Time course of angiopoietin-2 release during experimental human endotoxemia and sepsis

Kümpers, Philipp; Meurs, Matijs van; David, Sascha; Molema, Grietje; Bijzet, Johan; Lukasz, Alexander; Biertz, Frank; Haller, Hermann; Zijlstra, Jan G.

doi:10.1186/cc7866

Cited by 99 publications

(78 citation statements)

References 37 publications

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“…The temporal increase in Ang2 and VEGF-A expression observed with LPS in HPMECs is consistent with rodent and human studies showing increased expression of Ang2 or VEGF-A in the whole lung or systemic circulation after LPS administration or systemic sepsis, respectively (12,(31)(32)(33). Our data indicate that pulmonary microvascular endothelial cells respond to bacterial ligands with robust Ang2, Tie2, and VEGF-A expression.…”

Section: Journal Of Biological Chemistrysupporting

confidence: 74%

“…To the best of our knowledge, this is one of the initial reports to demonstrate regulation of Ang2 expression and proinflammatory angiogenesis by Nox-dependent signaling. Increased Ang2 expression in the systemic circulation or in the lung has been associated with mortality in humans with sepsis, severity of acute lung injury, and with development of BPD in premature infants (30,31,51). Although we showed that mouse lung endothelial cells express increased Ang2 and Tie2 after systemic LPS, the rest of our data were obtained in primary cells in vitro, and, therefore, verification of the results of this study in animal models expressing angiogenic factors in a tissue-restricted manner will enable us to better understand the significance of these findings.…”

Section: Journal Of Biological Chemistrymentioning

confidence: 99%

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Lipopolysaccharide (LPS)-mediated Angiopoietin-2-dependent Autocrine Angiogenesis Is Regulated by NADPH Oxidase 2 (Nox2) in Human Pulmonary Microvascular Endothelial Cells

Menden

Welak

Cossette

et al. 2015

Journal of Biological Chemistry

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Background:The mechanisms by which bacterial ligands alter angiogenesis remain unknown. Results: Lipopolysaccharide-mediated Angiopoietin-2-dependent autocrine angiogenesis in lung endothelial cells is regulated by NADPH oxidase 2. Conclusion: Endothelial Nox2 regulates Angiopoietin-2-dependent angiogenesis. Significance: This study presents new data regarding the regulation of proinflammatory angiogenesis.

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Section: Journal Of Biological Chemistrysupporting

confidence: 74%

Section: Journal Of Biological Chemistrymentioning

confidence: 99%

Lipopolysaccharide (LPS)-mediated Angiopoietin-2-dependent Autocrine Angiogenesis Is Regulated by NADPH Oxidase 2 (Nox2) in Human Pulmonary Microvascular Endothelial Cells

Menden

Welak

Cossette

et al. 2015

Journal of Biological Chemistry

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“…40,51 Higher levels of Ang2 in sputum correlate with more airway vascular leakiness in asthma. 52,53 High blood levels of Ang2 correlate with disease severity or poor outcome in patients with sepsis, 54,55 systemic lupus erythematosus, 56 inflammatory bowel disease, 57 and malaria.…”

Section: Discussionmentioning

confidence: 99%

Angiopoietin-2-Driven Vascular Remodeling in Airway Inflammation

Tabruyn

Colton

Morisada

et al. 2010

The American Journal of Pathology

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Vascular remodeling is a feature of chronic inflammation during which capillaries transform into venules that expand the region of the vasculature in which leakage and leukocyte emigration both occur. Recently, we found that angiopoietin/Tie2 receptor signaling drives the transformation of capillaries into venules at an early stage of the sustained inflammatory response in the airways of mice infected with Mycoplasma pulmonis. However, the precise contributions of both angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) are not clear. In this study, we sought to determine the contribution of Ang2 to this vascular remodeling. Ang2 mRNA expression levels increased and phosphorylated Tie2 immunoreactivity in mucosal blood vessels decreased, indicative of diminished receptor signaling after infection. Selective inhibition of Ang2 throughout the infection by administration of either of two distinct functionblocking antibodies reduced the suppression of Tie2 phosphorylation and decreased the remodeling of mucosal capillaries into venules, the amount of leukocyte influx, and disease severity. These findings are consistent with Ang2 acting as an antagonist of Tie2 receptors and the reduction of Tie2 phosphorylation in endothelial cells rendering the vasculature more responsive to cytokines that promote both vascular remodeling and the consequences of inflammation after M. pulmonis infection. By blocking such changes, Ang2 inhibitors may prove beneficial in the treatment of sustained inflammation in which vascular remodeling, leakage, and leukocyte influx contribute to its pathophysiology.

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“…Alternatively, Ang2 expressed by metastatic nodules, or by the host vasculature as a more general response to disease, might contribute to the determined serum Ang2. Indeed, elevated circulating Ang2 levels have been reported to predict for poor prognosis in numerous noncancerous diseases, such as sepsis and malaria [16,[42][43][44]. In these diseases, the activated endothelial cells of the normal vessels likely secrete Ang2 [45].…”

Section: Discussionmentioning

confidence: 99%

Association of angiopoietin-2 and Ki-67 expression with vascular density and sunitinib response in metastatic renal cell carcinoma

Lampinen¹,

Rautiola²,

Mirtti³

et al. 2016

European Journal of Cancer

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The Angiopoietin-2 (Ang2, Angpt2) growth factor is a context-dependent antagonist/agonist ligand of the endothelial Tie2 receptor tyrosine kinase and known to promote tumour angiogenesis and metastasis. Angiopoietin antagonists have been tested in clinical cancer trials in combination with VEGF-based anti-angiogenic therapy, including sunitinib, which is widely used as a first-line therapy for metastatic renal cell carcinoma (mRCC). However, little is known about Ang2 protein expression in human tumours and the correlation of tumour Ang2 expression with tumour vascularization, tumour cell proliferation and response to antiangiogenic therapies. Here, we evaluated, using immunohistochemistry, the expression of Ang2, CD31 and the cell proliferation marker Ki-67 in the primary kidney cancer from 136 mRCC patients, who received first-line sunitinib after nephrectomy. Ang2 protein expression was restrained to RCC tumour vessels, and correlated with tumour vascularization and response to sunitinib. High pre-therapeutic Ang2 expression, and more strongly, combined high expression of both Ang2 and CD31, were associated with a high clinical benefit rate (CBR). Low cancer Ki-67 expression, but not Ang2 or CD31 expression, was associated with favourable progression-free (PFS) and overall survival (OS) as compared to patients with high Ki-67 expression (PFS 6.5 vs. 10.6 months, P = 0.009; OS, 15.7 vs. 28.5 months, P = 0.015). In summary, in this study to investigate endothelial Ang2 in mRCC patients treated with first-line sunitinib, high cancer Ang2 expression was associated with the CBR, but not PFS or OS, whereas low Ki-67 expression was significantly associated with long PFS and OS.

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Time course of angiopoietin-2 release during experimental human endotoxemia and sepsis

Cited by 99 publications

References 37 publications

Lipopolysaccharide (LPS)-mediated Angiopoietin-2-dependent Autocrine Angiogenesis Is Regulated by NADPH Oxidase 2 (Nox2) in Human Pulmonary Microvascular Endothelial Cells

Lipopolysaccharide (LPS)-mediated Angiopoietin-2-dependent Autocrine Angiogenesis Is Regulated by NADPH Oxidase 2 (Nox2) in Human Pulmonary Microvascular Endothelial Cells

Angiopoietin-2-Driven Vascular Remodeling in Airway Inflammation

Association of angiopoietin-2 and Ki-67 expression with vascular density and sunitinib response in metastatic renal cell carcinoma

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