh
Choudhury, Soumen
Shukla, Amit
Prabhu, Shyama N.
Gangwar, Neeraj
Garg, Satish K.
Sepsis downregulates aortic Notch signaling to produce vascular hyporeactivity in mice
title Sepsis downregulates aortic Notch signaling to produce vascular hyporeactivity in mice
title_full Sepsis downregulates aortic Notch signaling to produce vascular hyporeactivity in mice
title_fullStr Sepsis downregulates aortic Notch signaling to produce vascular hyporeactivity in mice
title_full_unstemmed Sepsis downregulates aortic Notch signaling to produce vascular hyporeactivity in mice
title_short Sepsis downregulates aortic Notch signaling to produce vascular hyporeactivity in mice
title_sort sepsis downregulates aortic notch signaling to produce vascular hyporeactivity in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8861011/
https://www.ncbi.nlm.nih.gov/pubmed/35190630
http://dx.doi.org/10.1038/s41598-022-06949-3
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