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

doi:10.1016/j.mvr.2024.104694

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

Microvasc Res. 2024 May 8:154:104694. doi: 10.1016/j.mvr.2024.104694. Online ahead of print.

Authors

Anoek L I van Leeuwen¹, Nicole A M Dekker¹, Roselique Ibelings², Anita M Tuip-de Boer³, Matijs van Meurs⁴, Grietje Molema⁵, Charissa E van den Brom⁶

Affiliations

¹ Department of Anesthesiology, Amsterdam UMC, VU University, Amsterdam, the Netherlands; Department of Physiology, Amsterdam UMC, VU University, Amsterdam, the Netherlands.
² Department of Anesthesiology, Amsterdam UMC, VU University, Amsterdam, the Netherlands; Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam UMC, University of Amsterdam, the Netherlands.
³ Department of Intensive Care Medicine, Amsterdam UMC, University of Amsterdam, the Netherlands; Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam UMC, University of Amsterdam, the Netherlands.
⁴ Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands; Department of Critical Care, University Medical Center Groningen, Groningen, the Netherlands.
⁵ Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands.
⁶ Department of Anesthesiology, Amsterdam UMC, VU University, Amsterdam, the Netherlands; Department of Intensive Care Medicine, Amsterdam UMC, University of Amsterdam, the Netherlands; Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam UMC, University of Amsterdam, the Netherlands. Electronic address: c.vandenbrom@amsterdamumc.nl.

PMID: 38723844
DOI: 10.1016/j.mvr.2024.104694

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.

Keywords: Endothelium; Fluid extravasation; Permeability.