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.


Identification of Ang-110

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



Identification of Ang-211

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



Cooperativity between Ang and VEGF12

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


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



Ang-1 mechanism in endothelial cell survival20

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



Ang-2 has agonistic function21

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


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



Ang-2 functions during

Ang-2 facilitates endothelial cell responsiveness to inflammatory stimuli



Ang-2 and integrin signalling2

Ang-2 differentially regulates angiogenesis through Tie2 and integrin signalling



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



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



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.

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

Continue to


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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.



  • 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.


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


  • 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


  • 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)


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


  • 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


  • 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


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