tie 2 receptor

Summary

Summary: A TIE receptor tyrosine kinase that is found almost exclusively on ENDOTHELIAL CELLS. It is required for both normal embryonic vascular development (NEOVASCULARIZATION, PHYSIOLOGIC) and tumor angiogenesis (NEOVASCULARIZATION, PATHOLOGIC).

Top Publications

  1. Stoeltzing O, Ahmad S, Liu W, McCarty M, Wey J, Parikh A, et al. Angiopoietin-1 inhibits vascular permeability, angiogenesis, and growth of hepatic colon cancer tumors. Cancer Res. 2003;63:3370-7 pubmed
    ..Thus, Ang-1 could potentially serve as an antineoplastic or anti-permeability agent for patients with metastatic colorectal cancer. ..
  2. Barton W, Tzvetkova D, Nikolov D. Structure of the angiopoietin-2 receptor binding domain and identification of surfaces involved in Tie2 recognition. Structure. 2005;13:825-32 pubmed
    ..The structure reveals a fibrinogen fold with a unique C-terminal P domain. Conservation analysis and structure-based mutagenesis identify a groove on the Ang2 molecular surface that mediates receptor recognition. ..
  3. Weber C, Cai H, Ehrbar M, Kubota H, Martiny Baron G, Weber W, et al. Effects of protein and gene transfer of the angiopoietin-1 fibrinogen-like receptor-binding domain on endothelial and vessel organization. J Biol Chem. 2005;280:22445-53 pubmed
    ..Furthermore, we show that the isolated receptor-binding domain of Ang1 is capable of mediating some effects of full-length Ang1 independently of Tie2 phosphorylation, possibly through integrin ligation. ..
  4. Chen J, Stinnett A. Disruption of Ang-1/Tie-2 signaling contributes to the impaired myocardial vascular maturation and angiogenesis in type II diabetic mice. Arterioscler Thromb Vasc Biol. 2008;28:1606-13 pubmed publisher
    ..Ang-1 gene transfer restored Tie-2 expression and rescued these abnormalities in diabetes. Our findings underscore the important role of Ang-1-Tie-2 signaling in the diabetes-induced impairment of vascular maturation and angiogenesis. ..
  5. Cascone I, Napione L, Maniero F, Serini G, Bussolino F. Stable interaction between alpha5beta1 integrin and Tie2 tyrosine kinase receptor regulates endothelial cell response to Ang-1. J Cell Biol. 2005;170:993-1004 pubmed
    ..By using blocking antibodies, we consistently found that alpha5beta1, but not alphavbeta3 activation, is essential to Ang-1-dependent angiogenesis in vivo. ..
  6. Macdonald P, Progias P, Ciani B, Patel S, Mayer U, Steinmetz M, et al. Structure of the extracellular domain of Tie receptor tyrosine kinases and localization of the angiopoietin-binding epitope. J Biol Chem. 2006;281:28408-14 pubmed
    ..These findings might be of particular interest for drug development because Tie receptors are potential targets for treatment of angiogenesis-associated diseases. ..
  7. Saharinen P, Eklund L, Miettinen J, Wirkkala R, Anisimov A, Winderlich M, et al. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts. Nat Cell Biol. 2008;10:527-37 pubmed publisher
    ..This novel type of cellular microenvironment-dependent receptor tyrosine kinase activation may explain some of the effects of angiopoietins in angiogenesis and vessel stabilization. ..
  8. Martin V, Liu D, Fueyo J, Gomez Manzano C. Tie2: a journey from normal angiogenesis to cancer and beyond. Histol Histopathol. 2008;23:773-80 pubmed publisher
  9. Yuan H, Venkatesha S, Chan B, Deutsch U, Mammoto T, Sukhatme V, et al. Activation of the orphan endothelial receptor Tie1 modifies Tie2-mediated intracellular signaling and cell survival. FASEB J. 2007;21:3171-83 pubmed
    ..The experiments also constitute a paradigm for how endothelial integrity is fine-tuned by the interplay between closely related receptors by a single growth factor. ..

More Information

Publications64

  1. Gallagher D, Parikh S, Balonov K, Miller A, Gautam S, Talmor D, et al. Circulating angiopoietin 2 correlates with mortality in a surgical population with acute lung injury/adult respiratory distress syndrome. Shock. 2008;29:656-61 pubmed
    ..These data, coupled with our cell culture experiments, suggest that antagonism of Ang2 may provide a future novel therapeutic target for ARDS. ..
  2. Nobuhara Y, Onoda N, Fukai K, Hosomi N, Ishii M, Wakasa K, et al. TIE2 gain-of-function mutation in a patient with pancreatic lymphangioma associated with blue rubber-bleb nevus syndrome: report of a case. Surg Today. 2006;36:283-6 pubmed
    ..We describe the clinical features of this case and discuss a possible correlation between these two uncommon conditions...
  3. Zacharek A, Chen J, Cui X, Li A, Li Y, Roberts C, et al. Angiopoietin1/Tie2 and VEGF/Flk1 induced by MSC treatment amplifies angiogenesis and vascular stabilization after stroke. J Cereb Blood Flow Metab. 2007;27:1684-91 pubmed
    ..Our data indicate MSC treatment of stroke promotes angiogenesis and vascular stabilization, which is at least partially mediated by VEGF/Flk1 and Ang1/Tie2. ..
  4. Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte interactions. Circ Res. 2005;97:512-23 pubmed
    ..We finally highlight recent important data contributing to the understanding of the role of pericytes in tumor angiogenesis, diabetic retinopathy, and hereditary lymphedema. ..
  5. Dallabrida S, Ismail N, Oberle J, Himes B, Rupnick M. Angiopoietin-1 promotes cardiac and skeletal myocyte survival through integrins. Circ Res. 2005;96:e8-24 pubmed
    ..Angiopoietin-1 may prove therapeutically valuable in cardiac remodeling by supporting myocyte viability and preserving pump function. The full text of this article is available online at http://circres.ahajournals.org. ..
  6. Marron M, Singh H, Tahir T, Kavumkal J, Kim H, Koh G, et al. Regulated proteolytic processing of Tie1 modulates ligand responsiveness of the receptor-tyrosine kinase Tie2. J Biol Chem. 2007;282:30509-17 pubmed
    ..Furthermore the data suggest that regulated processing of Tie1 may be an important mechanism for controlling signaling by Tie2. ..
  7. Lewis C, De Palma M, Naldini L. Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2. Cancer Res. 2007;67:8429-32 pubmed
    ..Learning more about the regulation of TEMs by the tumor microenvironment may yield new strategies to ablate the tumor vasculature. ..
  8. Parikh S, Mammoto T, Schultz A, Yuan H, Christiani D, Karumanchi S, et al. Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans. PLoS Med. 2006;3:e46 pubmed
    ..Last, we show that excess systemic Ang-2 provokes pulmonary leak and congestion in otherwise healthy adult mice. Our results identify a critical role for Ang-2 in disrupting normal pulmonary endothelial function. ..
  9. Mofarrahi M, Nouh T, Qureshi S, Guillot L, Mayaki D, Hussain S. Regulation of angiopoietin expression by bacterial lipopolysaccharide. Am J Physiol Lung Cell Mol Physiol. 2008;294:L955-63 pubmed publisher
  10. Du R, Lu K, Petritsch C, Liu P, Ganss R, Passegue E, et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell. 2008;13:206-20 pubmed publisher
    ..VEGF also directly regulates tumor cell invasiveness. When VEGF activity is impaired, tumor cells invade deep into the brain in the perivascular compartment. ..
  11. Baumer S, Keller L, Holtmann A, Funke R, August B, Gamp A, et al. Vascular endothelial cell-specific phosphotyrosine phosphatase (VE-PTP) activity is required for blood vessel development. Blood. 2006;107:4754-62 pubmed
    ..No signs for enhanced endothelial apoptosis or proliferation were observed. Thus, the activity of VE-PTP is not required for the initial formation of blood vessels, yet it is essential for their maintenance and remodeling. ..
  12. Bogdanovic E, Nguyen V, Dumont D. Activation of Tie2 by angiopoietin-1 and angiopoietin-2 results in their release and receptor internalization. J Cell Sci. 2006;119:3551-60 pubmed
    ..Altogether, these data begin our understanding of the regulation of Tie2 and the activity of the angiopoietins after engaging the endothelial cell surface. ..
  13. Wakui S, Yokoo K, Muto T, Suzuki Y, Takahashi H, Furusato M, et al. Localization of Ang-1, -2, Tie-2, and VEGF expression at endothelial-pericyte interdigitation in rat angiogenesis. Lab Invest. 2006;86:1172-84 pubmed
    ..Moreover, EPI might serve as a pathway for the Ang-1/Tie-2 system, with VEGF promoting pericyte recruitment for microvascular integrity. ..
  14. Lee J, Yu Q, Shin J, Sebzda E, Bertozzi C, Chen M, et al. Klf2 is an essential regulator of vascular hemodynamic forces in vivo. Dev Cell. 2006;11:845-57 pubmed
    ..These findings identify Klf2 as an essential hemodynamic regulator in vivo and suggest that hemodynamic regulation in response to fluid shear stress is required for cardiovascular development and function. ..
  15. Androutsellis Theotokis A, Rueger M, Park D, Mkhikian H, Korb E, Poser S, et al. Targeting neural precursors in the adult brain rescues injured dopamine neurons. Proc Natl Acad Sci U S A. 2009;106:13570-5 pubmed publisher
    ..The cellular and pharmacological basis of the neuroprotective effects achieved by these single treatments merits further analysis. ..
  16. Venneri M, De Palma M, Ponzoni M, Pucci F, Scielzo C, Zonari E, et al. Identification of proangiogenic TIE2-expressing monocytes (TEMs) in human peripheral blood and cancer. Blood. 2007;109:5276-85 pubmed
    ..Human TEMs may provide a novel, biologically relevant marker of angiogenesis and represent a previously unrecognized target of cancer therapy. ..
  17. Schliemann C, Bieker R, Padro T, Kessler T, Hintelmann H, Buchner T, et al. Expression of angiopoietins and their receptor Tie2 in the bone marrow of patients with acute myeloid leukemia. Haematologica. 2006;91:1203-11 pubmed
    ..Furthermore, high pre-therapeutic levels of Ang-2 in the bone marrow indicate a favorable prognosis in AML patients treated with polychemotherapy, although the mechanism is not yet known. ..
  18. Roviezzo F, Tsigkos S, Kotanidou A, Bucci M, Brancaleone V, Cirino G, et al. Angiopoietin-2 causes inflammation in vivo by promoting vascular leakage. J Pharmacol Exp Ther. 2005;314:738-44 pubmed
    ..We conclude that Ang-2 by itself stimulates the extravasation of cell-poor fluid, but in the presence of ongoing inflammation it reduces cellular infiltration in tissues. ..
  19. Saharinen P, Kerkelä K, Ekman N, Marron M, Brindle N, Lee G, et al. Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2. J Cell Biol. 2005;169:239-43 pubmed
    ..These results should be important in dissecting the signal transduction pathways and biological functions of Tie1. ..
  20. Tammela T, Saaristo A, Lohela M, Morisada T, Tornberg J, Norrmen C, et al. Angiopoietin-1 promotes lymphatic sprouting and hyperplasia. Blood. 2005;105:4642-8 pubmed
    ..Furthermore, a soluble form of VEGFR-3 inhibited the observed lymphatic sprouting. Our results reinforce the concept that Ang1 therapy may be useful in settings of tissue edema. ..
  21. Loges S, Heil G, Bruweleit M, Schoder V, Butzal M, Fischer U, et al. Analysis of concerted expression of angiogenic growth factors in acute myeloid leukemia: expression of angiopoietin-2 represents an independent prognostic factor for overall survival. J Clin Oncol. 2005;23:1109-17 pubmed
    ..These results show that expression of Ang2 represents an independent prognostic factor in AML. Additional research into interactions of angiogenic cytokines in the pathogenesis of bone marrow angiogenesis in AML is warranted. ..
  22. Maliba R, Brkovic A, Neagoe P, Villeneuve L, Sirois M. Angiopoietin-mediated endothelial P-selectin translocation: cell signaling mechanisms. J Leukoc Biol. 2008;83:352-60 pubmed
    ..In addition, we demonstrate for the first time that angiopoietin-mediated endothelial P-selectin translocation is calcium-dependent and regulated through phospholipase C-gamma activation. ..
  23. Chen J, Cui X, Zacharek A, Chopp M. Increasing Ang1/Tie2 expression by simvastatin treatment induces vascular stabilization and neuroblast migration after stroke. J Cell Mol Med. 2009;13:1348-57 pubmed publisher
    ..Ang1/Tie2 expression induced by simvastatin treatment promotes neuroblast micro-vascular coupling after stroke. ..
  24. Fukuhara S, Sako K, Minami T, Noda K, Kim H, Kodama T, et al. Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1. Nat Cell Biol. 2008;10:513-26 pubmed publisher
  25. Kim K, Cho C, Kim H, Baluk P, McDonald D, Koh G. In vivo actions of angiopoietins on quiescent and remodeling blood and lymphatic vessels in mouse airways and skin. Arterioscler Thromb Vasc Biol. 2007;27:564-70 pubmed
    ..This study, one of the first to our knowledge to characterize the in vivo actions of all 4 angiopoietins, may expand the current concepts for use of angiopoietins for therapeutic angiogenesis and lymphangiogenesis. ..
  26. Arai F, Hirao A, Suda T. Regulation of hematopoietic stem cells by the niche. Trends Cardiovasc Med. 2005;15:75-9 pubmed
    ..Ang-1 produced by OBs activates Tie2 on HSCs and promotes tight adhesion of HSCs to the niche, resulting in quiescence and enhanced survival of HSCs. ..
  27. Daly C, Pasnikowski E, Burova E, Wong V, Aldrich T, Griffiths J, et al. Angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cells. Proc Natl Acad Sci U S A. 2006;103:15491-6 pubmed
    ..Our data suggests a model in which Ang-2 expression is induced in stressed endothelial cells, where it acts as an autocrine Tie2 agonist and protective factor. ..
  28. Singh H, Milner C, Aguilar Hernandez M, Patel N, Brindle N. Vascular endothelial growth factor activates the Tie family of receptor tyrosine kinases. Cell Signal. 2009;21:1346-50 pubmed publisher
    ..This novel mechanism of receptor tyrosine kinase activation is likely to be important in integrating signalling between two of the key receptor groups regulating angiogenesis. ..
  29. Barton W, Tzvetkova Robev D, Miranda E, Kolev M, Rajashankar K, Himanen J, et al. Crystal structures of the Tie2 receptor ectodomain and the angiopoietin-2-Tie2 complex. Nat Struct Mol Biol. 2006;13:524-32 pubmed
    ..Analysis of the structures and structure-based mutagenesis provide insight into the mechanism of receptor activation and support the hypothesis that all angiopoietins interact with Tie2 in a structurally similar manner. ..
  30. Pieh C, Agostini H, Buschbeck C, Kruger M, Schulte Mönting J, Zirrgiebel U, et al. VEGF-A, VEGFR-1, VEGFR-2 and Tie2 levels in plasma of premature infants: relationship to retinopathy of prematurity. Br J Ophthalmol. 2008;92:689-93 pubmed publisher
    ..Elevated plasma levels in active ROP were observed for sVEGFR-2 and sTie2. These increases have yet to be confirmed as predictive values for ROP. ..
  31. McLean K, Buckanovich R. Myeloid cells functioning in tumor vascularization as a novel therapeutic target. Transl Res. 2008;151:59-67 pubmed publisher
    ..The evidence that these myeloid cells represent bona fide therapeutic targets for solid tumors will be reviewed. Finally, we will address some controversies and challenges in the field with a focus on future directions. ..
  32. Murdoch C, Tazzyman S, Webster S, Lewis C. Expression of Tie-2 by human monocytes and their responses to angiopoietin-2. J Immunol. 2007;178:7405-11 pubmed
    ..In sum, our data indicate that Ang-2 may recruit Tie-2(+) monocytes to tumors and sites of inflammation, modulate their release of important cytokines and stimulate them to express a proangiogenic phenotype. ..
  33. De Palma M, Venneri M, Galli R, Sergi Sergi L, Politi L, Sampaolesi M, et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell. 2005;8:211-26 pubmed
    ..Therefore, Tie2 expression characterizes three distinct cell types required for tumor neovascularization: ECs, proangiogenic cells of hematopoietic origin, and pericyte precursors of mesenchymal origin. ..
  34. Kayisli U, Cayli S, Seval Y, Tertemiz F, Huppertz B, Demir R. Spatial and temporal distribution of Tie-1 and Tie-2 during very early development of the human placenta. Placenta. 2006;27:648-59 pubmed
    ..Due to their spatial distribution we speculate on an additional role in regulation of villous and extravillous trophoblastic behavior. ..
  35. Yuan H, Khankin E, Karumanchi S, Parikh S. Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium. Mol Cell Biol. 2009;29:2011-22 pubmed publisher
  36. Eklund L, Olsen B. Tie receptors and their angiopoietin ligands are context-dependent regulators of vascular remodeling. Exp Cell Res. 2006;312:630-41 pubmed
    ..Changes in the expression of Tie receptors and angiopoietins occur in many pathological conditions, and mutations in the Tie2 gene are found in familial cases of vascular disease. ..
  37. Cho C, Kim K, Byun J, Jang H, Kim D, Baluk P, et al. Long-term and sustained COMP-Ang1 induces long-lasting vascular enlargement and enhanced blood flow. Circ Res. 2005;97:86-94 pubmed
    ..Sustained overexpression of Tie2 could participate in the maintenance of vascular changes. Together, our findings indicate that sustained treatment with COMP-Ang1 can produce long-lasting vascular enlargement and increased blood flow. ..
  38. Scharpfenecker M, Fiedler U, Reiss Y, Augustin H. The Tie-2 ligand angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism. J Cell Sci. 2005;118:771-80 pubmed
  39. Shaw J, Basch R, Shamamian P. Hematopoietic stem cells and endothelial cell precursors express Tie-2, CD31 and CD45. Blood Cells Mol Dis. 2004;32:168-75 pubmed
    ..Selection of Tie-2+Sca-1+ BMC enriches for marrow-derived EPCs that participate in tumor angiogenesis and cells that can provide hematopoietic reconstitution of marrow-ablated mice. ..
  40. Sussman L, Upalakalin J, Roberts M, Kocher O, Benjamin L. Blood markers for vasculogenesis increase with tumor progression in patients with breast carcinoma. Cancer Biol Ther. 2003;2:255-6 pubmed
    ..Our data suggest increased circulating EPC markers in tumor patients, but further study of this cell population is needed to better define its role in tumor vasculogenesis. ..
  41. Cho C, Kammerer R, Lee H, Yasunaga K, Kim K, Choi H, et al. Designed angiopoietin-1 variant, COMP-Ang1, protects against radiation-induced endothelial cell apoptosis. Proc Natl Acad Sci U S A. 2004;101:5553-8 pubmed
    ..Thus, COMP-Ang1 could be used as a therapeutic protein for specific protection against endothelial cell injury. ..
  42. Cascone I, Audero E, Giraudo E, Napione L, Maniero F, Philips M, et al. Tie-2-dependent activation of RhoA and Rac1 participates in endothelial cell motility triggered by angiopoietin-1. Blood. 2003;102:2482-90 pubmed
    ..Taken together, these results further expand our understanding of angiopoietin-1-mediated endothelial cell motility during vascular network assembly and angiogenesis. ..
  43. Chen Konak L, Guetta Shubin Y, Yahav H, Shay Salit A, Zilberman M, Binah O, et al. Transcriptional and post-translation regulation of the Tie1 receptor by fluid shear stress changes in vascular endothelial cells. FASEB J. 2003;17:2121-3 pubmed
    ..The rapid down-regulation of Tie1 by shear stress changes and its rapid binding to Tie2 may be required for destabilization of endothelial cells in order to initiate the process of vascular restructuring. ..
  44. Puri M, Bernstein A. Requirement for the TIE family of receptor tyrosine kinases in adult but not fetal hematopoiesis. Proc Natl Acad Sci U S A. 2003;100:12753-8 pubmed
  45. Peters K, Kontos C, Lin P, Wong A, Rao P, Huang L, et al. Functional significance of Tie2 signaling in the adult vasculature. Recent Prog Horm Res. 2004;59:51-71 pubmed
  46. Fiedler U, Scharpfenecker M, Koidl S, Hegen A, Grunow V, Schmidt J, et al. The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies. Blood. 2004;103:4150-6 pubmed
  47. Nakayama T, Yoshizaki A, Kawahara N, Ohtsuru A, Wen C, Fukuda E, et al. Expression of Tie-1 and 2 receptors, and angiopoietin-1, 2 and 4 in gastric carcinoma; immunohistochemical analyses and correlation with clinicopathological factors. Histopathology. 2004;44:232-9 pubmed
    ..These findings suggest that the Tie-Ang receptor-ligand complex is one of the factors involved in the cellular differentiation and progression of human gastric adenocarcinoma. ..
  48. Chong A, Caine G, Freestone B, Blann A, Lip G. Plasma angiopoietin-1, angiopoietin-2, and angiopoietin receptor tie-2 levels in congestive heart failure. J Am Coll Cardiol. 2004;43:423-8 pubmed
    ..569, p < 0.001). We have demonstrated abnormal levels of Ang-2 and tie-2, but normal Ang-1, in both CHF patients. These abnormalities may, alongside VEGF, indicate a role for these angiogenic factors in the pathophysiology of CHF. ..
  49. Hata K, Nakayama K, Fujiwaki R, Katabuchi H, Okamura H, Miyazaki K. Expression of the angopoietin-1, angopoietin-2, Tie2, and vascular endothelial growth factor gene in epithelial ovarian cancer. Gynecol Oncol. 2004;93:215-22 pubmed
  50. Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K, et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004;118:149-61 pubmed
    ..These data suggest that the Tie2/Ang-1 signaling pathway plays a critical role in the maintenance of HSCs in a quiescent state in the BM niche. ..
  51. Ohashi H, Takagi H, Koyama S, Oh H, Watanabe D, Antonetti D, et al. Alterations in expression of angiopoietins and the Tie-2 receptor in the retina of streptozotocin induced diabetic rats. Mol Vis. 2004;10:608-17 pubmed
    ..Diabetes increases Ang-2 expression in the GCL accompanied by a reduction of alphaSMA positive perivascular cells. These changes may suggest a role for Ang-2 in the mechanism of pericyte loss in diabetic retinopathy. ..
  52. Lemieux C, Maliba R, Favier J, Théorêt J, Merhi Y, Sirois M. Angiopoietins can directly activate endothelial cells and neutrophils to promote proinflammatory responses. Blood. 2005;105:1523-30 pubmed
    ..Together, our data demonstrate that angiopoietins could promote acute recruitment of leukocytes, which might contribute to facilitate vascular remodeling and angiogenesis. ..
  53. Cho C, Kammerer R, Lee H, Steinmetz M, Ryu Y, Lee S, et al. COMP-Ang1: a designed angiopoietin-1 variant with nonleaky angiogenic activity. Proc Natl Acad Sci U S A. 2004;101:5547-52 pubmed
    ..Thus, COMP-Ang1 is an effective alternative to native Ang1 for therapeutic angiogenesis in vivo. ..
  54. Torimura T, Ueno T, Kin M, Harada R, Taniguchi E, Nakamura T, et al. Overexpression of angiopoietin-1 and angiopoietin-2 in hepatocellular carcinoma. J Hepatol. 2004;40:799-807 pubmed
    ..Our findings indicate that the increased expression of Angiopoietin-1 and Angiopoietin-2 play a critical role in the process of vascular development in HCC. ..
  55. Lee H, Cho C, Hwang S, Choi H, Kim K, Ahn S, et al. Biological characterization of angiopoietin-3 and angiopoietin-4. FASEB J. 2004;18:1200-8 pubmed
    ..Thus, Ang3 and Ang4 are agonists of Tie2, but mouse Ang3 has strong activity only on endothelial cells of its own species. ..