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

• Published in: PloS one Vol. 18; no. 11; p. e0293673
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: San Francisco Public Library of Science 16.11.2023; Public Library of Science (PLoS)
• Subjects: Angiopoietin; Animals; Circulation; Deletion; Demographic aspects; Diagnosis; Dropsy; Dry weight; Edema; Endothelium; Enzyme-linked immunosorbent assay; Estrogen; Estrogen receptors; Estrogens; Ethylenediaminetetraacetic acid; Experiments; Females; Gender differences; Gene expression; Genes; Hemorrhagic shock; Kidneys; Kinases; Lungs; Males; Neutrophils; Permeability; Phosphatase; Phosphorylation; Proteins; R&D; Renal agenesis; Research & development; Risk factors; RNA; Sex differences; Sexual dimorphism; Vascular endothelial growth factor; Weight; Netherlands; Minneapolis Minnesota; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0293673

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. Adult male and female heterozygous Tie2 knockout mice (Tie2.sup.+/-) and wild-type controls (Tie2.sup.+/+) 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. In Tie2.sup.+/+ 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.sup.+/+ females and males. Tie2.sup.+/+ females had lower circulating NGAL (41%, p<0.01) compared to males, whereas renal NGAL and KIM1 gene expression was unaffected. 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.