PT  - JOURNAL ARTICLE
AU  - Lukas Hobohm
AU  - Sebastian Kölmel
AU  - Caroline Niemann
AU  - Philipp Kümpers
AU  - Valentin J. Krieg
AU  - Magdalena L. Bochenek
AU  - Alexander H. Lukasz
AU  - Yvonne Reiss
AU  - Karl-Heinz Plate
AU  - Christoph Liebetrau
AU  - Christoph B. Wiedenroth
AU  - Stefan Guth
AU  - Thomas Münzel
AU  - Gerd Hasenfuß
AU  - Philip Wenzel
AU  - Eckhard Mayer
AU  - Stavros V. Konstantinides
AU  - Katrin Schäfer
AU  - Mareike Lankeit
TI  - Role of angiopoietin-2 in venous thrombus resolution and chronic thromboembolic disease
AID  - 10.1183/13993003.04196-2020
DP  - 2021 Dec 01
TA  - European Respiratory Journal
PG  - 2004196
VI  - 58
IP  - 6
4099  - http://erj.ersjournals.com/content/58/6/2004196.short
4100  - http://erj.ersjournals.com/content/58/6/2004196.full
SO  - Eur Respir J2021 Dec 01; 58
AB  - Background Defective angiogenesis, incomplete thrombus revascularisation and fibrosis are considered critical pathomechanisms of chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism. Angiopoietin-2 (ANGPT2) has been shown to regulate angiogenesis, but its importance for thrombus resolution and remodelling is unknown.Methods ANGPT2 plasma concentrations were measured in patients with CTEPH (n=68) and acute pulmonary embolism (n=84). Tissue removed during pulmonary endarterectomy (PEA) for CTEPH was analysed (immuno)histologically. A mouse model of inferior vena cava ligation was used to study the kinetics of venous thrombus resolution in wild-type mice receiving recombinant ANGPT2 via osmotic pumps, and in transgenic mice overexpressing ANGPT2 in endothelial cells.Results Circulating ANGPT2 levels were higher in CTEPH patients compared to patients with idiopathic pulmonary arterial hypertension and healthy controls, and decreased after PEA. Plasma ANGPT2 levels were elevated in patients with pulmonary embolism and diagnosis of CTEPH during follow-up. Histological analysis of PEA specimens confirmed increased ANGPT2 expression, and low levels of phosphorylated TIE2 were observed in regions with early-organised pulmonary thrombi, myofibroblasts and fibrosis. Microarray and high-resolution microscopy analysis could localise ANGPT2 overexpression to endothelial cells, and hypoxia and transforming growth factor-β1 were identified as potential stimuli. Gain-of-function experiments in mice demonstrated that exogenous ANGPT2 administration and transgenic endothelial ANGPT2 overexpression resulted in delayed venous thrombus resolution, and thrombi were characterised by lower TIE2 phosphorylation and fewer microvessels.Conclusion Our findings suggest that ANGPT2 delays venous thrombus resolution and that overexpression of ANGPT2 contributes to thrombofibrosis and may thus support the transition from pulmonary embolism to CTEPH.These findings in patients and mouse models reveal a new role for angiopoietin-2 in the pathophysiology of CTEPH, suggesting that its overexpression in pulmonary endothelium may contribute to defective angiogenesis and persistent vascular occlusion https://bit.ly/3gotczC