Angiopoietin-2 sensitizes endothelial cells to TNF-α and has a crucial role in the induction of inflammation

ArticleinNature Medicine 12(2):235-9 · March 2006with33 Reads
DOI: 10.1038/nm1351 · Source: PubMed
Abstract
The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the receptor tyrosine kinase Tie-2 (refs. 1,2). Paracrine Ang-1-mediated activation of Tie-2 acts as a regulator of vessel maturation and vascular quiescence. In turn, the antagonistic ligand Ang-2 acts by an autocrine mechanism and is stored in endothelial Weibel-Palade bodies from where it can be rapidly released upon stimulation. The rapid release of Ang-2 implies functions of the angiopoietin-Tie system beyond its established role during vascular morphogenesis as a regulator of rapid vascular responses. Here we show that mice deficient in Ang-2 (encoded by the gene Angpt2) cannot elicit an inflammatory response in thioglycollate-induced or Staphylococcus aureus-induced peritonitis, or in the dorsal skinfold chamber model. Recombinant Ang-2 restores the inflammation defect in Angpt2(-/-) mice. Intravital microscopy showed normal TNF-alpha-induced leukocyte rolling in the vasculature of Angpt2(-/-)mice, but rolling cells did not firmly adhere to activated endothelium. Cellular experiments showed that Ang-2 promotes adhesion by sensitizing endothelial cells toward TNF-alpha and modulating TNF-alpha-induced expression of endothelial cell adhesion molecules. Together, these findings identify Ang-2 as an autocrine regulator of endothelial cell inflammatory responses. Ang-2 thereby acts as a switch of vascular responsiveness exerting a permissive role for the activities of proinflammatory cytokines.
    • "Considering the stimulatory role of Ang-2 in various processes associated with vulnerable plaques [18] , such as increased inflam- mation [13], plaque vascularity [5], microvascular leakage [15] and MMP expression [5], we expected profound effects of Ang-2 antagonism on the stable plaque phenotype. However, Ang-2 deletion was only able to prevent fatty streak formation; it did not prevent plaque progression or changes in plaque stability. "
    [Show abstract] [Hide abstract] ABSTRACT: Angiopoietin-2 (Ang-2) blocking agents are currently undergoing clinical trials for use in cancer treatment. Ang-2 has also been associated with rupture-prone atherosclerotic plaques in humans, suggesting a role for Ang-2 in plaque stability. Despite the availability of Ang-2 blocking agents, their clinical use is still lacking. Our aim was to establish if Ang-2 has a role in atheroma development and in the transition of subclinical to clinically relevant atherosclerosis. We investigated the effect of antibody-mediated Ang-2 blockage on atherogenesis after in a mouse model of atherosclerosis. Hypercholesterolemic (low-density lipoprotein receptor(-/-) apolipoprotein B(100/100)) mice were subjected to high-cholesterol diet for eight weeks, one group with and one group without Ang-2 blocking antibody treatment during weeks 4-8.To enhance plaque development, a peri-adventitial collar was placed around the carotid arteries at the start of antibody treatment. Aortic root, carotid arteries and brachiocephalic arteries were analyzed to evaluate the effect of Ang-2 blockage on atherosclerotic plaque size and stable plaque characteristics. Anti-Ang-2 treatment reduced the size of fatty streaks in the brachiocephalic artery (-72%, p < 0.05). In addition, antibody-mediated Ang-2 blockage reduced plasma triglycerides (-27%, p < 0.05). In contrast, Ang-2 blockage did not have any effect on the size or composition (collagen content, macrophage percentage, adventitial microvessel density) of pre-existing plaques in the aortic root or collar-induced plaques in the carotid artery. Ang-2 blockage was beneficial as it decreased fatty streak formation and plasma triglyceride levels, but had no adverse effect on pre-existing atherosclerosis in hypercholesterolemic mice. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.
    Full-text · Article · Jun 2015
    • "Angiopoietin (Ang)-1, Ang-2, and their endothelial cell-specific tyrosine kinase receptor, Tie-2, interact with vascular endothelial growth factor (VEGF) to mediate endothelial activation [10]. Binding of the agonist Ang-1 to the Tie-2 receptor promotes vessel integrity, inhibits vascular permeability, and suppresses inflammatory response [11]. "
    [Show abstract] [Hide abstract] ABSTRACT: Objectives: Patients with acute myocardial infarction (AMI) are frequently complicated with major cardiovascular events (MACEs). Endothelial dysfunction has been found to be involved in pathogenesis of AMI, but its role in development of MACEs after AMI is not clearly investigated. This study aimed to determine whether the plasma markers of endothelial dysfunction could serve as independent predictors for MACEs in patients with AMI. Methods: This prospective study was conducted from March 2010 to July 2012 and enrolled consecutive 132 patients with acute ST elevation myocardial infarction (STEMI) receiving primary percutaneous coronary intervention (PCI). Plasma levels of thrombomodulin (TM), von Willebrand factor (vWF), angiopoietin (Ang)-1, Ang-2, Tie-2, and vascular endothelial growth factor (VEGF) were measured on day 1 of AMI. The development of MACEs at 1-year follow-up was recorded. Result: Patients with STEMI who developed MACEs had increased heart rate on admission (86±24 vs. 74±20bpm, p=0.006), lower left ventricular ejection fraction (LVEF) (49.0±12.4 vs. 57.2±12.4%, p=0.002), and higher incidence of multivessel disease (66.7% vs. 42.2%, p=0.018) comparing with those without MACEs. Plasma level of Ang-1 was lower in patients with MACEs than in those without (21,165±16,281 vs. 31,411±21,593pg/mL, p=0.018). In multivariate analysis, Ang-1 level<median value (OR 2.977, 95% CI 1.16-7.63, p=0.023), LVEF (OR 0.958, 95% CI 0.92-0.99, p=0.022) and multivessel disease (OR 3.013, 95% CI 1.19-7.60, p=0.019) independently predicted 1-year MACEs. Conclusion: Decreased plasma Ang-1 levels on admission, LVEF and multivessel disease independently predicted the development of 1-year MACEs in patients with STEMI. These results suggest that endothelial dysfunction may play an important role in mediating MACEs in patients with STEMI.
    Full-text · Article · Mar 2015
    • "To validate the results obtained with the ANG2-blocking antibody, we also analyzed the initial lymphatics in Ang2 gene-deleted (À/À) mice (Gale et al. 2002; Fiedler et al. 2006). In agreement with the results of the blocking antibody experiment, the zipper-to-button junctional transformation was also reduced in the diaphragm of Ang2 "
    [Show abstract] [Hide abstract] ABSTRACT: Primitive lymphatic vessels are remodeled into functionally specialized initial and collecting lymphatics during development. Lymphatic endothelial cell (LEC) junctions in initial lymphatics transform from a zipper-like to a button-like pattern during collecting vessel development, but what regulates this process is largely unknown. Angiopoietin 2 (Ang2) deficiency leads to abnormal lymphatic vessels. Here we found that an ANG2-blocking antibody inhibited embryonic lymphangiogenesis, whereas endothelium-specific ANG2 overexpression induced lymphatic hyperplasia. ANG2 inhibition blocked VE-cadherin phosphorylation at tyrosine residue 685 and the concomitant formation of button-like junctions in initial lymphatics. The defective junctions were associated with impaired lymph uptake. In collecting lymphatics, adherens junctions were disrupted, and the vessels leaked upon ANG2 blockade or gene deletion. ANG2 inhibition also suppressed the onset of lymphatic valve formation and subsequent valve maturation. These data identify ANG2 as the first essential regulator of the functionally important interendothelial cell-cell junctions that form during lymphatic development.
    Full-text · Article · Jul 2014
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