TY - JOUR
T1 - 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
AU - van Leeuwen, Anoek L. I.
AU - Beijer, Elise
AU - Ibelings, Roselique
AU - Dekker, Nicole A. M.
AU - van der Steen, Marjolein R. A.
AU - Roelofs, Joris J. T. H.
AU - van Meurs, Matijs
AU - Molema, Grietje
AU - van den Brom, Charissa E.
N1 - Funding Information: Funding: This research was supported by the Dutch Heart Foundation (2016T064, to NAMD, https://www.hartstichting.nl/), Dutch Research Council (ZonMW, Veni Grant 2019, to CEvdB, https://www.zonmw.nl/nl), European Society of Intensive Care Medicine (Basic research Award 2021 to CEvdB, https://www.esicm.org/) and European Society of Anaesthesiology and Intensive Care (ESAIC Research project grant 2022 to CEvdB, https://www.esaic.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: Copyright: © 2023 van Leeuwen et al.
PY - 2023/11
Y1 - 2023/11
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85177449847&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/37972011
UR - http://www.scopus.com/inward/record.url?scp=85177449847&partnerID=8YFLogxK
U2 - https://doi.org/10.1371/journal.pone.0293673
DO - https://doi.org/10.1371/journal.pone.0293673
M3 - Article
C2 - 37972011
SN - 1932-6203
VL - 18
SP - e0293673
JO - PLOS ONE
JF - PLOS ONE
IS - 11 November
M1 - e0293673
ER -