Angiopoietin

Last updated
angiopoietin 1
Identifiers
Symbol ANGPT1
NCBI gene 284
HGNC 484
OMIM 601667
RefSeq NM_001146
UniProt Q15389
Other data
Locus Chr. 8 q22.3-8q23
Search for
Structures Swiss-model
Domains InterPro
angiopoietin 2
1Z3U.pdb1.jpg
Crystal structure of the human angiopoietin-2 receptor binding domain. [1]
Identifiers
Symbol ANGPT2
NCBI gene 285
HGNC 485
OMIM 601922
RefSeq NM_001147
UniProt O15123
Other data
Locus Chr. 8 p23
Search for
Structures Swiss-model
Domains InterPro

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. [2] Angiopoietin cytokines are involved with controlling microvascular permeability, vasodilation, and vasoconstriction by signaling smooth muscle cells surrounding vessels. [3] There are now four identified angiopoietins: ANGPT1, ANGPT2, ANGPTL3, ANGPT4. [4]

Contents

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, or VEGF, it can promote neo-vascularization. [6]

Structure

Angiopoietin protein structure. It consists of the N-terminus super cluster domain, the linker region, the central coiled domain, and the binding site at the C terminus. Domain structure of angiopoietin.JPG
Angiopoietin protein structure. It consists of the N-terminus super cluster domain, the linker region, the central coiled domain, and the binding site at the C terminus.

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. [6]

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

Only clusters/multimers activate receptors

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

Tie pathway

The collective interactions between angiopoietins, receptor tyrosine kinases, 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.

Tie-2

Tie-2/Ang-1 signaling activates β1-integrin and N-cadherin in LSK-Tie2+ cells and promotes hematopoietic stem cell (HSC) interactions with extracellular matrix and 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 the endosteum, Tie-2/Ang-1 signaling is predominantly expressed by osteoblastic cells. [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 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. [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 a glycoprotein and 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

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. [15]

Vascular permeability signaling

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. [7]

Cancer

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

Deregulation of angiopoietin and the tyrosine kinase pathway is common in blood-related diseases such as diabetes, malaria, [17] sepsis, and pulmonary 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 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. [2]

Angiopoietin-2 is produced and stored in Weibel-Palade bodies in endothelial cells and acts as a TEK tyrosine kinase antagonist. 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 of multiple myeloma, [18] angiogenesis, and overall survival in oral squamous cell carcinoma. [19] Circulating angiopoietin-2 is a marker for early cardiovascular disease in children on chronic dialysis. [20] Kaposi's sarcoma-associated herpesvirus induces rapid release of angiopoietin-2 from endothelial cells. [21]

Angiopoietin-2 is elevated in patients with angiosarcoma. [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]

Related Research Articles

<span class="mw-page-title-main">Angiogenesis</span> Blood vessel formation, when new vessels emerge from existing vessels

Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and splitting, but processes such as coalescent angiogenesis, vessel elongation and vessel cooption also play a role. Vasculogenesis is the embryonic formation of endothelial cells from mesoderm cell precursors, and from neovascularization, although discussions are not always precise. The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease.

Vascular endothelial growth factor, originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis and angiogenesis.

An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels (angiogenesis). Some angiogenesis inhibitors are endogenous and a normal part of the body's control and others are obtained exogenously through pharmaceutical drugs or diet.

<span class="mw-page-title-main">Endostatin</span>

Endostatin is a naturally occurring, 20-kDa C-terminal fragment derived from type XVIII collagen. It is reported to serve as an anti-angiogenic agent, similar to angiostatin and thrombospondin.

Soluble fms-like tyrosine kinase-1 is a tyrosine kinase protein with antiangiogenic properties. A non-membrane associated splice variant of VEGF receptor 1 (Flt-1), sFlt-1 binds the angiogenic factors VEGF and PlGF, reducing blood vessel growth through reduction of free VEGF and PlGF concentrations. In humans, sFlt-1 is important in the regulation of blood vessel formation in diverse tissues, including the kidneys, cornea, and uterus. Abnormally high levels of sFlt-1 have been implicated in the pathogenesis of preeclampsia.

<span class="mw-page-title-main">VEGF receptor</span> Protein family

VEGF receptors (VEGFRs) are receptors for vascular endothelial growth factor (VEGF). There are three main subtypes of VEGFR, numbered 1, 2 and 3. Depending on alternative splicing, they may be membrane-bound (mbVEGFR) or soluble (sVEGFR).

The angiopoietin receptors are receptors that bind angiopoietin. TIE-1 and TIE-2 comprise the cell-surface receptors that bind and are activated by the angiopoietins,. The angiopoietins are protein growth factors required for the formation of blood vessels (angiogenesis).

<span class="mw-page-title-main">Angiopoietin 1</span> Protein-coding gene in the species Homo sapiens

Angiopoietin 1 is a type of angiopoietin and is encoded by the gene ANGPT1.

<span class="mw-page-title-main">ANGPT2</span> Protein-coding gene in the species Homo sapiens

Angiopoietin-2 is a protein that in humans is encoded by the ANGPT2 gene.

<span class="mw-page-title-main">VEGFR1</span> Protein-coding gene in the species Homo sapiens

Vascular endothelial growth factor receptor 1 is a protein that in humans is encoded by the FLT1 gene.

<span class="mw-page-title-main">Kinase insert domain receptor</span> Protein-coding gene in the species Homo sapiens

Kinase insert domain receptor also known as vascular endothelial growth factor receptor 2 (VEGFR-2) is a VEGF receptor. KDR is the human gene encoding it. KDR has also been designated as CD309. KDR is also known as Flk1.

<span class="mw-page-title-main">Vascular endothelial growth factor C</span> Growth factor protein found in humans

Vascular endothelial growth factor C (VEGF-C) is a protein that is a member of the platelet-derived growth factor / vascular endothelial growth factor (PDGF/VEGF) family. It is encoded in humans by the VEGFC gene, which is located on chromosome 4q34.

<span class="mw-page-title-main">TEK tyrosine kinase</span> Protein-coding gene in the species Homo sapiens

Angiopoietin-1 receptor also known as CD202B is a protein that in humans is encoded by the TEK gene. Also known as TIE2, it is an angiopoietin receptor.

<span class="mw-page-title-main">Placental growth factor</span> Protein-coding gene in the species Homo sapiens

Placental growth factor(PlGF) is a protein that in humans is encoded by the PGF gene.

<span class="mw-page-title-main">Vascular endothelial growth factor A</span> Protein involved in blood vessel growth

Vascular endothelial growth factor A (VEGF-A) is a protein that in humans is encoded by the VEGFA gene.

<span class="mw-page-title-main">FLT4</span> Protein-coding gene in the species Homo sapiens

Fms-related tyrosine kinase 4, also known as FLT4, is a protein which in humans is encoded by the FLT4 gene.

Angiogenesis is the process of forming new blood vessels from existing blood vessels, formed in vasculogenesis. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during normal physiological development, but it also occurs in adults during inflammation, wound healing, ischemia, and in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth. Proteolysis has been indicated as one of the first and most sustained activities involved in the formation of new blood vessels. Numerous proteases including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase domain (ADAM), a disintegrin and metalloproteinase domain with throbospondin motifs (ADAMTS), and cysteine and serine proteases are involved in angiogenesis. This article focuses on the important and diverse roles that these proteases play in the regulation of angiogenesis.

<span class="mw-page-title-main">AEE788</span> Chemical compound

AEE788 is a multitargeted human epidermal receptor (HER) 1/2 and vascular endothelial growth factor receptor (VEGFR) 1/2 receptor family tyrosine kinases inhibitor with IC50 of 2, 6, 77, 59 nM for EGFR, ErbB2, KDR, and Flt-1. In cells, growth factor-induced EGFR and ErbB2 phosphorylation was also efficiently inhibited with IC50s of 11 and 220 nM, respectively. It efficiently inhibited growth factor-induced EGFR and ErbB2 phosphorylation in tumors for >72 h, a phenomenon correlating with the antitumor efficacy of intermittent treatment schedules. It also inhibits VEGF-induced angiogenesis in a murine implant model. It has potential as an anticancer agent targeting deregulated tumor cell proliferation as well as angiogenic parameters.

Tumor-associated macrophages (TAMs) are a class of immune cells present in high numbers in the microenvironment of solid tumors. They are heavily involved in cancer-related inflammation. Macrophages are known to originate from bone marrow-derived blood monocytes or yolk sac progenitors, but the exact origin of TAMs in human tumors remains to be elucidated. The composition of monocyte-derived macrophages and tissue-resident macrophages in the tumor microenvironment depends on the tumor type, stage, size, and location, thus it has been proposed that TAM identity and heterogeneity is the outcome of interactions between tumor-derived, tissue-specific, and developmental signals.

<span class="mw-page-title-main">Nader Rahimi</span> Molecular biologist

Nader Rahimi is a Molecular Biologist and is currently an Associate Professor at the Department of Pathology and Laboratory Medicine at Boston University.

References

  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 . PMID   15893672.
  2. 1 2 Alves 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 . PMC   2890004 . PMID   20509945.
  3. ↑ Scott F. Gilbert (10 April 2010). Developmental Biology (Loose Leaf). Sinauer Associates Incorporated. ISBN   978-0-87893-558-1.
  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 . PMC   26709 . PMID   10051567.
  5. ↑ Santulli G (2014). "Angiopoietin-like proteins: a comprehensive look". Frontiers in Endocrinology. 5: 4. doi: 10.3389/fendo.2014.00004 . PMC   3899539 . PMID   24478758.
  6. 1 2 3 4 Fagiani E, Christofori G (2013). "Angiopoietins in angiogenesis". Cancer Lett. 328 (1): 18–26. doi:10.1016/j.canlet.2012.08.018. PMID   22922303.
  7. 1 2 Sarah Y. Yuan; Robert R. Rigor (30 September 2010). Regulation of Endothelial Barrier Function. Morgan & Claypool Publishers. ISBN   978-1-61504-120-6.
  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 . PMID   20614597.
  9. 1 2 3 Jeansson 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. PMC   3104773 . PMID   21606590.
  10. ↑ Harmey, Judith (2004). VEGF and cancer. Georgetown, Tex: Landes Bioscience/Eurekah.com New York, N.Y. Kluwer Academic/Plenum Publishers. ISBN   0-306-47988-5.
  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. PMID   23500414.
  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 . PMID   15562207.
  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. PMC   3100427 . PMID   21334414.
  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. PMC   3943922 . PMID   24412374.
  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 . PMC   6562915 . PMID   31108880.
  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 . PMC   7271246 . PMID   32565839.
  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. PMID   23758184. S2CID   12275550.
  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. PMID   23649549. S2CID   41226861.
  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 . PMC   3568077 . PMID   23409162.
  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. PMC   3648120 . PMID   23536671.
  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. PMID   15149523. S2CID   7399513.
  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. PMC   2774078 . PMID   19815705.
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