Angiopoietin/Tie Pathway

The angiopoietin (Ang)-Tie signaling pathway is an important signaling pathway involved in vascular development, angiogenesis and remodeling, as well as in the regulation of vascular permeability, homeostasis, quiescence and stability (Eklund and Saharinen 2013). Over the past decade, the angiopoietin-tie signaling pathway has been intensively researched in the search for therapeutic options for many diseases. In the cardiovascular system, dysregulation of the angiopoietin-Tie signaling axis has been associated with vascular impairment, ischemia/reperfusion injury, the development of atherosclerotic plaques, and peripheral arterial disease. In eye diseases such as diabetic macular edema and wet age-related macular degeneration, angiopoietin-Tie signaling plays a crucial role in the regulation of retinal and choroidal neovascularization and vascular leakage. The role of Tie2 in cancer and inflammation is also being actively investigated. Angiopoietin-1 (Ang1) acts as a neuroprotective agent that inhibits neuronal apoptosis.

The angiopoietin family consists of the proteins (angiopoietin-) Ang1, Ang2, Ang3 and Ang4, all of which bind to the receptor Tie2. Ang1 and Ang2 have been identified as the most important ligands for Tie2. Ang3 and Ang4 are mouse and human orthologs that are less well studied and whose biological functions are unclear. Ang1, the natural agonist of Tie2, binds and activates Tie2 to promote vascular stability and is expressed by quiescent mature vessels. Ang2 has historically been considered an antagonist that competitively inhibits the binding of Ang1 and is usually secreted in diseased or remodeled vessels. Recent discoveries that Ang2 can also act as an agonist under certain conditions suggest that the role of Ang2 is highly context-dependent.

Native Ang1 is present in a highly oligomerized form and forms higher order tetrameric or multimeric structures, whereas native Ang2 is present in a low oligomeric form and mainly forms dimers, trimers or tetramers. Ligand binding and ligand-specific responses of Tie2, including its trafficking and activation, have been shown to be influenced by the oligomerization state of the ligand, with the tetrameric form being the lowest oligomeric form of the ligand required for Tie2 activation (Kim M et al. 2016) .

Activation of Tie2 by Ang1 or Ang2 leads to internalization of the receptor and release of ligands. Vascular endothelial protein tyrosine phosphatase (VE-PTP) regulates the activation of Tie2 by catalyzing its dephosphorylation (Zhang Y et al. 2019).

Activation of Tie2 by Ang1 or Ang2 leads to internalization of the receptor and release of ligands. Vascular endothelial protein tyrosine phosphatase (VE-PTP) regulates the activation of Tie2 by catalyzing its dephosphorylation (Zhang Y et al. 2019).

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