Development of a functional cardiovascular system is dependent on the regulated proliferation, migration and differentiation of endothelial cells in two discrete processes known as vasculogenesis and angiogenesis. Angiogenesis is the formation of new capillaries from pre-existing vessels, whereas vasculogenesis is de novo capillary formation from EPCs (Endothelial Precursor Cells). New capillaries arise from pre-existing larger vessels to give rise to a more complex vascular network with a hierarchy of both large and small vessels (Ref. 1). These sequential vascular developments are tightly regulated by a range of pro- and anti-angiogenic factors, including VEGF (Vascular Endothelial Growth Factor), bFGF (basic Fibroblast Growth Factor ), Thrombospondin, Angiopoietins and more recently, Angptl (Angiopoietin-like proteins) (Ref. 2).

The angiopoietins are a new family of growth factor ligands that bind specifically to the TIE2/Tek RTK (Receptor Tyrosine Kinase). To date, four angiopoietins (Ang1 to 4) bind Tek and behave as either agonists (Ang1 and Ang4) or context-dependent antagonists (Ang2 and Ang3) of Tek kinase activity (Ref. 3). Angiopoietin mainly regulates two pathways that mediate cell motility, the first being through activation of the Phosphatidylinositol-3 Kinase pathway and the second involving Ras pathway (Ref. 4). ANG1 can promote endothelial cell survival through activation of the PI3K pathway, and similar results could be achieved with higher concentrations of ANG2. ANG2 can act as an agonist of the TIE2 receptor in the absence of ANGl and can activate the PI3K-AKT pathway, although with weaker potency than ANGl. ANGl has been shown to stimulate TIE2, AKT and eNOS phosphorylation in HUVECs in a PI3K-dependent manner. PI3K induces conversion of PIP2 (Phosphatidylinositol 4, 5-Bisphosphate) to PIP3 (Phosphatidylinositol 3, 4, 5-Trisphosphate). PIP3 formation is required for phosphorylation of Akt by the kinase PDK-1. Activation of the PI3K pathway contribute to ANGl-induced eNOS phosphorylation, NO production and angiogenesis in coronary artery endothelial cells (Ref. 4). Activation of Akt/PKB (Protein Kinase-B) also result in up-regulation of Caspase-9 and BCL2-Associated Death Promoter, leading to a concomitant increase in cell survival. Angiopoietin-1 can promote migration, sprouting and survival of endothelial cells through activation of different signaling pathways triggered by the Tie2 tyrosine kinase receptor. SHCA adapter proteins are targets of activated tyrosine kinases and are implicated in the transmission of activation signals to the Ras/MAPK (Mitogen-Activated Protein Kinase) pathway. Upstream molecules of the Ras/MAPK pathway, GRB2 and SHP2, acts as binding partners of TIE2. TIE2 also binds DOKR, an adapter molecule structurally homologous to p62DOK and IRS3 (Insulin-Receptor Substrate-3). DOKR is able to recruit the adapter protein Nck, PAK (p21-Activated Kinase) and RASGAP (Ras-GTPase-Activating Protein) (Ref. 5). Two other binding partners and the protein phosphatase SHP2 also use this pathway to potentiate cell migration. The docking protein DOKR is recruited in a phospho-specific manner and in response to associate with Nck, thereby enhancing PAK-dependent cell migration. The exact nature of, and residues involved in, the TIE2-ABIN2 interaction and the hypothetical mechanism by which ABIN2 may inhibit NF-kappaB activation is still under investigation. In contrast, Ang1 does not lead to activation of the receptor but is a naturally occurring antagonist of the receptor (Ref. 4). Ang2 makes mature vessels unstable by blocking the effects of Ang1. This Ang2-mediated vessel destabilization makes the vessels hypersensitive to other classes of angiogenic factors (Ref. 5). A20 binding inhibitor of NF-kappaB activation-2, ABIN-2, also interacts with the endothelial receptor TIE2. ABIN-2 inhibits nuclear factor-kappaB (NF-kappaB) activity and is a possible effector of A20 regulation of NF-kappaB (Ref. 6).

Angiogenesis plays an essential role in physiological processes such as embryonic development, and in pathologic conditions like wound healing, malignant tumor growth and metastasis, rheumatoid arthritis, proliferative diabetic retinopathy, atherosclerosis and postischemic vascularization of the myocardium. Angiogenesis is an essential component of endometrial repair and regeneration following menses. Perturbation of this process is associated with menorrhagia, a common gynecological disorder that results in excessive menstrual bleeding. In some human diseases such as in heart ischemia, this process can be used to restore the vital function of the affected organs. In other diseases such as cancer, aberrant angiogenesis can be therapeutically blocked to prevent disease progression, induce endothelial cell sprouting, promote blood vessel maturation during angiogenesis, and inhibit leakage from adult micro vessels (Ref. 6) via the receptor. Other known endogenous inhibitors that physiologically suppress angiogenesis include angiostatin, endostatin, Interferon-Alpha, platelet factor-4, prolactin, thrombospondin, TIMP1 (Tissue Inhibitors Of Metalloproteinase) and troponin.


Pathway

Angiopoietin-TIE2 Signaling

Key

Pathway Key

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References
  1. Angiogenesis and vasculogenesis in rheumatoid arthritis. Szekanecz Z, Besenyei T, Szentpétery A, Koch AE. Curr Opin Rheumatol. 2010 May;22(3):299-306. Review.
  2. Suppression of the Raf/MEK/ERK signaling cascade and inhibition of angiogenesis by the carboxyl terminus of angiopoietin-like protein 4. Arterioscler Thromb Vasc Biol. 2008 May;28(5):835-40. Epub 2008 Mar 13. Curr Opin Cell Biol. 2009 Apr;21(2):154-65. Epub 2009 Feb 21. Review.
  3. PI3K/AKT/mTOR Pathway in Angiogenesis. Karar J, Maity A. Front Mol Neurosci. 2011;4:51. Epub 2011 Dec 2.
  4. Adaptor ShcA protein binds tyrosine kinase Tie2 receptor and regulates migration and sprouting but not survival of endothelial cells. Audero E, Cascone I, Maniero F, Napione L, Arese M, Lanfrancone L, Bussolino F. J Biol Chem. 2004 Mar 26;279(13):13224-33. Epub 2003 Dec 9.
  5. ABIN-2 protects endothelial cells from death and has a role in the antiapoptotic effect of angiopoietin-1. Tadros A, Hughes DP, Dunmore BJ, Brindle NP.Blood. 2003 Dec 15;102(13):4407-9. Epub 2003 Aug 21.
  6. The role of vasculature and angiogenesis for the pathogenesis of degenerative tendons disease. Pufe T, Petersen WJ, Mentlein R, Tillmann BN. Scand J Med Sci Sports. 2005 Aug;15(4):211-22.