Fiedler, U. et al. Angiopoietin-2 sensitizes endothelial cells to TNF- and has a crucial role in the induction of inflammation. Nature Med. 12, 235-239
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.
- SourceAvailable from: Pao-Hsien Chu
[Show abstract] [Hide abstract]
- "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 . Binding of the agonist Ang-1 to the Tie-2 receptor promotes vessel integrity, inhibits vascular permeability, and suppresses inflammatory response . "
ABSTRACT: 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.International Journal of Cardiology 03/2015; 182. DOI:10.1016/j.ijcard.2014.12.172 · 6.18 Impact Factor
[Show abstract] [Hide abstract]
- "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 "
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.Genes & Development 07/2014; 28(14):1592-603. DOI:10.1101/gad.237677.114 · 12.64 Impact Factor
[Show abstract] [Hide abstract]
- "Furthermore , extensive overlap in endothelial responses to inflammatory and angiogenic activation exists, in which activation of the NFκB-pathway upregulates the expression of matrix metalloproteinases and urokinase-type plasminogen activator (uPA) and pro-inflammatory cytokines and chemokines Cell Tissue Res contribute to new vessel formation (Sakurai and Kudo 2011; Ribatti 2012). On the other hand, TNFα can attenuate VEGFR2 activation by employing SHP-1 phosphatase (Guo et al. 2000) and interfere with Notch and Jagged signaling in angiogenesis (Sainson et al. 2008), while pro-angiogenic Angiopoietin-2 can sensitize endothelial cells to TNFα (Fiedler et al. 2006) and facilitate inflammation-related vascular remodeling (Thurston and Daly 2012). "
ABSTRACT: Many studies on the molecular control underlying normal cell behavior and cellular responses to disease stimuli and pharmacological intervention are conducted in single-cell culture systems, while the read-out of cellular engagement in disease and responsiveness to drugs in vivo is often based on overall tissue responses. As the majority of drugs under development aim to specifically interact with molecular targets in subsets of cells in complex tissues, this approach poses a major experimental discrepancy that prevents successful development of new therapeutics. In this review, we address the shortcomings of the use of artificial (single) cell systems and of whole tissue analyses in creating a better understanding of cell engagement in disease and of the true effects of drugs. We focus on microvascular endothelial cells that actively engage in a wide range of physiological and pathological processes. We propose a new strategy in which in vivo molecular control of cells is studied directly in the diseased endothelium instead of at a (far) distance from the site where drugs have to act, thereby accounting for tissue-controlled cell responses. The strategy uses laser microdissection-based enrichment of microvascular endothelium which, when combined with transcriptome and (phospho)proteome analyses, provides a factual view on their status in their complex microenvironment. Combining this with miniaturized sample handling using microfluidic devices enables handling the minute sample input that results from this strategy. The multidisciplinary approach proposed will enable compartmentalized analysis of cell behavior and drug effects in complex tissue to become widely implemented in daily biomedical research and drug development practice.Cell and Tissue Research 09/2013; DOI:10.1007/s00441-013-1714-7 · 3.33 Impact Factor