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
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Key players in the Ang–Tie signalling pathway

Ang-1 and Ang-2 bind to the Tie2 receptor and are
important regulators of vascular stability.1

Select a ligand or receptor to learn more

The ligands and receptors below are part of or interact with the angiopoietin pathway.

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Discovery of the angiopoietin
pathway: A historical snapshot

Key milestones in our understanding of the Ang–Tie pathway — from early learnings to new
discoveries of its role in retinal diseases.

1996

Identification of Ang-110

Ang-1 identified as a ligand for the Tie2 receptor that could induce Tie2 activation in endothelial cells

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1997

Identification of Ang-211

Ang-2 identified as a natural antagonist for the Tie2 receptor

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1998

Cooperativity between Ang and VEGF12

Ang-1 and Ang-2 modulate VEGF-induced postnatal neovascularisation

1999

Role of VEGF and Ang-2 in tumour angiogenesis and growth13,14

VEGF and Ang-2 work together to initiate tumour angiogenesis and growth

Subsequent studies have suggested an association between Ang-2 serum levels and cancer progression, suggesting a potential role for Ang-2 as a prognostic factor15–19

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2000

Ang-1 mechanism in endothelial cell survival20

Ang-1 regulates endothelial cell survival via the Akt/survivin pathway

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2002

Ang-2 has agonistic function21

Ang-2 is agonistic in lymphatic vessels and antagonistic in blood vessels

2004

Role of Ang-2 in pericyte dropout (DR model)22

Upregulation of Ang-2 plays a critical role in the loss of pericytes in the diabetic retina

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2006

Ang-2 functions during
inflammation23

Ang-2 facilitates endothelial cell responsiveness to inflammatory stimuli

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2012

Ang-2 and integrin signalling2

Ang-2 differentially regulates angiogenesis through Tie2 and integrin signalling

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2013

Ang-2 and VEGF blockade impairs both tumour angiogenesis and metastasis24

Inhibiting the synergistic roles of Ang-2 and VEGF impairs tumour angiogenesis and metastasis, and enhances vessel maturation, with increased pericyte coverage

As such, numerous molecules are currently under investigation in cancer studies

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2016

Ang-2 is elevated in patients with retinal diseases4

Ang-2 levels are elevated in vitreous samples of patients with nAMD, DR, PDR, and RVO

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2020

Role of Ang-2 in neuroinflammation in a model of multiple sclerosis25

Ang-2 blockade ameliorates autoimmune neuroinflammation by inhibiting leukocyte recruitment into the CNS in a rodent model of multiple sclerosis

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Upregulation of Ang-2 via a Tie2-dependent positive-feedback loop26

High glucose in the presence of retinal damage further compounds vascular damage through Ang-2’s own upregulation and release in a positive feedback loop

AMD, age-related macular degeneration; Ang, angiopoietin; CNS, central nervous system; DR, diabetic retinopathy; 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; VE-PTP, vascular endothelial protein tyrosine phosphate.

Explore how the downstream effects of Ang–Tie signalling impact vascular stability under normal and pathologic conditions…

Continue to

References

  1. Saharinen P, et al. Nat Rev Drug Discov. 2017;16:635–61
  2. Felcht M, et al. J Clin Invest. 2012;122:1991–2005
  3. Hakanpaa L, et al. Nat Commun. 2015;30;6:5962
  4. Regula JT, et al. EMBO Mol Med. 2016;8:1265–88 
  5. Penn JS, et al. Prog Retin Eye Res. 2008;27:331–71
  6. Duffy AM, et al. Vascular endothelial growth factor (VEGF) and its role in non-endothelial cells: Autocrine signalling by VEGF. In: Madame Curie Bioscience Database. https://www.ncbi.nlm.nih.gov/books/NBK6482 [last accessed August 2022]
  7. Lowell CA, et al. Methods Mol Biol. 2012;757:369–97
  8. Souma T, et al. PNAS. 2018;115:1298–303
  9. Huang H, et al. Nat Rev Cancer. 2010;10:575–85
  10. Davis S, et al. Cell. 1996;87:1161–69
  11. Maisonpierre PC, et al. Science. 1997;277:55–60
  12. Asahara, T, et al. Circ Res. 1998;83:233–40
  13. Yu X, Ye F. Cells. 2020;9:457
  14. Holash J, et al. Science. 1999;284:1994–8
  15. Li P, et al. Int J Clin Exp Pathol. 2015;8:660–64
  16. Helfrich I, et al. Clin Cancer Res. 2009;15:1384–92
  17. Choi GH, et al. World J Gastroenerol. 2021;27:4453–67
  18. Xu Y, et al. Medicine. 2017;96:e8063
  19. Munakata S, et al. J Castrointest Cancer. 2021;52:237–42
  20. Kim I, et al. Circ Res. 2000;86:24–29
  21. Gale NW, et al. Dev Cell. 2002;3:411–23 
  22. Hammes HP, et al. Diabetes. 2004;53:1104–10
  23. Fiedler U, et al. Nat Med. 2006;12:235–39
  24. Kienast Y, et al. Clin Cancer Res. 2013;19:6730–40
  25. Li Z, et al. J Clin Invest. 2020;130:1977–1990 
  26. Chatterjee A, et al. Int J Mol Sci. 2020;21:E3713
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The Ang–Tie pathway

In addition to Ang-1 and Ang-2, other key players of the Ang–Tie signalling pathway include the Tie2 receptor and the Tie2 modulators Tie1 and VE-PTP.

The Ang–Tie pathway also cross talks with integrins (through direct Ang-2–integrin signalling) and VEGFR, via the signalling of downstream kinases.

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Ang-21-4

  • 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 Ang-2–Tie2 signalling in pathologic conditions and vascular instability.
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Ang-11,2

  • 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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VEGF1,5,6

  • Vascular endothelial growth factor essential for angiogenesis
  • VEGFR agonist
  • Upregulated in pathologic conditions
  • Expressed by vascular endothelial cells. In addition, VEGF is also expressed on numerous non-endothelial cells, some of which include neuronal cells (e.g. astrocytes), glial cells (e.g. Müller cells), epithelial cells (e.g. retinal pigment epithelium), stromal cells, haematopoietic cells, chondrocytes, and cancer cells
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Integrins2,7

  • Transmembrane receptors that regulate cell–cell and cell–matrix adhesion as well as transmembrane signalling
  • Modulate signalling via the Ang–Tie pathway by receptor sensitisation or internalisation and degradation
  • αvβ3, αvβ5, and α5β1 integrins are receptors for Ang-2
  • Expressed on all nucleated cells of multicellular animals. This includes endothelial cells, and non-endothelial cells (e.g. fibroblasts, myocytes, glioma, and breast cancer cells)
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VE-PTP1,8

  • Vascular endothelial protein tyrosine phosphatase
  • Expressed by vascular (not lymphatic) endothelial cells; upregulated in hypoxic conditions
  • Negative regulator of Tie2
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Tie21,9

  • 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
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Tie11,8

  • Transmembrane tyrosine kinase 
  • Expressed by both vascular and lymphatic endothelial cells
  • Colocalises with Tie2 at cell–cell contacts, but exact role in Tie2 signalling is unclear
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VEGFR5

  • Transmembrane tyrosine kinase
  • Expressed by multiple cell types
  • Receptor for VEGF