The Tie-2 ligand Angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies

Fiedler, Ulrike; Scharpfenecker, Marion; Koidl, Stefanie; Hegen, Anja; Grunow, Verena; Schmidt, Jarno M.; Kriz, Wilhelm; Thurston, Gavin; Augustin, Hellmut G.

doi:10.1182/blood-2003-10-3685

Cited by 646 publications

(596 citation statements)

References 45 publications

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“…18 Competing with angiopoietin 1 for Tie-2 receptor, angiopoietin 2 has been implicated in pleiotropic actions depending on the biologic context, from proinflammatory with increased vascular permeability to cytoprotective in stressed endothelial cells 19 -24 ; therefore, a delicate balance could be envisaged between the proinflammatory actions of angiopoietin 2 (among other released constituents of WPB) and its HSC-and EPC-mobilizing action serving as a pharmacologic preconditioner. It is quite possible that a more severe tissue injury and/or higher levels of UA result in an intense angiopoietin 2 signaling with proinflammatory actions prevailing over its HSC-and EPCmobilizing effect.…”

Section: Discussionmentioning

confidence: 99%

Ischemia-Induced Exocytosis of Weibel-Palade Bodies Mobilizes Stem Cells

Kuo

Patschan

et al. 2008

Journal of the American Society of Nephrology

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Recruitment of various stem and progenitor cells is crucial for the regeneration of an injured organ. Levels of uric acid, one of the prototypical "alarm signals," surge after ischemia-reperfusion injury. Exogenous uric acid rapidly mobilizes endothelial progenitor cells and hematopoietic stem cells and protects the kidney from ischemia. The relatively fast responses to uric acid suggest that preformed second messengers may be released from a storage pool. Here, it is reported that monosodium urate (MSU) results in exocytosis of Weibel-Palade bodies in vitro and in vivo, leading to the release of IL-8, von Willebrand factor, and angiopoietin 2 in the culture medium or circulation. Confocal and immunoelectron microscopy confirmed depletion of von Willebrand factor in MSU-treated aortic endothelial cells. Angiopoietin 2 alone induced exocytosis of Weibel-Palade bodies, mobilized hematopoietic stem cells and depleted splenic endothelial progenitor cells, partially reproducing the actions of MSU. In addition, pretreatment with angiopoietin 2 protected the kidneys from an ischemic insult, suggesting that the previously reported renoprotection conferred by MSU likely results from exocytosis of Weibel-Palade bodies. Furthermore, experiments with toll-like receptor 4 (TLR-4)-and TLR-2-deficient mice demonstrated that uric acid-induced exocytosis of Weibel-Palade bodies is mediated by TLR-4 and that uric acid-induced release of IL-8 requires both TLR-2 and TLR-4. In summary, these results suggest that exocytosis of Weibel-Palade bodies links postischemic repair with inflammation and mobilization of stem cells.

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Section: Discussionmentioning

confidence: 99%

Ischemia-Induced Exocytosis of Weibel-Palade Bodies Mobilizes Stem Cells

Kuo

Patschan

et al. 2008

Journal of the American Society of Nephrology

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“…7 In response to VEGF, the endothelium is activated and several proteins are expressed by endothelial cells including vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), von Willebrand factor (vWF), angiopoietin-2 (Ang-2) and Tie-2 (Tie-2). [8][9][10][11] VCAM-1 and ICAM-1 are adhesion molecules and their soluble ectodomains (sVCAM-1 and sICAM-1) can be proteolytically released from the endothelial cell surface into the circulation. [12][13][14] Next to upregulation of VCAM-1 and ICAM-1, VEGF is also known to activate exocytosis of intracellular secretory granules in endothelial cells, the so-called Weibel-Palade bodies, thereby releasing vasoactive substances, including von Willebrand factor (vWF) and Ang-2.…”

mentioning

confidence: 99%

“…[12][13][14] Next to upregulation of VCAM-1 and ICAM-1, VEGF is also known to activate exocytosis of intracellular secretory granules in endothelial cells, the so-called Weibel-Palade bodies, thereby releasing vasoactive substances, including von Willebrand factor (vWF) and Ang-2. 8,9 The glycoprotein vWF is produced uniquely by endothelial cells upon endothelial cell activation and is essential for platelet adhesion to the subendothelial matrix after vascular injury. Ang-2 acts as a natural antagonist of its receptor Tie-2.…”

mentioning

confidence: 99%

Sunitinib‐induced changes in circulating endothelial cell‐related proteins in patients with metastatic renal cell cancer

Veldt

Vroling

Haas

et al. 2011

Intl Journal of Cancer

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Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors are effective agents in the treatment of metastatic renal cell cancer (mRCC). We here investigated whether inhibition of VEGFR signalin by sunitinib causes changes in plasma proteins associated with tumor endothelium. Forty-three patients with mRCC received sunitinib 50 mg/day in a 4-weeks on 2-weeks off schedule. Sequential plasma samples were obtained before treatment (C1D1), on C1D14, on C1D28, and on C2D1 before start of cycle 2. Plasma levels were assessed for VEGF, soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular cell adhesion molecule-1 (sICAM-1), von Willebrand factor (vWF), circulating angiopoietin-2 (Ang-2) and soluble Tie-2 (sTie-2). Total tumor burden was calculated at baseline and at first evaluation. Progression-free survival (PFS) and overall survival (OS) were determined. Tumor burden was positively associated with baseline circulating Ang-2 [Spearman's rho (q) 5 0.378, p 5 0.028] and vWF (q 5 0.417, p 5 0.008). During sunitinib treatment, circulating Ang-2 and sTie-2 significantly decreased (p < 0.001 for both), plasma levels of sVCAM-1 and VEGF significantly increased (p 5 0.022 and p < 0.001), whereas those of sICAM-1 and vWF remained stable. These protein changes had recovered on C2D1. The reduction in circulating Ang-2 levels on C1D28 was positively correlated with the percentage decrease in tumor burden (q 5 0.605; p 5 0.002). Baseline protein levels and subsequent changes were not associated with PFS or OS. In conclusion, sunitinib-induced changes in Ang-2, sTie-2, sVCAM-1 and VEGF are related to the administration schedule, while reduction in Ang-2 is also associated with decrease in tumor burden.

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“…A pesar de que en el presente estudio, el regulador de activación endotelial Ang-2 se expresó con ligeras diferencias en los casos de dengue grave, fiebre por dengue y leptospirosis, siempre se ha comportado de forma diferente en los casos graves y en los que no lo son, y en los sujetos sanos y tanto en enfermedades infecciosas diferentes al dengue como en reacciones homeostáticas de inflamación y coagulación en pruebas de laboratorios (4,26). Se ha observado que los reguladores Ang-1 y Ang-2 en infantes con infecciones graves por dengue tienen un comportamiento característico (disminución en la expresión de Ang-1 y elevación en la de Ang-2) (27).…”

Section: Discussionunclassified

Reguladores de integridad endotelial como posibles predictores de la gravedad en casos de dengue

2016

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Introducción. El dengue es una de las enfermedades trasmitidas por mosquitos de mayor impacto en el mundo. La evolución clínica de la enfermedad suele ser impredecible, por lo cual su adecuado manejo en las fases tempranas podría incidir en la mejoría del paciente. Objetivo. Evaluar los niveles séricos de algunos reguladores endoteliales (VEGF, sICAM-1, endoglina soluble, Ang-1 y Ang-2) como marcadores de predicción de la gravedad del dengue. Materiales y métodos. Se hizo un estudio de casos y controles anidado en una cohorte. En la fase temprana, los niveles de los reguladores endoteliales se midieron con ELISA. La relación entre las variables clínicas y los reguladores se analizó mediante regresión logística utilizando como variable de salida la gravedad del dengue. Con base en la relación entre las variables de interés y el resultado, se estableció un posible modelo predictor de la gravedad empleando la mejor área bajo la curva (ROC). Resultados. La mediana de la edad fue de 24 años. Los casos graves se asociaron con niveles séricos de Ang-2 a partir de un punto de corte mayor o igual a 1.490 pg/ml, (Odds ratio, OR=3,1 p=0,015). Los niveles séricos de Ang-2, así como un área de 0,73 bajo la curva ROC, contribuyeron al modelo de predicción de la gravedad, conjuntamente con las variables de exantema, trastorno de conciencia y dolor abdominal, con OR de 3,2 (IC95% 1,16-8,9; p=0,024). Conclusión. El regulador endotelial Ang-2 podría ser un predictor de la gravedad en el dengue.

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The Tie-2 ligand Angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies

Cited by 646 publications

References 45 publications

Ischemia-Induced Exocytosis of Weibel-Palade Bodies Mobilizes Stem Cells

Ischemia-Induced Exocytosis of Weibel-Palade Bodies Mobilizes Stem Cells

Sunitinib‐induced changes in circulating endothelial cell‐related proteins in patients with metastatic renal cell cancer

Reguladores de integridad endotelial como posibles predictores de la gravedad en casos de dengue

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