Cargando…

Female sex protects against renal edema, but not lung edema, in mice with partial deletion of the endothelial barrier regulator Tie2 compared to male sex

BACKGROUND: The endothelial angiopoietin/Tie2 system is an important regulator of endothelial permeability and targeting Tie2 reduces hemorrhagic shock-induced organ edema in males. However, sexual dimorphism of the endothelium has not been taken into account. This study investigated whether there a...

Descripción completa

Detalles Bibliográficos
Autores principales: van Leeuwen, Anoek L. I., Beijer, Elise, Ibelings, Roselique, Dekker, Nicole A. M., van der Steen, Marjolein R. A., Roelofs, Joris J. T. H., van Meurs, Matijs, Molema, Grietje, van den Brom, Charissa E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10653528/
https://www.ncbi.nlm.nih.gov/pubmed/37972011
http://dx.doi.org/10.1371/journal.pone.0293673
_version_ 1785147796862533632
author van Leeuwen, Anoek L. I.
Beijer, Elise
Ibelings, Roselique
Dekker, Nicole A. M.
van der Steen, Marjolein R. A.
Roelofs, Joris J. T. H.
van Meurs, Matijs
Molema, Grietje
van den Brom, Charissa E.
author_facet van Leeuwen, Anoek L. I.
Beijer, Elise
Ibelings, Roselique
Dekker, Nicole A. M.
van der Steen, Marjolein R. A.
Roelofs, Joris J. T. H.
van Meurs, Matijs
Molema, Grietje
van den Brom, Charissa E.
author_sort van Leeuwen, Anoek L. I.
collection PubMed
description BACKGROUND: The endothelial angiopoietin/Tie2 system is an important regulator of endothelial permeability and targeting Tie2 reduces hemorrhagic shock-induced organ edema in males. However, sexual dimorphism of the endothelium has not been taken into account. This study investigated whether there are sex-related differences in the endothelial angiopoietin/Tie2 system and edema formation. METHODS: Adult male and female heterozygous Tie2 knockout mice (Tie2(+/−)) and wild-type controls (Tie2(+/+)) were included (n = 9 per group). Renal and pulmonary injury were determined by wet/dry weight ratio and H&E staining of tissue sections. Protein levels were studied in plasma by ELISA and pulmonary and renal mRNA expression levels by RT-qPCR. RESULTS: In Tie2(+/+) mice, females had higher circulating angiopoietin-2 (138%, p<0.05) compared to males. Gene expression of angiopoietin-1 (204%, p<0.01), angiopoietin-2 (542%, p<0.001) were higher in females compared to males in kidneys, but not in lungs. Gene expression of Tie2, Tie1 and VE-PTP were similar between males and females in both organs. Renal and pulmonary wet/dry weight ratio did not differ between Tie2(+/+) females and males. Tie2(+/+) females had lower circulating NGAL (41%, p<0.01) compared to males, whereas renal NGAL and KIM1 gene expression was unaffected. Interestingly, male Tie2(+/-) mice had 28% higher renal wet/dry weight ratio (p<0.05) compared to Tie2(+/+) males, which was not observed in females nor in lungs. Partial deletion of Tie2 did not affect circulating angiopoietin-1 or angiopoietin-2, but soluble Tie2 was 44% and 53% lower in males and females, respectively, compared to Tie2(+/+) mice of the same sex. Renal and pulmonary gene expression of angiopoietin-1, angiopoietin-2, estrogen receptors and other endothelial barrier regulators was comparable between Tie2(+/-) and Tie2(+/+) mice in both sexes. CONCLUSION: Female sex seems to protect against renal, but not pulmonary edema in heterozygous Tie2 knock-out mice. This could not be explained by sex dimorphism in the endothelial angiopoietin/Tie2 system.
format Online
Article
Text
id pubmed-10653528
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-106535282023-11-16 Female sex protects against renal edema, but not lung edema, in mice with partial deletion of the endothelial barrier regulator Tie2 compared to male sex van Leeuwen, Anoek L. I. Beijer, Elise Ibelings, Roselique Dekker, Nicole A. M. van der Steen, Marjolein R. A. Roelofs, Joris J. T. H. van Meurs, Matijs Molema, Grietje van den Brom, Charissa E. PLoS One Research Article BACKGROUND: The endothelial angiopoietin/Tie2 system is an important regulator of endothelial permeability and targeting Tie2 reduces hemorrhagic shock-induced organ edema in males. However, sexual dimorphism of the endothelium has not been taken into account. This study investigated whether there are sex-related differences in the endothelial angiopoietin/Tie2 system and edema formation. METHODS: Adult male and female heterozygous Tie2 knockout mice (Tie2(+/−)) and wild-type controls (Tie2(+/+)) were included (n = 9 per group). Renal and pulmonary injury were determined by wet/dry weight ratio and H&E staining of tissue sections. Protein levels were studied in plasma by ELISA and pulmonary and renal mRNA expression levels by RT-qPCR. RESULTS: In Tie2(+/+) mice, females had higher circulating angiopoietin-2 (138%, p<0.05) compared to males. Gene expression of angiopoietin-1 (204%, p<0.01), angiopoietin-2 (542%, p<0.001) were higher in females compared to males in kidneys, but not in lungs. Gene expression of Tie2, Tie1 and VE-PTP were similar between males and females in both organs. Renal and pulmonary wet/dry weight ratio did not differ between Tie2(+/+) females and males. Tie2(+/+) females had lower circulating NGAL (41%, p<0.01) compared to males, whereas renal NGAL and KIM1 gene expression was unaffected. Interestingly, male Tie2(+/-) mice had 28% higher renal wet/dry weight ratio (p<0.05) compared to Tie2(+/+) males, which was not observed in females nor in lungs. Partial deletion of Tie2 did not affect circulating angiopoietin-1 or angiopoietin-2, but soluble Tie2 was 44% and 53% lower in males and females, respectively, compared to Tie2(+/+) mice of the same sex. Renal and pulmonary gene expression of angiopoietin-1, angiopoietin-2, estrogen receptors and other endothelial barrier regulators was comparable between Tie2(+/-) and Tie2(+/+) mice in both sexes. CONCLUSION: Female sex seems to protect against renal, but not pulmonary edema in heterozygous Tie2 knock-out mice. This could not be explained by sex dimorphism in the endothelial angiopoietin/Tie2 system. Public Library of Science 2023-11-16 /pmc/articles/PMC10653528/ /pubmed/37972011 http://dx.doi.org/10.1371/journal.pone.0293673 Text en © 2023 van Leeuwen et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
van Leeuwen, Anoek L. I.
Beijer, Elise
Ibelings, Roselique
Dekker, Nicole A. M.
van der Steen, Marjolein R. A.
Roelofs, Joris J. T. H.
van Meurs, Matijs
Molema, Grietje
van den Brom, Charissa E.
Female sex protects against renal edema, but not lung edema, in mice with partial deletion of the endothelial barrier regulator Tie2 compared to male sex
title Female sex protects against renal edema, but not lung edema, in mice with partial deletion of the endothelial barrier regulator Tie2 compared to male sex
title_full Female sex protects against renal edema, but not lung edema, in mice with partial deletion of the endothelial barrier regulator Tie2 compared to male sex
title_fullStr Female sex protects against renal edema, but not lung edema, in mice with partial deletion of the endothelial barrier regulator Tie2 compared to male sex
title_full_unstemmed Female sex protects against renal edema, but not lung edema, in mice with partial deletion of the endothelial barrier regulator Tie2 compared to male sex
title_short Female sex protects against renal edema, but not lung edema, in mice with partial deletion of the endothelial barrier regulator Tie2 compared to male sex
title_sort female sex protects against renal edema, but not lung edema, in mice with partial deletion of the endothelial barrier regulator tie2 compared to male sex
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10653528/
https://www.ncbi.nlm.nih.gov/pubmed/37972011
http://dx.doi.org/10.1371/journal.pone.0293673
work_keys_str_mv AT vanleeuwenanoekli femalesexprotectsagainstrenaledemabutnotlungedemainmicewithpartialdeletionoftheendothelialbarrierregulatortie2comparedtomalesex
AT beijerelise femalesexprotectsagainstrenaledemabutnotlungedemainmicewithpartialdeletionoftheendothelialbarrierregulatortie2comparedtomalesex
AT ibelingsroselique femalesexprotectsagainstrenaledemabutnotlungedemainmicewithpartialdeletionoftheendothelialbarrierregulatortie2comparedtomalesex
AT dekkernicoleam femalesexprotectsagainstrenaledemabutnotlungedemainmicewithpartialdeletionoftheendothelialbarrierregulatortie2comparedtomalesex
AT vandersteenmarjoleinra femalesexprotectsagainstrenaledemabutnotlungedemainmicewithpartialdeletionoftheendothelialbarrierregulatortie2comparedtomalesex
AT roelofsjorisjth femalesexprotectsagainstrenaledemabutnotlungedemainmicewithpartialdeletionoftheendothelialbarrierregulatortie2comparedtomalesex
AT vanmeursmatijs femalesexprotectsagainstrenaledemabutnotlungedemainmicewithpartialdeletionoftheendothelialbarrierregulatortie2comparedtomalesex
AT molemagrietje femalesexprotectsagainstrenaledemabutnotlungedemainmicewithpartialdeletionoftheendothelialbarrierregulatortie2comparedtomalesex
AT vandenbromcharissae femalesexprotectsagainstrenaledemabutnotlungedemainmicewithpartialdeletionoftheendothelialbarrierregulatortie2comparedtomalesex