The Angiopoietin—Tie System: Common Signaling Pathways for Angiogenesis, Cancer, and Inflammation

Reiss, Yvonne; Scholz, Alexander; Plate, Karl H.

doi:10.1007/978-1-4939-2907-8_13

Cited by 13 publications

(23 citation statements)

References 121 publications

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Section: Introductionmentioning

confidence: 99%

“…Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) are secreted growth factors that exert downstream signaling through the Tie2 receptor tyrosine kinase [ 5 , 24 , 47 ]. Tie2 is predominantly expressed in endothelial cells and controls vessel remodeling and maturation [ 23 , 47 , 51 ]. Ang-1 activates the Tie2 receptor by phosphorylation, while Ang-2 is able to prevent receptor phosphorylation by competitive binding in a context-dependent manner, thus leading to inactivation of Tie2 and facilitating angiogenesis [ 5 , 19 , 28 , 39 , 47 , 58 ].…”

Section: Introductionmentioning

confidence: 99%

“…Tie2 is predominantly expressed in endothelial cells and controls vessel remodeling and maturation [ 23 , 47 , 51 ]. Ang-1 activates the Tie2 receptor by phosphorylation, while Ang-2 is able to prevent receptor phosphorylation by competitive binding in a context-dependent manner, thus leading to inactivation of Tie2 and facilitating angiogenesis [ 5 , 19 , 28 , 39 , 47 , 58 ]. Accordingly, Ang-2 is not expressed in the normal adult brain endothelium, but upregulated in brain tumors such as glioblastoma [ 32 , 52 , 57 , 63 ].…”

Section: Introductionmentioning

confidence: 99%

“…Accordingly, Ang-2 is not expressed in the normal adult brain endothelium, but upregulated in brain tumors such as glioblastoma [ 32 , 52 , 57 , 63 ]. Ang-1, in contrast, has shown to be constitutively expressed in non-endothelial cells, such as pericytes [ 47 ]. These findings suggest that Tie2 signaling in activated endothelium is mainly regulated via the expression of Ang-2 [ 47 , 52 ].…”

Section: Introductionmentioning

confidence: 99%

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Angiopoietin-2-induced blood–brain barrier compromise and increased stroke size are rescued by VE-PTP-dependent restoration of Tie2 signaling

et al. 2016

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The homeostasis of the central nervous system is maintained by the blood–brain barrier (BBB). Angiopoietins (Ang-1/Ang-2) act as antagonizing molecules to regulate angiogenesis, vascular stability, vascular permeability and lymphatic integrity. However, the precise role of angiopoietin/Tie2 signaling at the BBB remains unclear. We investigated the influence of Ang-2 on BBB permeability in wild-type and gain-of-function (GOF) mice and demonstrated an increase in permeability by Ang-2, both in vitro and in vivo. Expression analysis of brain endothelial cells from Ang-2 GOF mice showed a downregulation of tight/adherens junction molecules and increased caveolin-1, a vesicular permeability-related molecule. Immunohistochemistry revealed reduced pericyte coverage in Ang-2 GOF mice that was supported by electron microscopy analyses, which demonstrated defective intra-endothelial junctions with increased vesicles and decreased/disrupted glycocalyx. These results demonstrate that Ang-2 mediates permeability via paracellular and transcellular routes. In patients suffering from stroke, a cerebrovascular disorder associated with BBB disruption, Ang-2 levels were upregulated. In mice, Ang-2 GOF resulted in increased infarct sizes and vessel permeability upon experimental stroke, implicating a role of Ang-2 in stroke pathophysiology. Increased permeability and stroke size were rescued by activation of Tie2 signaling using a vascular endothelial protein tyrosine phosphatase inhibitor and were independent of VE-cadherin phosphorylation. We thus identified Ang-2 as an endothelial cell-derived regulator of BBB permeability. We postulate that novel therapeutics targeting Tie2 signaling could be of potential use for opening the BBB for increased CNS drug delivery or tighten it in neurological disorders associated with cerebrovascular leakage and brain edema.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1551-3) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Angiopoietin-2-induced blood–brain barrier compromise and increased stroke size are rescued by VE-PTP-dependent restoration of Tie2 signaling

et al. 2016

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“…Among the drugs targeting angiopoietin signaling, a peptibody that blocks Ang‐2 (and to a lesser extent Ang‐1) is currently being evaluated in clinical phase III for ovarian cancer (Liontos et al , ; Monk et al , ). In conjunction with VEGF and its receptors, the angiopoietin/Tie system is fundamental for blood vessel growth (Augustin et al , ; Eklund & Saharinen, ; Reiss et al , ; Scholz et al , ). Angiopoietin signaling critically drives angiogenesis and remodeling during cancer progression.…”

Section: Introductionmentioning

confidence: 99%

Endothelial cell‐derived angiopoietin‐2 is a therapeutic target in treatment‐naive and bevacizumab‐resistant glioblastoma

et al. 2015

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Glioblastoma multiforme (GBM) is treated by surgical resection followed by radiochemotherapy. Bevacizumab is commonly deployed for anti‐angiogenic therapy of recurrent GBM; however, innate immune cells have been identified as instigators of resistance to bevacizumab treatment. We identified angiopoietin‐2 (Ang‐2) as a potential target in both naive and bevacizumab‐treated glioblastoma. Ang‐2 expression was absent in normal human brain endothelium, while the highest Ang‐2 levels were observed in bevacizumab‐treated GBM. In a murine GBM model, VEGF blockade resulted in endothelial upregulation of Ang‐2, whereas the combined inhibition of VEGF and Ang‐2 leads to extended survival, decreased vascular permeability, depletion of tumor‐associated macrophages, improved pericyte coverage, and increased numbers of intratumoral T lymphocytes. CD206+ (M2‐like) macrophages were identified as potential novel targets following anti‐angiogenic therapy. Our findings imply a novel role for endothelial cells in therapy resistance and identify endothelial cell/myeloid cell crosstalk mediated by Ang‐2 as a potential resistance mechanism. Therefore, combining VEGF blockade with inhibition of Ang‐2 may potentially overcome resistance to bevacizumab therapy.

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Structure and Function of the Blood–Brain Barrier (BBB)

Benz

Liebner

2020

Handbook of Experimental Pharmacology

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The Angiopoietin—Tie System: Common Signaling Pathways for Angiogenesis, Cancer, and Inflammation

Cited by 13 publications

References 121 publications

Angiopoietin-2-induced blood–brain barrier compromise and increased stroke size are rescued by VE-PTP-dependent restoration of Tie2 signaling

Angiopoietin-2-induced blood–brain barrier compromise and increased stroke size are rescued by VE-PTP-dependent restoration of Tie2 signaling

Endothelial cell‐derived angiopoietin‐2 is a therapeutic target in treatment‐naive and bevacizumab‐resistant glioblastoma

Structure and Function of the Blood–Brain Barrier (BBB)

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