Angiopoietin

Protein family

Angiopoietin is part of a family of vascular growth factors that play a role in embryonic and postnatal angiogenesis. Angiopoietin signaling most directly corresponds with angiogenesis, the process by which new arteries and veins form from preexisting blood vessels. Angiogenesis proceeds through sprouting, endothelial cell migration, proliferation, and vessel destabilization and stabilization. They are responsible for assembling and disassembling the endothelial lining of blood vessels. Angiopoietin cytokines are involved with controlling microvascular permeability, vasodilation, and vasoconstriction by signaling smooth muscle cells surrounding vessels. There are now four identified angiopoietins: ANGPT1, ANGPT2, ANGPTL3, ANGPT4. In addition, there are a number of proteins that are closely related to ('like') angiopoietins (Angiopoietin related protein 1, , , , , , , ). 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.

Structurally, angiopoietins have an N terminal super clustering domain, a central coiled domain, a linker region, and a C terminal fibrinogen related domain responsible for the binding between the ligand and receptor. Although which specific TIE receptors mediate signals downstream of angiogenesis stimulation is highly contested, it is clear that TIE 2 is capable of activation as a result of binding angiopoietins. Angiopoietin proteins 1 through 4 are all ligands for Tie 2 receptors. Tie 1 heterodimerizes with Tie 2 to enhance and modulate signal transduction of Tie 2 for vascular development and maturation. These Tyrosine kinase receptors are typically expressed on vascular endothelial cells and specific macrophages for immune responses. Angiopoietin 1 and tyrosine kinase signaling are essential for regulating blood vessel development and the stability of mature vessels. 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 VEGF to mediate angiogenesis. Ang 2 works as an antagonist of Ang 1 and promotes vessel regression if VEGF is not present. Ang 2 works with VEGF to facilitate cell proliferation and migration of endothelial cells. Changes in expression of Ang 1, Ang 2 and VEGF have been reported in the rat brain after cerebral ischemia.

To migrate, the endothelial cells need to loosen the endothelial connections by breaking down the basal lamina and the ECM scaffold of blood vessels. These connections are a key determinant of vascular permeability and relieve peri endothelial cell contact, which is also a major factor in vessel stability and maturity. After the physical barrier is removed, under the influence of the growth factors VEGF with addition contributions of other factors like angiopoietin 1, integrins, and chemokines play an essential role. VEGF and ang 1 are involved in endothelial tube formation.

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, which then binds to the extracellular matrix and is stored within the endothelial cells.

Angiopoietin 2 has been proposed as a biomarker in different cancer types. Angiopoietin 2 expression levels are proportional to the cancer stage for both small and non small cell lung cancers. It has been also implicated to play role in hepatocellular and endometrial carcinoma induced angiogenesis. Experiments using blocking antibodies for angiopoietin 2 have shown to decrease metastasis to lungs and lymph nodes.

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. To be specific, angiopoietin levels provide an indication for sepsis. Research on angiopoietin 2 has shown that it is involved in the onset of septic shock. The combination of fever and high levels of angiopoietin 2 are correlated with a greater prospect of the development of septic shock. It has also been shown that imbalances between angiopoietin 1 and angiopoietin 2 signaling can act independently of each other. One angiopoietin factor can signal at high levels while the other angiopoieting factor remains at baseline level signaling. angiogenesis, and overall survival in oral squamous cell carcinoma. Circulating angiopoietin 2 is a marker for early cardiovascular disease in children on chronic dialysis. Kaposi's sarcoma associated herpesvirus induces rapid release of angiopoietin 2 from endothelial cells. Angiopoietin 2 is elevated in patients with angiosarcoma. Research has shown angiopoietin signaling to be 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 number of pro angiogenic molecules are increased. Angiopoietins have been known to be recruited as well as VEGFs and platelet derived growth factors (PDGFs). This is relevant for clinical use relative to cancer treatments because the inhibition of angiogenesis can aid in suppressing tumor proliferation.