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
Ang-1 and Ang-2 bind to the Tie2 receptor and are important regulators of vascular stability.1
In addition to Ang-1 and Ang-2, other key factors in the Ang–Tie signalling pathway include the receptor Tie2 and the Tie2 modulators Tie1 and VE-PTP.
The Ang–Tie pathway interacts with integrins (via direct Ang-2–integrin signalling) and VEGFR via downstream kinase signalling.
- angiogenic growth factor
- it is produced mainly by endothelial cells, lower levels of Ang-1 under normal conditions
- expression and function are context dependent
- Tie2 antagonist in pathological conditions
- it can also act through integrins under certain conditions
- values are increased in retinal disease (including AMD, DR, and RVO), where Ang -2 displaces Ang-1, binds to Tie2, and the resulting signaling leads to 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
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-18
Ang-1 identified as a ligand for the Tie2 receptor that could induce Tie2 activation in endothelial cells
Identification of Ang-29
Ang-2 identified as a natural antagonist for the Tie2 receptor
Role of VEGF and Ang-2 in tumour angiogenesis and growth11, 12
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 factor13 – 17
Ang-1 mechanism in endothelial cell survival18
Ang-1 regulates endothelial cell survival via the Akt/survivin pathway
Ang-2 has agonistic function19
Ang-2 is agonistic in lymphatic vessels and antagonistic in blood vessels
Ang-2 is agonistic in lymphatic vessels and antagonistic in blood vessels20
Upregulation of Ang-2 plays a critical role in the loss of pericytes in the diabetic retina
Ang-2 functions during inflammation21
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 metastasis22
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 sclerosis23
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 loop24
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 effects of Ang–Tie signalling influence vascular stability under normal and pathological conditions…
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