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August 21, 2016Journal of Clinical InvestigationOpen Access

Opposing actions of angiopoietin-2 on Tie2 signaling and FOXO1 activation

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Key result

ANG2 acts as a Tie2 agonist to support stable enlargement of normal vessels, but during inflammation, reduction of Tie1 leads to ANG2 antagonism of Tie2, promoting FOXO1-driven ANG2 expression and vascular leakage.

Population

Mouse models under pathogen-free conditions or infected with Mycoplasma pulmonis to induce…

Comparison

Manipulation of ANG2/Tie2 signaling using… vs Control treatments or pathogen-free baseline…

Design

Preclinical

Follow-up

Up to 7 days for infection models; up to 25 weeks for…

Authors

BABreanna M. AllenUniversity of California, San FranciscoEKEmilia A. KorhonenUniversity of HelsinkiMNMaximilian NitschkéGenesys (United States)

Discussion

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Overview

Context-dependent ANG2 effects caution against non-specific targeting in inflammation; leaves open whether Tie1 modulation prevents leakiness in patients.

Structured PICO

P
Population
Mouse models used to study vascular remodeling under pathogen-free conditions and during Mycoplasma pulmonis infection.
I
Intervention
Manipulation of ANG2/Tie2 signaling using anti-ANG2 antibody (REGN910), anti-Tie2 antibody (REGN1376), Tie2 agonists (BowANG1, BowANG2), or genetic overexpression.
C
Comparator
Control treatments (e.g., human IgG) or pathogen-free baseline conditions.
O
Outcome
Vascular remodeling, Tie2 phosphorylation (p-Tie2), FOXO1 activation, ANG2 expression, and vessel leakiness.surrogate

ANG2 acts as a context-dependent regulator of vascular remodeling, functioning as a Tie2 agonist in normal vessels but as an antagonist during inflammation due to Tie1 cleavage, driving a positive feedback loop of vascular leakage.

Limitations

  • Animal models may not fully replicate human pathology
  • Further studies are needed to understand the links between the phosphorylation states of Tie1 and Tie2 and the relationship between Tie1 ectodomain shedding and Tie1 expression

Cite This Study

Allen et al. (2016) studied Vascular remodeling. ANG2 manipulation vs. Control was evaluated on Tie2 phosphorylation, FOXO1 activation, and vascular leakage. ANG2 acts as a Tie2 agonist to support stable enlargement of normal vessels, but during inflammation, reduction of Tie1 leads to ANG2 antagonism of Tie2, promoting FOXO1-driven ANG2 expression and vascular leakage.

synapsesocial.com/papers/6a9627fdd4400ecf0522f7dbhttps://doi.org/10.1172/jci84871
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Angiopoietin-2 Functions as a Tie2 Agonist in Tumor Models, Where It Limits the Effects of VEGF Inhibition2012 · 232 citations
  2. 2Angiopoietin-1 Inhibits Endothelial Cell Apoptosis via the Akt/Survivin Pathway2000 · 639 citations
  3. 3COMP-Ang1: A designed angiopoietin-1 variant with nonleaky angiogenic activity2004 · 262 citations
  4. 4TNF-α drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice2009 · 207 citations
  5. 5Angiopoietin-1 Guides Directional Angiogenesis Through Integrin α v β 5 Signaling for Recovery of Ischemic Retinopathy2013 · 134 citations