Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell–cell and cell–matrix contacts

Saharinen, Pipsa; Eklund, Lauri; Miettinen, Juho J.; Wirkkala, Riikka; Anisimov, Andrey; Winderlich, Mark; Nottebaum, Astrid F.; Vestweber, Dietmar; Deutsch, Urban; Koh, Gou Young; Olsen, Bjørn R.; Alitalo, Kari

doi:10.1038/ncb1715

Cited by 394 publications

(414 citation statements)

References 41 publications

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“…Antibodies against VE-PTP selectively down-regulate the Tie-2-associated but not the VE-cadherin-associated VE-PTP protein fraction VE-PTP associates with Tie-2 (Fachinger et al, 1999;Saharinen et al, 2008) and with VE-cadherin (Nawroth et al, 2002). We confirmed this by showing that VE-PTP and Tie-2, endogenously expressed in mouse and human endothelial cells, can indeed be coprecipitated (Fig.…”

Section: Ve-ptp Controls Blood Vessel Development By Balancing Tie-2 supporting

confidence: 73%

VE-PTP controls blood vessel development by balancing Tie-2 activity

Winderlich¹,

Keller²,

Cagna³

et al. 2009

J Exp Med

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Section: Ve-ptp Controls Blood Vessel Development By Balancing Tie-2 supporting

confidence: 73%

VE-PTP controls blood vessel development by balancing Tie-2 activity

Winderlich¹,

Keller²,

Cagna³

et al. 2009

J Exp Med

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“…The presence of endothelial markers on osteoprogenitors has also recently been described by others [5]. Additionally, we noted that in some cases, Tie-2 had a surprisingly asymmetric localization on cells, which may indicate a migrating rather than matrix-bound cell, as described by Saharinen et al [32]. Additionally, these cells express musashi and p75 that are phenotypic markers of neural crest stem cells [23].…”

Section: Discussionsupporting

confidence: 84%

Osteoblasts Have a Neural Origin in Heterotopic Ossification

Lazard

Olmsted-Davis

Salisbury

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background Heterotopic ossification (HO) is the process of bone formation at a nonskeletal site. Recently, we showed that the earliest steps occur in sensory nerves. We now extend these studies by identifying unique osteogenic progenitors within the endoneurial compartment of sensory nerves. Questions/purposes We asked: (1) What is the nature of the osteoprogenitor in the endoneurium of peripheral nerves? (2) How do osteoprogenitors travel from the nerve to the site of new bone formation? Methods HO was induced by intramuscular injection of Ad5BMP-2-transduced cells in mice. Osteoprogenitors were identified through immunohistochemistry and then quantified and further characterized by fluorescence-activated cell sorting and immunocytochemistry. The kinetics of the appearance of markers of extravasation was determined by quantitative reverse transcription-polymerase chain reaction. In each experiment mice were injected with bone morphogenetic protein-2 (BMP-2)-producing cells (experimental) or with cells transduced with empty vector or, in some cases, a group receiving no injection (control). Results Induction of HO leads to the expression, within 24 hours, of osteoblast-specific transcription factors in cells in the endoneurium followed by their coordinate disappearance from the nerve at 48 hours. They reappear in 123Clin Orthop Relat Res (2015) 473:2790-2806 DOI 10.1007 Clinical Orthopaedics and Related Research ® A Publication of The Association of Bone and Joint Surgeons® blood also at 48 hours after induction. During vessel entrance they begin to express the tight junction molecule, claudin 5. The cells expressing both the osteoblast-specific transcription factor, osterix, as well as claudin 5, then disappear from circulation at approximately 3 to 4 days by extravasation into the site of new bone formation. These endoneurial osteoprogenitors express neural markers PDGFRa, musashi-1, and the low-affinity nerve growth factor receptor p75(NTR) as well as the endothelial marker Tie-2. In a key experiment, cells that were obtained from mice that were injected with cells transduced with an empty vector, at 2 days after injection, contained 0.83% (SD, 0.07; 95% confidence interval [CI], 0.59-1.05) cells expressing claudin 5. However, cells that were obtained from mice 2 days after injection of BMP-2-producing cells contained 4.5% cells expressing claudin 5 (SD, 0.72%; 95% CI, 2.01-6.94; p \ 0.0015). Further analysis revealed that all of the cells expressing claudin 5 were found to be positive for osteoblast-specific markers, whereas cells not expressing claudin 5 were negative for these same markers. Conclusions The findings suggest that the endoneurial progenitors are the major osteogenic precursors that are used for HO. They exit the nerve through the endoneurial vessels, flow through vessels to the site of new bone formation, and then extravasate out of the vessels into this site. Clinical Relevance The biogenesis of osteoblasts in HO is very different than expected and shows that HO is, at least in par...

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“…17 Ang1 induces rapid Tie2 receptor phosphorylation, and its effects in endothelial cells are dependent on cell confluence and tethering of the Tie2 receptor at cell-cell or cell-matrix contacts. 18,19 Ang2 and Ang3 were initially reported to be incapable of inducing phosphorylation of Tie2 and therefore considered as Tie2 antagonists. 14,20 However, recent data show that Ang2, like Ang1, can activate Tie2 signaling, suggesting that the effects of Ang2 are context-dependent.…”

mentioning

confidence: 99%

Angiopoietin/Tie2 Signaling Transforms Capillaries into Venules Primed for Leukocyte Trafficking in Airway Inflammation

Fuxe

Lashnits

O’Brien

et al. 2010

The American Journal of Pathology

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Vascular endothelial growth factor (VEGF) is a key angiogenic factor in tumors, but less is known about what drives vascular remodeling in inflammation,where plasma leakage and leukocyte influx are prominent features. In chronic airway inflammation in mice infected by the bacterium Mycoplasma pulmonis (M. pulmonis), the segment of the microvasculature that supports leukocyte adhesion and migration expands through remodeling of capillaries into vessels with features of venules. Here, we report that the angiopoietin/Tie2 pathway is an essential driving force for capillary remodeling into venules in M. pulmonisinfected mouse airways. Similar to M. pulmonis infection, systemic overexpression of angiopoietin-1 (Ang1) resulted in remodeling of airway capillaries into venular-like vessels that expressed venous markers like Pselectin, ICAM-1, and EphB4 and were sites of leukocyte adhesion during lipopolysaccharide-induced acute inflammation. Ang1 and Ang2 protein increased in M. pulmonis-infected mouse airways but came from different cellular sources: Ang1 was expressed in infiltrating neutrophils and Ang2 in endothelial cells. Indeed, systemic administration of soluble Tie2 inhibited capillary remodeling, induction of venous markers, and leukocyte influx in M. pulmonis-infected mouse airways. Together, these findings suggest that blockade of the Ang/ Tie2 pathway may represent a therapeutic approach in airway inflammation.

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Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell–cell and cell–matrix contacts

Cited by 394 publications

References 41 publications

VE-PTP controls blood vessel development by balancing Tie-2 activity

VE-PTP controls blood vessel development by balancing Tie-2 activity

Osteoblasts Have a Neural Origin in Heterotopic Ossification

Angiopoietin/Tie2 Signaling Transforms Capillaries into Venules Primed for Leukocyte Trafficking in Airway Inflammation

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