Modulation of angiopoietin-2 and Tie2: Organ specific effects of microvascular leakage and edema in mice

Anoek L I van Leeuwen, Nicole A M Dekker, Roselique Ibelings, Anita M Tuip-de Boer, Matijs van Meurs, Grietje Molema, Charissa E van den Brom*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

11 Downloads (Pure)

Abstract

INTRODUCTION: Critical illness is associated with organ failure, in which endothelial hyperpermeability and tissue edema play a major role. The endothelial angiopoietin/Tie2 system, a regulator of endothelial permeability, is dysbalanced during critical illness. Elevated circulating angiopoietin-2 and decreased Tie2 receptor levels are reported, but it remains unclear whether they cause edema independent of other critical illness-associated alterations. Therefore, we have studied the effect of angiopoietin-2 administration and/or reduced Tie2 expression on microvascular leakage and edema under normal conditions.

METHODS: Transgenic male mice with partial deletion of Tie2 (heterozygous exon 9 deletion, Tie2 +/-) and wild-type controls (Tie2 +/+) received 24 or 72 pg/g angiopoietin-2 or PBS as control (n = 12 per group) intravenously. Microvascular leakage and edema were determined by Evans blue dye (EBD) extravasation and wet-to-dry weight ratio, respectively, in lungs and kidneys. Expression of molecules related to endothelial angiopoietin/Tie2 signaling were determined by ELISA and RT-qPCR.

RESULTS: In Tie2 +/+ mice, angiopoietin-2 administration increased EBD extravasation (154 %, p < 0.05) and wet-to-dry weight ratio (133 %, p < 0.01) in lungs, but not in the kidney compared to PBS. Tie2 +/- mice had higher pulmonary (143 %, p < 0.001), but not renal EBD extravasation, compared to wild-type control mice, whereas a more pronounced wet-to-dry weight ratio was observed in lungs (155 %, p < 0.0001), in contrast to a minor higher wet-to-dry weight ratio in kidneys (106 %, p < 0.05). Angiopoietin-2 administration to Tie2 +/- mice did not further increase pulmonary EBD extravasation, pulmonary wet-to-dry weight ratio, or renal wet-to-dry weight ratio. Interestingly, angiopoietin-2 administration resulted in an increased renal EBD extravasation in Tie2 +/- mice compared to Tie2 +/- mice receiving PBS. Both angiopoietin-2 administration and partial deletion of Tie2 did not affect circulating angiopoietin-1, soluble Tie2, VEGF and NGAL as well as gene expression of angiopoietin-1, -2, Tie1, VE-PTP, ELF-1, Ets-1, KLF2, GATA3, MMP14, Runx1, VE-cadherin, VEGFα and NGAL, except for gene and protein expression of Tie2, which was decreased in Tie2 +/- mice compared to Tie2 +/+ mice.

CONCLUSIONS: In mice, the microvasculature of the lungs is more vulnerable to angiopoietin-2 and partial deletion of Tie2 compared to those in the kidneys with respect to microvascular leakage and edema.

Original languageEnglish
Article number104694
Number of pages12
JournalMicrovascular research
Volume154
Early online date8-May-2024
DOIs
Publication statusPublished - Jul-2024

Fingerprint

Dive into the research topics of 'Modulation of angiopoietin-2 and Tie2: Organ specific effects of microvascular leakage and edema in mice'. Together they form a unique fingerprint.

Cite this