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Angiopoietin-Related/Angiopoietin-Like Proteins Regulate Angiogenesis

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Abstract

A general understanding of the molecular mechanisms underlying angiogenesis is emerging from the analysis of targeted mutations in vasculature-related genes.These analyses reveal that angiopoietin signaling through the TIE2 receptor is involved in regulating angiogenesis. Recently, we and several other groups have independently identified several molecules containing a coiled-coil domain and a fibrinogen-like domain, both of which are structurally conserved in angiopoietins. Because these molecules do not bind to the angiopoietin-specific receptor,TIE2, they have been named angiopoietin-related proteins (ARPs) or angiopoietin-like proteins (Angptls).ARPs/Angptls, which are all currently orphan ligands, also have potent activity for regulating angiogenesis as proangiogenic or antiangiogenic factors, suggesting that their receptors may be expressed on endothelial cells. In addition, ARPs/Angptls show pleiotropic effects not only on vascular cells but also on cells of other lineages, such as skin and chondrocyte cells. More recent studies have proposed that ARPs/Angptls are involved in various pathologies, such as tumor angiogenesis and metabolic diseases. To summarize the current findings relating to these proteins, we focus in this review on the functions of ARPs/Angptls as new angiogenic modulating factors in the vascular system and discuss the pleiotropic functions of ARPs/Angptls in nonvascular cell lineages.

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References

  1. Risau W, Flamme I.Vasculogenesis. Annu Rev Cell Dev Biol. 1995; 11:73–91.

    Article  PubMed  CAS  Google Scholar 

  2. Risau W. Mechanisms of angiogenesis. Nature. 1997;386:671–674.

    Article  PubMed  CAS  Google Scholar 

  3. Hanahan D. Signaling vascular morphogenesis and maintenance. Science. 1997;277:48–50.

    Article  PubMed  CAS  Google Scholar 

  4. Gale NW,Yancopoulos GD. Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev. 1999;13:1055–1066.

    Article  PubMed  CAS  Google Scholar 

  5. Fong GH, Rossant J, Gertsenstein M, Breitman ML. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature. 1995;376:66–70.

    Article  PubMed  CAS  Google Scholar 

  6. Shalaby F, Rossant J, Yamaguchi TP, et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 1995; 376:62–66.

    Article  PubMed  CAS  Google Scholar 

  7. Carmeliet P, Ferreira V, Breier G, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996;380:435–439.

    Article  PubMed  CAS  Google Scholar 

  8. Ferrara N, Carver-Moore K, Chen H, et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996;380:439–442.

    Article  PubMed  CAS  Google Scholar 

  9. Dumont DJ, Yamaguchi TP, Conlon RA, Rossant J, Breitman ML. Tek, a novel tyrosine kinase gene located on mouse chromosome 4, is expressed in endothelial cells and their presumptive precursors. Oncogene. 1992;7:1417–1480.

    Google Scholar 

  10. Partanen J, Armstrong E, Makela TP, et al. A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains. Mol Cell Biol. 1992;12: 1698–1707.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Iwama A, Hamaguchi I, Hashiyama M, Murayama T, Yasunaga K, Suda T. Molecular cloning and characterization of mouse TIE and TEK receptor tyrosine kinase genes and their expression in hematopoietic stem cells. Biochem Biophys Res Commun. 1993; 195:301–309.

    Article  PubMed  CAS  Google Scholar 

  12. Davis S, Gale NW, Aldrich TH, et al. Ligands for EPH-related receptor tyrosine kinases that require membrane attachment or clustering for activity. Science. 1994;266:816–819.

    Article  PubMed  CAS  Google Scholar 

  13. Sato TN, Tozawa Y, Deutsch U, et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature. 1995;376:70–74.

    Article  PubMed  CAS  Google Scholar 

  14. Suri C, Jones PF, Patan S, et al. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell. 1996;87:1171–1180.

    Article  PubMed  CAS  Google Scholar 

  15. Valenzuela DM, Griffiths JA, Rojas J, et al. Angiopoietin 3 and 4: diverging gene counterparts in mice and human. Proc Natl Acad Sci U S A. 1999;96:1904–1909.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Kim I, Moon SO, Koh KN, et al. Molecular cloning, expression, and characterization of angiopoietin-related protein: angiopoietinrelated protein induces endothelial cell sprouting. J Biol Chem. 1999;274:26523–26528.

    Article  PubMed  CAS  Google Scholar 

  17. Kim I, Kim H-G, Kim H, t al. Hepatic expression, synthesis and secretion of a novel fibrinogen/angiopoietin-related protein that prevents endothelial-cell apoptosis. Biochem J. 2000;346:603–610.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Yoon JC, Chickering TW, Rosen ED, et al. Peroxisome proliferator- activated receptor γ target gene encoding a novel angiopoietinrelated protein associated with adipose differentiation. Mol Cell Biol. 2000;20:5343–5349.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Kersten S, Mandard S, Tan NS, et al. Characterization of the fastinginduced adipose factor FIAF, a novel peroxisome proliferatoractivated receptor target gene. J Biol Chem. 2000;275:28488–28493.

    Article  PubMed  CAS  Google Scholar 

  20. Koishi R, Ando Y, Ono M, et al. Angptl3 regulates lipid metabolism in mice. Nat Genet. 2002;30:151–157.

    Article  PubMed  CAS  Google Scholar 

  21. Camenisch G, Pisabarro MT, Sherman D, et al. ANGPTL3 stimulates endothelial cell adhesion and migration via integrin α vβ3 and induces blood vessel formation in vivo. J Biol Chem. 2002;277: 17281–17290.

    Article  PubMed  CAS  Google Scholar 

  22. Dhanabal M, LaRochelle WJ, Jeffers M, et al. Angioarrestin: an antiangiogenic protein with tumor-inhibiting properties. Cancer Res. 2002;62:3834–3841.

    PubMed  CAS  Google Scholar 

  23. Le Jan S, Amy C, Cazes A, et al. Angiopoietin-like 4 is a proangiogenic factor produced during ischemia and in conventional renal cell carcinoma. Am J Pathol. 2003;162:1521–1528.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Oike Y, Yasunaga K, Ito Y, et al. Angiopoietin-related growth factor (AGF) promotes epidermal proliferation, remodeling and regeneration. Proc Natl Acad Sci U S A. 2003;100:9494–9499.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Oike Y, Ito Y, Maekawa H, et al. Angiopoietin-related growth factor (AGF) promotes angiogenesis. Blood. 2004;103:2760–3765.

    Article  CAS  Google Scholar 

  26. Ito Y, Oike Y, Yasunaga K, et al. Inhibition of angiogenesis and vascular leakiness by angiopoietin-related protein 4. Cancer Res. 2003; 63:6651–6657.

    PubMed  CAS  Google Scholar 

  27. Procopio WN, Pelavin PI, Lee WMF, Yeilding NM. Angiopoietin-1 and -2 coiled coil domain mediate distinct homo-oligomerization patterns, but fibrinogen-like domains mediate ligand activity. J Biol Chem. 1999;274:30196–30201.

    Article  PubMed  CAS  Google Scholar 

  28. Shimizugawa T, Ono M, Shimamura M, et al. ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase. J Biol Chem. 2002;277:33742–33748.

    Article  PubMed  CAS  Google Scholar 

  29. Yoshida K, Shimizugawa T, Ono M, Furukawa H. Angiopoietinlike protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase. J Lipid Res. 2002;43: 1770–1772.

    Article  PubMed  CAS  Google Scholar 

  30. Ando Y, Shimizugawa T, Takeshita S, et al. A decreased expression of angiopoietin-like 3 is protective against atherosclerosis in apoEdeficient mice. J Lipid Res. 2003;44:1216–1223.

    Article  PubMed  CAS  Google Scholar 

  31. Ono M, Shimizugawa T, Shimamura M, et al. Protein region important for regulation of lipid metabolism in angiopoietin-like 3 (ANGPTL3): ANGPTL3 is cleaved and activated in vivo. J Biol Chem. 2003;278:41804–41809.

    Article  PubMed  CAS  Google Scholar 

  32. Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science. 1997; 277:55–61.

    Article  PubMed  CAS  Google Scholar 

  33. Carlson TR, Feng Y, Maisonpierre PC, Mrksich M, Morla AO. Direct cell adhesion to the angiopoietins mediated by integrins. J Biol Chem. 2001;276:26516–26525.

    Article  PubMed  CAS  Google Scholar 

  34. Ivanovic Z, Dello Sbarba PD, Trimoreau F, Faucher J-L, Praloran V. Primitive human HPCs are better maintained and expanded in vitro at 1 percent oxygen than at 20 percent. Transfusion. 2000;40: 1482–1488.

    Article  PubMed  CAS  Google Scholar 

  35. Ivanovic Z, Belloc F, Faucher J-L, Cipolleschi MG, Praloran V, Dello Sbarba P. Hypoxia maintains and interleukin-3 reduces the pre-colony-forming cell potential of dividing CD34+ murine bone marrow cells. Exp Hematol. 2002;30:67–73.

    Article  PubMed  CAS  Google Scholar 

  36. Desplat V, Faucher J-L, Mahon FX, Dello Sbarba P, Praloran V, Ivanovic Z. Hypoxia modifies proliferation and differentiation of CD34+ CML cells. Stem Cells. 2002;20:347–354.

    Article  PubMed  CAS  Google Scholar 

  37. Takakura N, Watanabe T, Suenobu S, et al. A role for hematopoietic stem cells in promoting angiogenesis. Cell. 2000;102:199–209.

    Article  PubMed  CAS  Google Scholar 

  38. Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease. Nature. 2000;405:421–424.

    Article  PubMed  CAS  Google Scholar 

  39. Carmeliet P, Jain RK. Angiogenesis in cancer and other disease. Nature. 2000;407:249–257.

    Article  PubMed  CAS  Google Scholar 

  40. Metinko AP, Kunkel SL, Standiford TJ, Strieter RM. Anoxiahyperoxia induces monocyte-derived interleukin-8. J Clin Invest. 1992;90:791–798.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Harmey JH, Dimitriadis E, Kay E, Redmond HP, Bouchier-Hayes D. Regulation of macrophage production of vascular endothelial growth factor (VEGF) by hypoxia and transforming growth factor beta-1. Ann Surg Oncol. 1998;5:271–278.

    Article  PubMed  CAS  Google Scholar 

  42. Kuwabara K, Ogawa S, Matsumoto M, et al. Hypoxia-mediated induction of acidic/basic fibroblast growth factor and plateletderived growth factor in mononuclear phagocytes stimulates growth of hypoxic endothelial cells. Proc Natl Acad Sci U S A. 1995; 92:4606–4610.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. White JR, Harris RA, Lee SR, et al. Genetic amplification of the transcriptional response to hypoxia as a novel means of identifying regulators of angiogenesis. Genomics. 2004;83:1–8.

    Article  PubMed  CAS  Google Scholar 

  44. Belanger AJ, Lu H, Date T, et al. Hypoxia up-regulates expression of peroxisome proliferator-activated receptor γ angiopoietinrelated gene (PGAR) in cardiomyocytes: role of hypoxia inducible factor 1γ. J Mol Cell Cardiol. 2002;34:765–774.

    Article  PubMed  CAS  Google Scholar 

  45. Tonnesen MG, Feng X, Clark RAF. Angiogenesis in wound healing. J Invest Dermatol. 2000;5:40–46.

    Article  CAS  Google Scholar 

  46. Yamada Y, Oike Y, Ogawa H, et al. Neuropilin-1 on hematopoietic cells as a source of vascular development. Blood. 2003;101: 1801–1809.

    Article  PubMed  CAS  Google Scholar 

  47. Knighton DR, Hunt TK, Scheuenstuhl BJ, Halliday BJ, Werb Z, Banda MJ. Oxygen tension regulates the expression of angiogenesis factor by macrophages. Science. 1983;221:1283–1285.

    Article  PubMed  CAS  Google Scholar 

  48. Singer AJ, Clerk RAF. Cutaneous wound healing. N Engl J Med. 1999;341:738–746.

    Article  PubMed  CAS  Google Scholar 

  49. Lewis JS, Lee JA, Underwood JC, Harris AL, Lewis CE. Macrophage responses to hypoxia: relevance to disease mechanisms. J Leukocyte Biol. 1999;66:889–900.

    Article  PubMed  CAS  Google Scholar 

  50. Sasaki H, Moriyama S, Sekimura A, et al. Angioarrestin mRNA expression in early-stage lung cancers. Eur J Surg Oncol. 2003;29: 649–653.

    Article  PubMed  CAS  Google Scholar 

  51. Kaneda A, Kaminishi M, Yanagihara K, Sugimura T, Ushijima T. Identification of silencing of nine genes in human gastric cancers. Cancer Res. 2002;62:6645–6650.

    PubMed  Google Scholar 

  52. Machtens S, Serth J, Bokemeyer C, et al. Expression of the p53 and Maspin protein in primary prostate cancer: correlation with clinical features. Int J Cancer. 2001;95:337–342.

    Article  PubMed  CAS  Google Scholar 

  53. Kodama J, Hashimoto I, Seki N, et al. Thrombospondin-1 and -2 messenger RNA expression in epithelial ovarian tumor. Anticancer Res. 2001;21:2983–2987.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, 160-8582, Tokyo, Japan

    Yuichi Oike & Toshio Suda

  2. Molecular Medicine Laboratories, Yamanouchi Pharmaceutical Co, Ltd, Tsukuba, Japan

    Kunio Yasunaga

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  1. Yuichi Oike
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  2. Kunio Yasunaga
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  3. Toshio Suda
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Correspondence to Toshio Suda.

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Oike, Y., Yasunaga, K. & Suda, T. Angiopoietin-Related/Angiopoietin-Like Proteins Regulate Angiogenesis. Int J Hematol 80, 21–28 (2004). https://doi.org/10.1532/IJH97.04034

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