Jump to content

Angiopoietin

From Wikipedia, the free encyclopedia
(Redirected fromAngiopoietins)
Not to be confused withangiogenin.
angiopoietin 1
Identifiers
SymbolANGPT1
NCBI gene284
HGNC484
OMIM601667
RefSeqNM_001146
UniProtQ15389
Other data
LocusChr. 8q22.3-8q23
Search for
StructuresSwiss-model
DomainsInterPro
angiopoietin 2
Crystal structure of the human angiopoietin-2 receptor binding domain.[1]
Identifiers
SymbolANGPT2
NCBI gene285
HGNC485
OMIM601922
RefSeqNM_001147
UniProtO15123
Other data
LocusChr. 8p23
Search for
StructuresSwiss-model
DomainsInterPro

Angiopoietinis part of a family of vasculargrowth factorsthat play a role in embryonic and postnatalangiogenesis.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.[2]Angiopoietincytokinesare involved with controlling microvascular permeability, vasodilation, and vasoconstriction by signalingsmooth muscle cellssurrounding vessels.[3] There are now four identified angiopoietins:ANGPT1,ANGPT2,ANGPTL3,ANGPT4.[4]

In addition, there are a number of proteins that are closely related to ('like') angiopoietins (Angiopoietin-related protein 1,ANGPTL2,ANGPTL3,ANGPTL4,ANGPTL5,ANGPTL6,ANGPTL7,ANGPTL8).[5]

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, orVEGF,it can promote neo-vascularization.[6]

Structure

[edit]
Angiopoietin protein structure. It consists of theN-terminussuper cluster domain, the linker region, the central coiled domain, and the binding site at theC terminus.

Structurally, angiopoietins have anN-terminalsuper clustering domain, a central coiled domain, a linker region, and aC-terminalfibrinogen-related domain responsible for the binding between the ligand and receptor.[6]

Angiopoietin-1 encodes a 498 amino acidpolypeptidewith a molecular weight of 57 kDa whereas angiopoietin-2 encodes a 496 amino acid polypeptide.[7]

Only clusters/multimers activate receptors

[edit]

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 receptor can only be activated at the tetramer level or higher.[6]

Specific mechanisms

[edit]

Tie pathway

[edit]

The collective interactions between angiopoietins,receptor tyrosine kinases,vascular endothelial growth factorsand their receptors form the two signaling pathways—Tie-1andTie-2.The two receptor pathways are named as a result of their role in mediating cell signals by inducing thephosphorylationof specific tyrosines. This in turn initiates the binding and activation of downstream intracellularenzymes,a process known as cell signaling.

Tie-2

[edit]

Tie-2/Ang-1 signaling activates β1-integrinand N-cadherinin LSK-Tie2+ cells and promoteshematopoietic stem cell(HSC) interactions withextracellular matrixand its cellular components. Ang-1 promotes quiescence of HSC in vivo. This quiescence or slow cell cycling of HSCs induced by Tie-2/Ang-1 signaling contributes to the maintenance of long-term repopulating ability of HSC and the protection of the HSC compartment from various cellular stresses. Tie-2/Ang-1 signaling plays a critical role in the HSC that is required for the long-term maintenance and survival of HSC in bone marrow. In theendosteum,Tie-2/Ang-1 signaling is predominantly expressed byosteoblasticcells.[8]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 allligandsfor 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 specificmacrophagesfor immune responses.[6]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 aglycoproteinand functions as an agonist for the tyrosine receptor found in endothelial cells.[9]Angiopoietin-1 and tyrosine kinase signaling are essential for regulating blood vessel development and the stability of mature vessels.[9]

The expression of Angiopoietin-2 in the absence of vascular endothelial growth factor (VEGF) leads to endothelial cell death and vascular regression.[10]Increased levels of Ang2 promote tumor angiogenesis,metastasis,and inflammation. Effective means to control Ang2 in inflammation and cancer should have clinical value.[11]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.[12]Changes in expression of Ang-1, Ang-2 and VEGF have been reported in the rat brain after cerebral ischemia.[13][14]

Angiogenesis signaling

[edit]

To migrate, the endothelial cells need to loosen the endothelial connections by breaking down thebasal laminaand 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, andchemokinesplay an essential role. VEGF and ang-1 are involved in endothelial tube formation.[15]

Vascular permeability signaling

[edit]

Angiopoietin-1 and angiopoietin-2 are modulators of endothelial permeability and barrier function. Endothelial cells secrete angiopoietin-2 forautocrine signalingwhileparenchymalcells of the extravascular tissue secrete angiopoietin-2 onto endothelial cells forparacrine signaling,which then binds to the extracellular matrix and is stored within the endothelial cells.[7]

Cancer

[edit]

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.[16]

Clinical relevance

[edit]

Deregulation of angiopoietin and the tyrosine kinase pathway is common in blood-related diseases such asdiabetes,malaria,[17]sepsis,andpulmonary hypertension.This[clarification needed]is demonstrated by an increased ratio of angiopoietin-2 and angiopoietin-1 in blood serum. To be specific, angiopoietin levels provide an indication forsepsis.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.[2]

Angiopoietin-2 is produced and stored inWeibel-Palade bodiesin endothelial cells and acts as aTEK tyrosine kinaseantagonist. As a result, the promotion of endothelial activation, destabilization, and inflammation are promoted. Its role during angiogenesis depends on the presence of Vegf-a.[9]

Serum levels of angiopoietin-2 expression are associated with the growth ofmultiple myeloma,[18]angiogenesis, and overall survival in oralsquamous cell carcinoma.[19]Circulating angiopoietin-2 is a marker for earlycardiovascular diseasein children on chronicdialysis.[20]Kaposi's sarcoma-associated herpesvirusinduces rapid release of angiopoietin-2 from endothelial cells.[21]

Angiopoietin-2 is elevated in patients withangiosarcoma.[22]

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.[23]

References

[edit]
  1. ^PDB:1Z3U​;Barton WA, Tzvetkova D, Nikolov DB (May 2005)."Structure of the angiopoietin-2 receptor binding domain and identification of surfaces involved in Tie2 recognition".Structure.13(5): 825–32.doi:10.1016/j.str.2005.03.009.PMID15893672.
  2. ^abAlves BE, Montalvao SA, Aranha FJ, Siegl TF, Souza CA, Lorand-Metze I, et al. (2010)."Imbalances in serum angiopoietin concentrations are early predictors of septic shock development in patients with post chemotherapy febrile neutropenia".BMC Infect Dis.10:143.doi:10.1186/1471-2334-10-143.PMC2890004.PMID20509945.
  3. ^Scott F. Gilbert (10 April 2010).Developmental Biology (Loose Leaf).Sinauer Associates Incorporated.ISBN978-0-87893-558-1.
  4. ^Valenzuela DM, Griffiths JA, Rojas J, Aldrich TH, Jones PF, Zhou H, McClain J, Copeland NG, Gilbert DJ, Jenkins NA, Huang T, Papadopoulos N, Maisonpierre PC, Davis S, Yancopoulos GD (Apr 1999)."Angiopoietins 3 and 4: Diverging gene counterparts in mice and humans".Proc Natl Acad Sci U S A.96(5): 1904–9.Bibcode:1999PNAS...96.1904V.doi:10.1073/pnas.96.5.1904.PMC26709.PMID10051567.
  5. ^Santulli G (2014)."Angiopoietin-like proteins: a comprehensive look".Frontiers in Endocrinology.5:4.doi:10.3389/fendo.2014.00004.PMC3899539.PMID24478758.
  6. ^abcdFagiani E, Christofori G (2013). "Angiopoietins in angiogenesis".Cancer Lett.328(1): 18–26.doi:10.1016/j.canlet.2012.08.018.PMID22922303.
  7. ^abSarah Y. Yuan; Robert R. Rigor (30 September 2010).Regulation of Endothelial Barrier Function.Morgan & Claypool Publishers.ISBN978-1-61504-120-6.
  8. ^Arai, F. (July 11, 2008)."Quiescent stem cells in the niche".Stembook.Cambridge, MA: Harvard Stem Cell Institute.doi:10.3824/stembook.1.6.1.PMID20614597.
  9. ^abcJeansson M, Gawlik A, Anderson G, Li C, Kerjaschki D, Henkelman M, et al. (2011)."Angiopoietin-1 is essential in mouse vasculature during development and in response to injury".J Clin Invest.121(6): 2278–89.doi:10.1172/JCI46322.PMC3104773.PMID21606590.
  10. ^Harmey, Judith (2004).VEGF and cancer.Georgetown, Tex: Landes Bioscience/Eurekah.com New York, N.Y. Kluwer Academic/Plenum Publishers.ISBN0-306-47988-5.
  11. ^Eklund L, Saharinen P (2013). "Angiopoietin signaling in the vasculature".Exp Cell Res.319(9): 1271–80.doi:10.1016/j.yexcr.2013.03.011.PMID23500414.
  12. ^Lim HS, Blann AD, Chong AY, Freestone B, Lip GY (2004)."Plasma vascular endothelial growth factor, angiopoietin-1, and angiopoietin-2 in diabetes: implications for cardiovascular risk and effects of multifactorial intervention".Diabetes Care.27(12): 2918–24.doi:10.2337/diacare.27.12.2918.PMID15562207.
  13. ^Zan L, Wu H, Jiang J, Zhao S, Song Y, Teng G, Li H, Jia Y, Zhou M, Zhang X, Qi J, Wang J (2011)."Temporal profile of Src, SSeCKS, and angiogenic factors after focal cerebral ischemia: correlations with angiogenesis and cerebral edema".Neurochem. Int.58(8): 872–9.doi:10.1016/j.neuint.2011.02.014.PMC3100427.PMID21334414.
  14. ^Zan L, Zhang X, Xi Y, Wu H, Song Y, Teng G, Li H, Qi J, Wang J (2014)."Src regulates angiogenic factors and vascular permeability after focal cerebral ischemia-reperfusion".Neuroscience.262:118–28.doi:10.1016/j.neuroscience.2013.12.060.PMC3943922.PMID24412374.
  15. ^Félétou, M. (2011). "Chapter 2, Multiple Functions of the Endothelial Cells.".The Endothelium: Part 1: Multiple Functions of the Endothelial Cells—Focus on Endothelium-Derived Vasoactive Mediators.San Rafael, CA: Morgan & Claypool Life Sciences.
  16. ^Akwii RG, Sajib MS, Zahra FT, Mikelis CM (May 2019)."Role of Angiopoietin-2 in Vascular Physiology and Pathophysiology".Cells.8(5): 471.doi:10.3390/cells8050471.PMC6562915.PMID31108880.
  17. ^A. O. Oluboyo; S. I. Chukwu; B. O. Oluboyo; O. O. Odewusi (2020)."Evaluation of angiopoietins 1 and 2 in malaria-infested children".Journal of Environmental and Public Health.2020:1–5.doi:10.1155/2020/2169763.PMC7271246.PMID32565839.
  18. ^Pappa CA, Tsirakis G, Samiotakis P, Tsigaridaki M, Alegakis A, Goulidaki N, et al. (2013). "Serum levels of angiopoietin-2 are associated with the growth of multiple myeloma".Cancer Invest.31(6): 385–9.doi:10.3109/07357907.2013.800093.PMID23758184.S2CID12275550.
  19. ^Li C, Sun CJ, Fan JC, Geng N, Li CH, Liao J, et al. (2013). "Angiopoietin-2 expression is correlated with angiogenesis and overall survival in oral squamous cell carcinoma".Med Oncol.30(2): 571.doi:10.1007/s12032-013-0571-2.PMID23649549.S2CID41226861.
  20. ^Shroff RC, Price KL, Kolatsi-Joannou M, Todd AF, Wells D, Deanfield J, et al. (2013)."Circulating angiopoietin-2 is a marker for early cardiovascular disease in children on chronic dialysis".PLOS ONE.8(2): e56273.Bibcode:2013PLoSO...856273S.doi:10.1371/journal.pone.0056273.PMC3568077.PMID23409162.
  21. ^Ye FC, Zhou FC, Nithianantham S, Chandran B, Yu XL, Weinberg A, et al. (2013)."Kaposi's sarcoma-associated herpesvirus induces rapid release of angiopoietin-2 from endothelial cells".J Virol.87(11): 6326–35.doi:10.1128/JVI.03303-12.PMC3648120.PMID23536671.
  22. ^Amo Y, Masuzawa M, Hamada Y, Katsuoka K (May 2004). "Observations on angiopoietin 2 in patients with angiosarcoma".Br. J. Dermatol.150(5): 1028–9.doi:10.1111/j.1365-2133.2004.05932.x.PMID15149523.S2CID7399513.
  23. ^Falcón BL, Hashizume H, Koumoutsakos P, Chou J, Bready JV, Coxon A, et al. (2009)."Contrasting actions of selective inhibitors of angiopoietin-1 and angiopoietin-2 on the normalization of tumor blood vessels".Am J Pathol.175(5): 2159–70.doi:10.2353/ajpath.2009.090391.PMC2774078.PMID19815705.
[edit]
Retrieved from "https://en.wikipedia.org/w/index.php?title=Angiopoietin&oldid=1213901100"