A new slant in retinal diseases

Discover how angiopoietins regulate vascular stability under normal conditions and drive vascular instability in retinal and choroidal vascular diseases.

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At a glance

Beyond VEGF

What are angiopoietins?

Angiopoietins (Ang) are a family of angiogenic growth factors, with Ang-1 and Ang-2 being best characterised for their key roles in vascular development and vascular stability.1

Hear from the experts:
Introduction to angiopoietins

Pipsa Saharinen, PhD

University of Helsinki

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Select a ligand or receptor to learn more

Learn about other key players of the Ang–Tie pathway and view a timeline of key discoveries...

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Ang-Tie signalling and vascular stability

Ang-1–Tie2 signalling promotes vascular stability, maintaining homeostasis. When Ang-2 is upregulated, Ang-2–Tie2 binding drives vascular instability.1

Hear from the experts:
Vascular stability:
What is it really?

Patricio G. Schlottmann, MD

Organizacion Medica de Investigacion

Use the switch to view different conditions

Normal conditions

Pathologic conditions

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Vascular stability 1,5,6

Under normal conditions, Ang-1 is expressed at higher levels than Ang-2, maintaining vascular homeostasis.

In healthy vessels, Ang-1–Tie2 signalling promotes vascular stability by maintaining endothelial cell integrity and cell junctions.

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Vascular instability 1,9-11

Under pathologic conditions, Ang-2 and VEGF are upregulated following an angiogenic switch (shift in the balance of pro- and anti-angiogenic factors).

Ang-2 competes with Ang-1 for binding to the Tie2 receptor. Ang-2–Tie2 binding leads to inhibition of Tie2.

Ang-2 and VEGF drive vascular instability characterised by:

  • Vascular leakage
  • Neovascularisation
  • Inflammation
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Angiopoietins:
Key regulators of vascular stability

Download a detailed illustration showing how Ang-1 and Ang-2
promote vascular stability or instability.

Take a closer look at vascular instability and downstream effects of Ang–Tie signalling...

Explore the evidence

Clinical relevance

Ang-2 levels are elevated in retinal and choroidal vascular diseases, whereas Ang-1 levels remain balanced.7,12

Hear from the experts:
It’s all in the balance:
Ang-1 vs Ang-2

Anat Loewenstein, MD

Tel Aviv Medical Center

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Preclinical evidence

Preclinical evidence has shown that Ang-2 and VEGF have distinct effects but also work together to drive vascular instability characterised by vascular leakage, neovascularisation, and inflammation.7,13-15

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Hear from the experts:
Ang-2 and vascular instability: Explore the evidence

Charles Wykoff, MD, PhD

Retina Consultants of Houston

Uncover the evidence supporting the role of Ang-2 in retinal diseases...

Eye Travel Systems 2.0

Explore our interactive video to see how VEGF and angiopoietins promote vascular instability, leading to DME and nAMD.

Start your voyage here…

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Start your voyage here…

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AMD, age-related macular degeneration; Ang, angiopoietin; DME, diabetic macular edema; DR, diabetic retinopathy; IVT, intravitreal; nAMD, neovascular age-related macular degeneration; PDR, proliferative diabetic retinopathy; RVO, retinal vein occlusion; Tie, tyrosine kinase with immunoglobulin-like domains; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

References

  1. Saharinen P, et al. Nat Rev Drug Discov. 2017;16:635–61
  2. Chakravarthy U, et al. Retina. 2018;38:343–51
  3. Swaroop A, et al. Annu Rev Genomics Hum Genet. 2009
  4. Ciulla TA, et al. Ophthalmol Retina. 2020;4:19–308
  5. Felcht M, et al. J Clin Invest. 2012;122:1991–2005
  6. Hakanpaa L, et al. Nat Commun. 2015;30;6:5962
  7. Regula JT, et al. EMBO Molecular Med. 2016;8(11):1265–88
  8. Huang H, et al. Nat Rev Cancer. 2010;10:575–85
  9. Klaassen I, et al. Prog Retin Eye Res. 2013;34:19–48
  10. Bolinger MT, et al. Int J Mol Sci. 2016;17:1498
  11. Fiedler U, Augustin HG. Trends Immunol. 2006;27:552–8
  12. Regula JT, et al. EMBO Mol Med. 2019;11:e10666
  13. Benest AV, et al. PLoS One. 2013;8:e70459
  14. Chakravarthy U, et al. Presented at ARVO May 2020, Virtual Meeting
  15. Fiedler U, et al. Nat Med. 2006;12:235–9

Learn more about the key players of the Ang–Tie pathway, and uncover a timeline of key discoveries…

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Ang-1
Ang-1 levels in human vitreous samples
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Median values

Adapted from Regula JT, et al. EMBO Mol Med. 2019;11:e10666.

Ang-1 levels were similar in the vitreous samples from patients with retinal or choroidal vascular diseases and in samples from healthy individuals, suggesting stable expression in normal and pathologic conditions.7,12

Ang-2
Ang-2 levels in human vitreous samples
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Median values

*p<0.05; ****p<0.0001.

A nonparametric Kruskal–Wallis analysis followed by Dunn’s method for multiple comparisons was used to show significant differences of the groups to control.

Adapted from Regula JT, et al. EMBO Molecular Med. 2016;8(11):1265–88.

Ang-2 levels are increased in the vitreous of patients with retinal or choroidal vascular diseases, including AMD, DR, and RVO,2,3 supporting a role for the Ang-2–Tie2 pathway in these pathologic conditions.

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The Ang–Tie pathway1

Ang-1 and Ang-2 are ligands to the Tie2 receptor. Binding of Ang-1 results in Tie2 receptor activation, leading to downstream signalling that promotes vascular stability.

Under pathologic conditions, Ang-2 competes with Ang-1 in binding to the Tie2 receptor, preventing its activation and promoting vascular instability.

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Ang-21,5-7

  • Angiogenic growth factor
  • Produced mainly by endothelial cells; expressed at lower levels than Ang-1 under normal conditions
  • Expression and function are context dependent:
    • Tie2 antagonist under pathologic conditions
    • Can also act via integrins under certain conditions
  • Levels are increased in retinal diseases (including AMD, DR, and RVO), supporting a role for the Ang-2–Tie2 pathway in pathologic conditions and vascular instability
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Ang-11,5

  • Angiogenic growth factor
  • Constitutively expressed by multiple cell types and maintained at high levels under normal conditions
  • Tie2 receptor agonist
  • Maintains vascular stability
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Tie21,8

  • Transmembrane tyrosine kinase 
  • Constitutively active in stable blood vessels; expressed at high levels by pericytes and the blood endothelium
  • Receptor for Ang-1 and Ang-2