Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation
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.
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ABSTRACT: Angiopoietin-2 (Ang-2) impairs endothelial integrity. The association of Ang-2 in the presence of oedema and outcome of patients with acute decompensated heart failure (ADHF) has not been investigated. Angiopoietin-2 was measured in 132 ADHF patients, which were included in a monocentric, prospective trial (Clinicaltrials.gov: NCT01429857). Primary endpoint was all-cause death at 6-months. 20 healthy persons served as control group (HC). In ADHF patients, mean Ang-2 concentration at admission was significantly increased compared to HC (2,111 ± 117 vs. 971 ± 46 pg/ml, p = 0.0002). Ang-2 was increased in patients with compared to those without peripheral oedema (2,294 ± 140 vs. 1,540 ± 170 pg/ml; p = 0.009) and in patients with NYHA class III or IV symptoms compared to those with NYHA class II symptoms (2,256 ± 132 vs. 1,341 ± 380 pg/ml, p = 0.023). During the 6-month follow-up, 10 patients died. In survivors, Ang-2 significantly decreased at discharge compared to admission (2,046 ± 118 vs. 1,431 ± 93 pg/ml; p < 0.0001). Non-survivors showed no difference between Ang-2 concentration at admission and discharge (3,296 ± 594 vs. 2,909 ± 536 pg/ml). Ang-2 concentrations at discharge above 2,500 pg/ml were associated with an increased risk of death compared to Ang-2 concentrations below this threshold (Hazard ratio 8.8; 95 % confidence interval; 2.48-31.16, p < 0.001). In ADHF patients, Ang-2 is significantly increased compared to healthy controls, shows a relationship in the presence of oedema and is a predictor of poor outcome.Clinical Research in Cardiology 11/2014; DOI:10.1007/s00392-014-0787-y · 4.17 Impact Factor
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ABSTRACT: Plasmodium vivax can cause severe malaria, however its pathogenesis is poorly understood. In contrast to P. falciparum, circulating vivax parasitemia is low, with minimal apparent sequestration in endothelium-lined microvasculature, and pathogenesis thought unrelated to parasite biomass. However, the relationships between vivax disease-severity and total parasite biomass, endothelial autocrine activation and microvascular dysfunction are unknown. We measured circulating parasitemia and markers of total parasite biomass (plasma parasite lactate dehydrogenase [pLDH] and PvLDH) in adults with severe (n = 9) and non-severe (n = 53) vivax malaria, and examined relationships with disease-severity, endothelial activation, and microvascular function. Healthy controls and adults with non-severe and severe falciparum malaria were enrolled for comparison. Median peripheral parasitemia, PvLDH and pLDH were 2.4-fold, 3.7-fold and 6.9-fold higher in severe compared to non-severe vivax malaria (p = 0.02, p = 0.02 and p = 0.015, respectively), suggesting that, as in falciparum malaria, peripheral P. vivax parasitemia underestimates total parasite biomass, particularly in severe disease. P. vivax schizonts were under-represented in peripheral blood. Severe vivax malaria was associated with increased angiopoietin-2 and impaired microvascular reactivity. Peripheral vivax parasitemia correlated with endothelial activation (angiopoietin-2, von-Willebrand-Factor [VWF], E-selectin), whereas markers of total vivax biomass correlated only with systemic inflammation (IL-6, IL-10). Activity of the VWF-cleaving-protease, ADAMTS13, was deficient in proportion to endothelial activation, IL-6, thrombocytopenia and vivax disease-severity, and associated with impaired microvascular reactivity in severe disease. Impaired microvascular reactivity correlated with lactate in severe vivax malaria. Findings suggest that tissue accumulation of P. vivax may occur, with the hidden biomass greatest in severe disease and capable of mediating systemic inflammatory pathology. The lack of association between total parasite biomass and endothelial activation is consistent with accumulation in parts of the circulation devoid of endothelium. Endothelial activation, associated with circulating parasites, and systemic inflammation may contribute to pathology in vivax malaria, with microvascular dysfunction likely contributing to impaired tissue perfusion.PLoS Pathogens 01/2015; 11(1):e1004558. DOI:10.1371/journal.ppat.1004558 · 8.06 Impact Factor
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ABSTRACT: Leukemia-inhibitory factor (LIF) and Angiopoietin-2 (Ang-2) are important factors in fertility. In the present study, it was investigated whether Bu Shen Huo Xue Decoction (BSHXD) prevents controlled ovarian hyperstimulation (COH) treatment-induced changes in endometrial LIF and Ang-2 expression and whether it has an effect on the number of implantation sites and live births in rats. Uteri were collected on day (D) 3, 4 and 5 of pregnancy, and LIF and Ang-2 protein and mRNA expression were detected using western blot analysis and quantitative polymerase chain reaction. On pregnancy D10, the average number of implantation sites was observed. The number of live births from each group was recorded. The results indicated that BSHXD treatment markedly increased the number of live births by restoring endometrial LIF expression and the implantation capacity in the COH rat model. In addition, no association was identified between LIF and Ang-2 expression. Therefore, this suggests that BSHXD may be useful for female reproduction.Experimental and therapeutic medicine 03/2015; 9(3):751-757. DOI:10.3892/etm.2015.2193 · 0.94 Impact Factor