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

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.

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

1997
Identification of Ang-211
Ang-2 identified as a natural antagonist for the Tie2 receptor

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

2000
Ang-1 mechanism in endothelial cell survival20
Ang-1 regulates endothelial cell survival via the Akt/survivin pathway

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

2006
Ang-2 functions during
inflammation23
Ang-2 facilitates endothelial cell responsiveness to inflammatory stimuli

2012
Ang-2 and integrin signalling2
Ang-2 differentially regulates angiogenesis through Tie2 and integrin signalling

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

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

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

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.
References
- Saharinen P, et al. Nat Rev Drug Discov. 2017;16:635–61
- Felcht M, et al. J Clin Invest. 2012;122:1991–2005
- Hakanpaa L, et al. Nat Commun. 2015;30;6:5962
- Regula JT, et al. EMBO Mol Med. 2016;8:1265–88
- Penn JS, et al. Prog Retin Eye Res. 2008;27:331–71
- 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]
- Lowell CA, et al. Methods Mol Biol. 2012;757:369–97
- Souma T, et al. PNAS. 2018;115:1298–303
- Huang H, et al. Nat Rev Cancer. 2010;10:575–85
- Davis S, et al. Cell. 1996;87:1161–69
- Maisonpierre PC, et al. Science. 1997;277:55–60
- Asahara, T, et al. Circ Res. 1998;83:233–40
- Yu X, Ye F. Cells. 2020;9:457
- Holash J, et al. Science. 1999;284:1994–8
- Li P, et al. Int J Clin Exp Pathol. 2015;8:660–64
- Helfrich I, et al. Clin Cancer Res. 2009;15:1384–92
- Choi GH, et al. World J Gastroenerol. 2021;27:4453–67
- Xu Y, et al. Medicine. 2017;96:e8063
- Munakata S, et al. J Castrointest Cancer. 2021;52:237–42
- Kim I, et al. Circ Res. 2000;86:24–29
- Gale NW, et al. Dev Cell. 2002;3:411–23
- Hammes HP, et al. Diabetes. 2004;53:1104–10
- Fiedler U, et al. Nat Med. 2006;12:235–39
- Kienast Y, et al. Clin Cancer Res. 2013;19:6730–40
- Li Z, et al. J Clin Invest. 2020;130:1977–1990
- Chatterjee A, et al. Int J Mol Sci. 2020;21:E3713