Angiopoietin

Angiopoietins are endothelial growth factors that play a role in embryonic and postnatal angiogenesis. They also regulate vascular permeability and pathological vascular remodeling in inflammation, tumor angiogenesis and metastasis formation. Angiopoietins are glycosylated proteins that bind to TIE receptors (Tyr kinase with Ig and epidermal growth factor homology domains). The ANG-TIE signaling system achieves this capacity for complex differentiated actions through a variety of mechanisms.

Four angiopoietins are currently known:

• ANGPT1
• ANGPT2
• ANGPTL3
• ANGPT4.

In addition, there are a number of proteins that are closely related to the angiopoietins (angiopoietin-related protein 1, ANGPTL2, ANGPTL3, ANGPTL4, ANGPTL5, ANGPTL6, ANGPTL7, ANGPTL8).

Angiopoietins (Ang1, Ang2) are endothelial growth factors that are ligands for the tyrosine kinase receptor Tie2, which is expressed by endothelial cells. Ang1 promotes the migration, proliferation and survival of endothelial cells, while Ang2 blocks the activation of Tie2 triggered by Ang1.

Angiopoietin-1 is crucial for vascular maturation, adhesion, migration and survival. Angiopoietin-2, on the other hand, promotes cell death and disrupts vessel formation. In conjunction with vascular endothelial growth factors (VEGF), however, it can promote the formation of new vessels.

Both Ang1 and Ang2 are expressed by high-grade astrocytoma cells and endothelial cells. The expression of Ang2 in the absence of VEGF leads to destabilization and regression of the vessels. In vivo, Ang2 expression has been shown to be associated with vascular cell apoptosis, which is associated with vascular regression.

Angiopoietin ligands (ANG1-ANG4) and the TIE receptor tyrosine kinases (TIE1 and TIE2) form an endothelial signaling pathway that is necessary for embryonic cardiovascular and lymphatic development. In adults, this system regulates vascular homeostasis and controls vascular permeability, inflammation and angiogenic responses.

ANG1 has vasoprotective effects. It increases the stability of newly formed vessels, inhibits vascular permeability induced by various inflammatory cytokines and attenuates pathological responses, including fibrosis.

ANG2 can act as both a context-dependent agonist and antagonist of TIE2. Autocrine ANG2 can act as a TIE2 agonist during normal homeostasis in certain vascular beds, e.g. in the lymphatic vasculature. In inflammation, ANG2 acts as an antagonist and promotes endothelial permeability in synergy with inflammatory cytokines.

Elevated serum ANG2 levels have been found in numerous diseases, including cancer, viral and bacterial infections, sepsis and diabetes, and ANG2 levels in the vitreous are elevated in ocular vascular disease.

ANG2-blocking antibodies inhibit angiogenesis and metastasis of tumors in mice. Recombinant ANG1 protein, ANG2-blocking antibodies and inhibitors of vascular endothelial protein tyrosine phosphatase (VE-PTP) reduce inflammation-induced vascular leakage and have therapeutic effects in models of diabetes, atherosclerosis, neovascular eye disease and organ transplantation.

The orphan receptor TIE1 regulates ANG signaling and can promote inflammation and angiogenesis in atherosclerosis and tumors. Mutations in the TIE2 signaling pathway can cause venous malformations and primary congenital glaucoma.

Angiopoietin-like proteins play a variety of roles in the regulation of vascular remodeling. ANGPTL1 inhibits angiogenesis, ANGPTL2 induces angiogenesis and endothelial cell migration, ANGPTL4 is associated with angiogenesis, and ANGPTL6 is associated with endothelial dysfunction in pregnancy-induced hypertension.102 However, the angiopoietin-like proteins may have additional functions beyond regulating angiogenesis. ANGPTL3, ANGPTL4 and ANGPTL8 inhibit lipoprotein lipase. ANGPTL5 is involved in the expansion of hematopoietic stem cells in human umbilical cord blood. ANPTL7 is involved in the remodeling of the extracellular matrix in glaucoma.

The unique function of the ANG-TIE pathway in vascular stabilization also makes this pathway an attractive target in sepsis, organ transplantation, atherosclerosis and vascular complications of diabetes. Drugs targeting the ANG-TIE signaling pathway are in clinical development for oncology and ophthalmology applications. They are intended to complement current vascular endothelial growth factor (VEGF)-based anti-angiogenesis therapies for cancer, wet age-related macular degeneration and macular edema. The ANG-TIE system has emerged as an important area for clinical drug development in the field of oncology and neovascular eye diseases. In ongoing clinical trials, ANG-TIE-targeted drugs are being combined with other anti-angiogenic or immunotherapies. The phosphatase VE-PTP is a negative regulator of TIE2 and represents another therapeutic target.

1. Akwii RG et al. (2021) Targeting the Angiopoietin/Tie Pathway: Prospects for Treatment of Retinal and Respiratory Disorders. Drugs 81:1731-1749.
2. Eklund L et al. (2017) Angiopoietin-Tie signaling in the cardiovascular and lymphatic systems. Clin Sci (Lond) 131:87-103.
3. Fodor LE et al. (2018) Variation in the TEK gene is not associated with asthma but with allergic conjunctivitis. Int J Immunogenet 45:102-108
4. Teichert M et al. (2017) Pericyte-expressed Tie2 controls angiogenesis and vessel maturation. Nat Commun 8:16106.
5. Zhang Y et al. (2019) Angiopoietin-Tie Signaling Pathway in Endothelial Cells: A Computational Model. iScience 20:497-511.