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Introduction
Angiopoietins are a family of vascular growth factors that play a role in embryonic and postnatal angiogenesis. It is responsible for assembling and disassembling the endothelial lining of blood vessels. Angiopoietin cytokines are involved with controlling microvascular permeability and allow the smooth muscle cells and smooth muscle-like pericytes to cover the vessels making vasodilation and vasoconstriction possible. Angiopoietin signaling corresponds with the process of angiogenesis. Angiogenesis is the process by which new arteries and veins form from pre-existing blood cells. Overall, angiogenesis proceeds through sprouting, endothelial cell migration, proliferation, and vessel destabilization and stabilization.

There are now four identified angiopoietins: Ang1, Ang2, Ang3, Ang4. In addition, there are a number of proteins that are closely related to angiopoietins (ANGPTL2, ANGPTL3, ANGPTL4,, , ANGPTL7).

Angiopoietin-1 is critical for vessel maturation, adhesion, migration, and survival. Angiopoietin-2, on the other hand, promotes cell death and disrupts vascularization. Yet, when it is in conjunction with vascular endothelial growth factors, or VEGF, it can promote neo-vascularization.

Specific Mechanisms of Angiopoietins
The collective interactions between angiopoietins, tyrosine kinase receptors, vascular endothelial growth factors and their receptors form the two signaling pathways— Tie-1 and Tie-2. The two receptor pathways are named as a result of their role in mediating cell signals by inducing the phosphorylation of specific tyrosines. This in turn initiates the binding and activation of downstream intracellular enzymes, a process known as cell signaling. Although it is highly contested which specific TIE receptors mediate signals downstream of angiogenesis stimulation, it is clear that TIE-2 is capable of activation as a result of binding angiopoietins.

They are mostly exclusive to endothelial cells and bind to tyrosine kinase receptor 2. Angiopoietin proteins 1 through 4 are all ligands for the Tie-2 receptors. Tie-1 heterodimerizes with Tie-2 to enhance and modulate signal transduction of Tie-2 for vascular development and maturation. The tyrosine kinase receptors are typically expressed on vascular endothelial cells and specific macrophages for the immune response. Angiopoietin-1 is a growth factor produced by vascular support cells, specialized pericytes in the kidney, and hepatic stellate cells (ITO) cells in the liver. This growth factor is also a glycoprotein and functions as an agonist for the tyrosine receptor found in endothelial cells. Angiopoietin-1 and tyrosine kinase signaling are essential for regulating blood vessel development, and the stability of mature vessels. Perivascular cells that coat mature vessels express angiopoietin-1, while angiopoietin-2 is expressed by endothelial cells. This angiopoietin also maintains endothelial barrier integrity.

The expression of Angiopoietin-2 in the absence of VEGF leads to endothelial cell death and vascular regression. Increased levels of Ang2 promote tumor angiogenesis, metastasis, and inflammation. Effective means to control Ang2 in inflammation and cancer should have clinical value. Angiopoeitin, more specifically Ang-1 and Ang-2, work hand in hand with vascular endothelial growth factor (VEGF) to mediate angiogenesis. Ang-2 works as an antagonist of Ang-1 and promotes vessel regression if VEGF isn’t present. Ang-2 works with VEGF to facilitate cell proliferation and migration of endothelial cells.

Angiopoietin-1 and angiopoietin-2 are modulators of endothelial permeability and barrier function. Endothelial cells secrete angiopoietin-2 for autocrine signaling while parenchymal cells of the extravascular tissue secrete angiopoietin-2 onto endothelial cells for paracrine signaling. It then binds to the extracellular matrix and is stored within the endothelial cells.

Structure of Angiopoietins
Angiopoietin proteins 1-4 are all ligands for the Tie-2 receptors. TIe-1 heterodimerizes with Tie-2 to enhance and modulate signal transduction of Tie-2. Angiopoietin-1 encodes a 498 amino acid polypeptide with a molecular weight of 57 kDa whereas angiopoietin-2 encodes a 496 amino acid polypeptide. Structurally, angiopoietins have an N-terminal super clustering domain, a central coiled domain, a linker region, and a C terminal fibrinogen-related domain which is responsible for the binding between the ligand and receptor. Angiopoietin-1 and angiopoietin- 2 can form dimers, trimers, and tetramers. Angiopoietin-1 has the ability to form higher order multimers through its super clustering domain. However, not all of the structures can interact with the tyrosine kinase receptor. The tyrosine kinase receptor can only be activated at the tetramer level or higher.

Clinical Relevance
Deregulation of angiopoietin and the tyrosine kinase pathway is common in blood related diseases such as diabetes, malaria, sepsis, and pulmonary hypertension. This is demonstrated by an increased ratio of angiopoietin-2 and angiopoietin-1 in blood serum. For example, angiopoietin-2 is elevated in patients with angiosarcoma.

Angiopoietin-2, is a produced in stored in Weibel-Palade bodies in endothelial cells, and acts as a Tek antagonist, causing the promotion of endothelial activation, destabilization as well as inflammation. Its role during angiogenesis depends on the presence of Vegf-a.

Angiopoietins are relevant in treating cancer as well. During tumor growth, pro-angiogenic molecules and anti-angiogenic molecules are off balance. Equilibrium is disrupted such that the pro-angiogenic molecules are increasing. Angiopoietins have been known to be recruited as well as VEGFs and PDGFs. Clinically, this is relevant for cancer treatments because the inhibition of angiogenesis can aid in suppressing tumor proliferation.

Angiopoietins can also provide an indication on sepsis and a possible treatment. Angiopoietin levels are indicators for sepsis and can be clinically treated to prevent illness. Research on angiopoietin-2 has shown that it is involved in the onset of septic shock. With a fever onset and high levels of angiopoietin-2, the onset of septic shock is likely. It has also been shown that imbalances between angiopoietin-1 and angiopoietin-2 can act independently such that one might signal at high levels while the other remains at normal level signaling.