Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP.
Tomokazu Souma,Benjamin R. Thomson,Stefan Heinen,Isabel Anna Carota,Shinji Yamaguchi,Tuncer Onay,Pan Liu,Asish K. Ghosh,Chengjin Li,Vera Eremina,Young-Kwon Hong,Aris N. Economides,Dietmar Vestweber,Kevin G. Peters,Jing Jin,Susan E. Quaggin +15 more
TL;DR: It is demonstrated that the absence of VEPTP expression in the lymphatic endothelium confers an agonist function of Angiopoietin (ANGPT)–TIE2 receptor tyrosine kinase pathway ligand effect on TIE2, but VEP TP expression in blood endothelia abrogates its activity, providing mechanistic insights needed to advance therapeutic targeting of this pathway.
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Abstract: The angiopoietin (ANGPT)-TIE2/TEK signaling pathway is essential for blood and lymphatic vascular homeostasis. ANGPT1 is a potent TIE2 activator, whereas ANGPT2 functions as a context-dependent agonist/antagonist. In disease, ANGPT2-mediated inhibition of TIE2 in blood vessels is linked to vascular leak, inflammation, and metastasis. Using conditional knockout studies in mice, we show TIE2 is predominantly activated by ANGPT1 in the cardiovascular system and by ANGPT2 in the lymphatic vasculature. Mechanisms underlying opposing actions of ANGPT2 in blood vs. lymphatic endothelium are poorly understood. Here we show the endothelial-specific phosphatase VEPTP (vascular endothelial protein tyrosine phosphatase) determines TIE2 response to ANGPT2. VEPTP is absent from lymphatic endothelium in mouse in vivo, permitting ANGPT2/TIE2-mediated lymphangiogenesis. Inhibition of VEPTP converts ANGPT2 into a potent TIE2 activator in blood endothelium. Our data support a model whereby VEPTP functions as a rheostat to modulate ANGPT2 ligand effect on TIE2.
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Role of Angiopoietin-2 in Vascular Physiology and Pathophysiology.
TL;DR: The activity of Ang2 on blood and lymphatic endothelial cells, its significance in human physiology and disease, and a current view of the molecular signaling pathways regulated by Ang2 in endothelium cells are summarized.
424
The quiescent endothelium: signalling pathways regulating organ-specific endothelial normalcy.
TL;DR: Signalling pathways involved in the maintenance of functionally quiescent endothelia are starting to be identified and are a combination of endocrine, autocrine, paracrine and mechanical inputs.
Single-Cell Analysis of Blood-Brain Barrier Response to Pericyte Loss
Maarja Andaloussi Mäe,Liqun He,Liqun He,Sofia Nordling,Sofia Nordling,Elisa Vazquez-Liebanas,Khayrun Nahar,Bongnam Jung,Xidan Li,Bryan C. Tan,Juat Chin Foo,Amaury Cazenave-Gassiot,Markus R. Wenk,Yvette Zarb,Bàrbara Laviña,Susan E. Quaggin,Marie Jeansson,Marie Jeansson,Chengua Gu,David L. Silver,Michael Vanlandewijck,Michael Vanlandewijck,Eugene C. Butcher,Annika Keller,Christer Betsholtz,Christer Betsholtz +25 more
TL;DR: In this article, pericytes are described as capillary mural cells playing a role in stabilizing newly formed blood vessels during development and tissue repair, and loss of pericyte has been described in several brain d...
137
Angiopoietin/Tie2 signalling and its role in retinal and choroidal vascular diseases: a review of preclinical data.
Antonia M. Joussen,Federico Ricci,Liliana P. Paris,Claudia Korn,Carlos Quezada-Ruiz,Marco A. Zarbin +5 more
TL;DR: The angopoietin/tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (Ang/Tie) pathway is an emerging key regulator in vascular development and maintenance as discussed by the authors.
Disruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias.
Christiane Jungen,Katharina Scherschel,Christian Eickholt,Pawel Kuklik,Niklas Klatt,Nadja I. Bork,Tim Salzbrunn,Fares Alken,Stephan Angendohr,Christiane Klene,Janos Mester,Nikolaj Klöcker,Marieke W. Veldkamp,Udo Schumacher,Stephan Willems,Viacheslav O. Nikolaev,Christian Meyer +16 more
TL;DR: It is shown that cardiac cholinergic neurons modulate ventricular electrophysiology and have an influence on the regulation of ventricular function and arrhythmogenesis.
120
References
Cell signaling by receptor-tyrosine kinases
TL;DR: Understanding of the complex signaling networks downstream from RTKs and how alterations in these networks are translated into cellular responses provides an important context for therapeutically countering the effects of pathogenic RTK mutations in cancer and other diseases.
7.8K
Angiopoietin-2, a Natural Antagonist for Tie2 That Disrupts in vivo Angiogenesis
Maisonpierre Peter C,Chitra Suri,Pamela F. Jones,Sona Bartunkova,Stanley J. Wiegand,Czeslaw Radziejewski,Debra L Compton,Joyce Mcclain,Aldrich Thomas H,Nick Papadopoulos,Thomas J. Daly,Samuel Davis,Thomas N. Sato,George D. Yancopoulos +13 more
TL;DR: The discovery of a negative regulator acting on Tie2 emphasizes the need for exquisite regulation of this angiogenic receptor system.
3.7K
Requisite Role of Angiopoietin-1, a Ligand for the TIE2 Receptor, during Embryonic Angiogenesis
Chitra Suri,Pamela F. Jones,Sybill Patan,Sona Bartunkova,Maisonpierre Peter C,Samuel Davis,Thomas N. Sato,George D. Yancopoulos +7 more
TL;DR: It is shown that mice engineered to lack Angiopoietin-1 display angiogenic deficits reminiscent of those previously seen in mice lacking TIE2, demonstrating that AngiopOietIn-1 is a primary physiologic ligand for TIE1 and that it has critical in vivo angiogenesis actions that are distinct from VEGF and that are not reflected in the classic in vitro assays used to characterize VEGf.
3K
A tissue-specific atlas of mouse protein phosphorylation and expression.
Edward L. Huttlin,Mark P. Jedrychowski,Joshua E. Elias,Tapasree Goswami,Ramin Rad,Sean A. Beausoleil,Judit Villén,Wilhelm Haas,Mathew E. Sowa,Steven P. Gygi +9 more
TL;DR: The data suggest that the "typical" phosphoprotein is widely expressed yet displays variable, often tissue-specific phosphorylation that tunes protein activity to the specific needs of each tissue, and is offered as an online resource for the biological research community.
1.7K
Control of vascular morphogenesis and homeostasis through the angiopoietin–Tie system
TL;DR: The Tie receptors and their angiopoietin (Ang) ligands have been identified as the second vascular tissue-specific receptor Tyr kinase system and provide unique insights into the functions of this vascular signalling system.
1.4K