The assembly of a functional vascular system requires coordinated signalling between various growth factors and receptors. The Tie receptors and their angiopoietin (Ang) ligands have important functions during embryonic vessel assembly and maturation and control adult vascular homeostasis.
ANG1 and TIE2-deficiency in mice lead to lethality at embryonic day 10.5 (E10.5) as a consequence of perturbed vessel organization and maturation. TIE1-deficient mice have no overt angiogenesis-related phenotype but die in late gestation as a consequence of widespread oedema and haemorrhage. ANG2 is dispensable for embryonic development, but mice that overexpress ANG2 have essentially the same phenotypes as ANG1- and TIE2-deficient mice.
Constitutive stimulation of TIE2 by ANG1 leads to vessel maturation and contributes to the maintenance of vascular quiescence. Vascular quiescence is associated with the recruitment of peri-endothelial cells (pericytes and smooth muscle cells).
TIE2 activation drives several signalling pathways. The dominant signalling pathway is the phosphoinositide 3-kinase (PI3K)–AKT pathway, which transduces survival signals.
The antagonist of constitutive ANG1–TIE2 signalling, ANG2, is produced and stored by endothelial cells (ECs). It acts through an autocrine-loop mechanism to control EC responsiveness to multiple cytokines, which include angiogenesis-inducing cytokines, such as vascular endothelial growth factor (VEGF), permeability-inducing molecules, such as histamine and bradykinin, and inflammation-inducing factors, such as tumour-necrosis factor-α (TNFα).
TIE1 is an orphan receptor of which the mechanism of action has not been uncovered. An emerging concept suggests that TIE1–TIE2 heterodimerization might contribute to TIE2 signal transduction.
Non-vascular functions of Ang–Tie signalling are only recently being uncovered. Most notably, ANG1–TIE2 signalling has a crucial role in maintaining the haematopoietic stem cell niche.
Angiogenesis, the growth of blood vessels, is a fundamental biological process that controls embryonic development and is also involved in numerous life-threatening human diseases. Much work in the field of angiogenesis research has centred on the vascular endothelial growth factor (VEGF)–VEGF receptor system. The Tie receptors and their angiopoietin (Ang) ligands have been identified as the second vascular tissue-specific receptor Tyr kinase system. Ang–Tie signalling is essential during embryonic vessel assembly and maturation, and functions as a key regulator of adult vascular homeostasis. The structural characteristics and the spatio-temporal regulation of the expression of receptors and ligands provide unique insights into the functions of this vascular signalling system.
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Senger, D. R. et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219, 983–985 (1983).
Ferrara, N. & Henzel, W. J. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem. Biophys. Res. Commun. 161, 851–858 (1989).
Partanen, J. et al. A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains. Mol. Cell. Biol. 12, 1698–1707 (1992).
Dumont, D. J., Yamaguchi, T. P., Conlon, R. A., Rossant, J. & Breitman, M. L. tek, a novel tyrosine kinase gene located on mouse chromosome 4, is expressed in endothelial cells and their presumptive precursors. Oncogene 7, 1471–1480 (1992).
Sato, T. N., Qin, Y., Kozak, C. A. & Audus, K. L. Tie-1 and tie-2 define another class of putative receptor tyrosine kinase genes expressed in early embryonic vascular system. Proc. Natl Acad. Sci. USA 90, 9355–9358 (1993).
Maisonpierre, P. C., Goldfarb, M., Yancopoulos, G. D. & Gao, G. Distinct rat genes with related profiles of expression define a TIE receptor tyrosine kinase family. Oncogene 8, 1631–1637 (1993).
Iwama, A. et al. Molecular cloning and characterization of mouse TIE and TEK receptor tyrosine kinase genes and their expression in hematopoietic stem cells. Biochem. Biophys. Res. Commun. 195, 301–309 (1993).
Davis, S. et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87, 1161–1169 (1996).
Maisonpierre, P. C. et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277, 55–60 (1997).
Valenzuela, D. M. et al. Angiopoietins 3 and 4: diverging gene counterparts in mice and humans. Proc. Natl Acad. Sci. USA 96, 1904–1909 (1999).
Olsen, M. W. et al. Angiopoietin-4 inhibits angiogenesis and reduces interstitial fluid pressure. Neoplasia 8, 364–372 (2006).
Xu, Y., Liu, Y. J. & Yu, Q. Angiopoietin-3 inhibits pulmonary metastasis by inhibiting tumor angiogenesis. Cancer Res. 64, 6119–6126 (2004).
Lee, H. J. et al. Biological characterization of angiopoietin-3 and angiopoietin-4. FASEB J. 18, 1200–1208 (2004).
Kim, K. E. et al. In vivo actions of angiopoietins on quiescent and remodeling blood and lymphatic vessels in mouse airways and skin. Arterioscler Thromb. Vasc. Biol. 27, 564–570 (2007).
Hato, T., Tabata, M. & Oike, Y. The role of angiopoietin-like proteins in angiogenesis and metabolism. Trends Cardiovasc. Med. 18, 6–14 (2008).
Adams, R. H. & Alitalo, K. Molecular regulation of angiogenesis and lymphangiogenesis. Nature Rev. Mol. Cell Biol. 8, 464–478 (2007).
Patan, S. TIE1 and TIE2 receptor tyrosine kinases inversely regulate embryonic angiogenesis by the mechanism of intussusceptive microvascular growth. Microvasc. Res. 56, 1–21 (1998).
Sato, T. N. et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376, 70–74 (1995).
Dumont, D. J. et al. Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev. 8, 1897–1909 (1994).
Takakura, N. et al. Critical role of the TIE2 endothelial cell receptor in the development of definitive hematopoiesis. Immunity 9, 677–686 (1998).
Puri, M. C., Rossant, J., Alitalo, K., Bernstein, A. & Partanen, J. The receptor tyrosine kinase TIE is required for integrity and survival of vascular endothelial cells. EMBO J. 14, 5884–5891 (1995).
Rodewald, H. R. & Sato, T. N. Tie1, a receptor tyrosine kinase essential for vascular endothelial cell integrity, is not critical for the development of hematopoietic cells. Oncogene 12, 397–404 (1996).
Puri, M. C., Partanen, J., Rossant, J. & Bernstein, A. Interaction of the TEK and TIE receptor tyrosine kinases during cardiovascular development. Development 126, 4569–4580 (1999).
Suri, C. et al. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87, 1171–1180 (1996).
Gale, N. W. et al. Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. Dev. Cell 3, 411–423 (2002).
Fiedler, U. et al. Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nature Med. 12, 235–239 (2006). Establishes ANG2 as an autocrine-acting gatekeeper of rapid vascular responses during inflammation.
Hackett, S. F., Wiegand, S., Yancopoulos, G. & Campochiaro, P. A. Angiopoietin-2 plays an important role in retinal angiogenesis. J. Cell. Physiol. 192, 182–187 (2002).
Goede, V., Schmidt, T., Kimmina, S., Kozian, D. & Augustin, H. G. Analysis of blood vessel maturation processes during cyclic ovarian angiogenesis. Lab. Invest. 78, 1385–1394 (1998).
Pitera, J. E., Woolf, A. S., Gale, N. W., Yancopoulos, G. D. & Yuan, H. T. Dysmorphogenesis of kidney cortical peritubular capillaries in angiopoietin-2-deficient mice. Am. J. Pathol. 165, 1895–1906 (2004).
Suri, C. et al. Increased vascularization in mice overexpressing angiopoietin-1. Science 282, 468–471 (1998).
Thurston, G. et al. Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286, 2511–2514 (1999).
Thurston, G. et al. Angiopoietin-1 protects the adult vasculature against plasma leakage. Nature Med. 6, 460–463 (2000).
Kim, I., Moon, S. O., Park, S. K., Chae, S. W. & Koh, G. Y. Angiopoietin-1 reduces VEGF-stimulated leukocyte adhesion to endothelial cells by reducing ICAM-1, VCAM-1, and E-selectin expression. Circ. Res. 89, 477–479 (2001).
Gamble, J. R. et al. Angiopoietin-1 is an antipermeability and anti-inflammatory agent in vitro and targets cell junctions. Circ. Res. 87, 603–607 (2000).
Li, X. et al. Basal and angiopoietin-1-mediated endothelial permeability is regulated by sphingosine kinase-1. Blood 111, 3489–3497 (2008).
Jeon, B. H. et al. Tie-ing the antiinflammatory effect of angiopoietin-1 to inhibition of NF-κB. Circ. Res. 92, 586–588 (2003).
Nykanen, A. I. et al. Angiopoietin-1 protects against the development of cardiac allograft arteriosclerosis. Circulation 107, 1308–1314 (2003).
Witzenbichler, B., Westermann, D., Knueppel, S., Schultheiss, H. P. & Tschope, C. Protective role of angiopoietin-1 in endotoxic shock. Circulation 111, 97–105 (2005).
Kwak, H. J. et al. Angiopoietin-1 inhibits irradiation- and mannitol-induced apoptosis in endothelial cells. Circulation 101, 2317–2324 (2000).
Kim, I. et al. Angiopoietin-1 negatively regulates expression and activity of tissue factor in endothelial cells. FASEB J. 16, 126–128 (2002).
Voskas, D. et al. A cyclosporine-sensitive psoriasis-like disease produced in Tie2 transgenic mice. Am. J. Pathol. 166, 843–855 (2005).
Vikkula, M. et al. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell 87, 1181–1190 (1996).
Reiss, Y. et al. Angiopoietin-2 impairs revascularization after limb ischemia. Circ. Res. 101, 88–96 (2007). Provides solid biochemical evidence for a TIE2 antagonistic mode of action of ANG2 on the resting endothelium.
Lobov, I. B., Brooks, P. C. & Lang, R. A. Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc. Natl Acad. Sci. USA 99, 11205–11210 (2002).
Oshima, Y. et al. Angiopoietin-2 enhances retinal vessel sensitivity to vascular endothelial growth factor. J. Cell. Physiol. 199, 412–417 (2004).
Oshima, Y. et al. Different effects of angiopoietin-2 in different vascular beds: new vessels are most sensitive. FASEB J. 19, 963–965 (2005).
Hammes, H. P. et al. Angiopoietin-2 causes pericyte dropout in the normal retina: evidence for involvement in diabetic retinopathy. Diabetes 53, 1104–1110 (2004).
Bhandari, V. et al. Hyperoxia causes angiopoietin 2-mediated acute lung injury and necrotic cell death. Nature Med. 12, 1286–1293 (2006).
Holash, J. et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284, 1994–1998 (1999). Establishes the role of ANG2 for co-optive early tumour vascularization inducing the angiogenic switch in a hypoxia-dependent manner.
Hawighorst, T. et al. Activation of the tie2 receptor by angiopoietin-1 enhances tumor vessel maturation and impairs squamous cell carcinoma growth. Am. J. Pathol. 160, 1381–1392 (2002).
Hayes, A. J. et al. Expression and function of angiopoietin-1 in breast cancer. Br. J. Cancer 83, 1154–1160 (2000).
Machein, M. R. et al. Angiopoietin-1 promotes tumor angiogenesis in a rat glioma model. Am. J. Pathol. 165, 1557–1570 (2004).
Stoeltzing, O. et al. Angiopoietin-1 inhibits vascular permeability, angiogenesis, and growth of hepatic colon cancer tumors. Cancer Res. 63, 3370–3377 (2003).
Ahmad, S. A. et al. The effects of angiopoietin-1 and -2 on tumor growth and angiogenesis in human colon cancer. Cancer Res. 61, 1255–1259 (2001).
Jain, R. K. Molecular regulation of vessel maturation. Nature Med. 9, 685–693 (2003).
Winkler, F. et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6, 553–563 (2004).
Etoh, T. et al. Angiopoietin-2 is related to tumor angiogenesis in gastric carcinoma: possible in vivo regulation via induction of proteases. Cancer Res. 61, 2145–2153 (2001).
Hu, B. et al. Angiopoietin-2 induces human glioma invasion through the activation of matrix metalloprotease-2. Proc. Natl Acad. Sci. USA 100, 8904–8909 (2003).
Yoshiji, H. et al. Angiopoietin 2 displays a vascular endothelial growth factor dependent synergistic effect in hepatocellular carcinoma development in mice. Gut 54, 1768–1775 (2005).
Yu, Q. & Stamenkovic, I. Angiopoietin-2 is implicated in the regulation of tumor angiogenesis. Am. J. Pathol. 158, 563–570 (2001).
Cao, Y. et al. Systemic overexpression of angiopoietin-2 promotes tumor microvessel regression and inhibits angiogenesis and tumor growth. Cancer Res. 67, 3835–3844 (2007).
Nasarre, P. et al. Host-derived Angiopoietin-2 affects early stages of tumor development and vessel maturation, but is dispensable for later stages of tumor growth. Cancer Res. (in the press).
Lin, P. et al. Inhibition of tumor angiogenesis using a soluble receptor establishes a role for Tie2 in pathologic vascular growth. J. Clin. Invest. 100, 2072–2078 (1997).
Lin, P. et al. Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2. Proc. Natl Acad. Sci. USA 95, 8829–8834 (1998).
Siemeister, G. et al. Two independent mechanisms essential for tumor angiogenesis: inhibition of human melanoma xenograft growth by interfering with either the vascular endothelial growth factor receptor pathway or the Tie-2 pathway. Cancer Res. 59, 3185–3191 (1999).
Popkov, M., Jendreyko, N., McGavern, D. B., Rader, C. & Barbas, C. F. 3rd. Targeting tumor angiogenesis with adenovirus-delivered anti-Tie-2 intrabody. Cancer Res. 65, 972–981 (2005).
Jendreyko, N., Popkov, M., Rader, C. & Barbas, C. F. 3rd. Phenotypic knockout of VEGF-R2 and Tie-2 with an intradiabody reduces tumor growth and angiogenesis in vivo. Proc. Natl Acad. Sci. USA 102, 8293–8298 (2005).
Oliner, J. et al. Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 6, 507–516 (2004). Describes effective ANG2 neutralizing reagents with potent anti-tumour activity.
Semones, M. et al. Pyridinylimidazole inhibitors of Tie2 kinase. Bioorg. Med. Chem. Lett. 17, 4756–4760 (2007).
Hodous, B. L. et al. Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor. J. Med. Chem. 50, 611–626 (2007).
Cee, V. J. et al. Alkynylpyrimidine amide derivatives as potent, selective, and orally active inhibitors of Tie-2 kinase. J. Med. Chem. 50, 627–640 (2007).
Hasegawa, M. et al. Discovery of novel benzimidazoles as potent inhibitors of TIE-2 and VEGFR-2 tyrosine kinase receptors. J. Med. Chem. 50, 4453–4470 (2007).
Schnurch, H. & Risau, W. Expression of tie-2, a member of a novel family of receptor tyrosine kinases, in the endothelial cell lineage. Development 119, 957–968 (1993).
Barton, W. A. et al. Crystal structures of the Tie2 receptor ectodomain and the angiopoietin-2–Tie2 complex. Nature Struct. Mol. Biol. 13, 524–532 (2006). Sheds important structural insight into ANG2–TIE2-binding characteristics.
Fiedler, U. et al. Angiopoietin-1 and angiopoietin-2 share the same binding domains in the Tie-2 receptor involving the first Ig-like loop and the epidermal growth factor-like repeats. J. Biol. Chem. 278, 1721–1727 (2003).
Macdonald, P. R. et al. Structure of the extracellular domain of Tie receptor tyrosine kinases and localization of the angiopoietin-binding epitope. J. Biol. Chem. 281, 28408–28414 (2006).
Kaipainen, A. et al. Enhanced expression of the tie receptor tyrosine kinase mesenger RNA in the vascular endothelium of metastatic melanomas. Cancer Res. 54, 6571–6577 (1994).
Porat, R. M. et al. Specific induction of tie1 promoter by disturbed flow in atherosclerosis-prone vascular niches and flow-obstructing pathologies. Circ. Res. 94, 394–401 (2004).
De Palma, M., Venneri, M. A., Roca, C. & Naldini, L. Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nature Med. 9, 789–795 (2003).
De Palma, 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 8, 211–226 (2005). Establishes a crucial role of TIE2-positive monocytes as important paracrine acting stimulators of tumour angiogenesis.
Procopio, W. N., Pelavin, P. I., Lee, W. M. & Yeilding, N. M. Angiopoietin-1 and -2 coiled coil domains mediate distinct homo-oligomerization patterns, but fibrinogen-like domains mediate ligand activity. J. Biol. Chem. 274, 30196–30201 (1999).
Davis, S. et al. Angiopoietins have distinct modular domains essential for receptor binding, dimerization and superclustering. Nature Struct. Biol. 10, 38–44 (2003). Provides evidence that higher-order Ang proteins stimulate TIE2, whereas dimeric Ang proteins antagonize TIE2 activation.
Cho, C. H. et al. Designed angiopoietin-1 variant, COMP-Ang1, protects against radiation-induced endothelial cell apoptosis. Proc. Natl Acad. Sci. USA 101, 5553–5558 (2004).
Ward, N. L., Van Slyke, P. & Dumont, D. J. Functional inhibition of secreted angiopoietin: a novel role for angiopoietin 1 in coronary vessel patterning. Biochem. Biophys. Res. Commun. 323, 937–946 (2004).
Kim, K. T. et al. Oligomerization and multimerization are critical for angiopoietin-1 to bind and phosphorylate Tie2. J. Biol. Chem. 280, 20126–20131 (2005).
Koblizek, T. I., Weiss, C., Yancopoulos, G. D., Deutsch, U. & Risau, W. Angiopoietin-1 induces sprouting angiogenesis in vitro. Curr. Biol. 8, 529–532 (1998).
Cho, C. H. et al. COMP-Ang1: a designed angiopoietin-1 variant with nonleaky angiogenic activity. Proc. Natl Acad. Sci. USA 101, 5547–5552 (2004). Describes COMP-ANG1 as an engineered, pentameric Ang ligand that potently stimulates TIE2 activation.
Cho, C. H. et al. COMP-angiopoietin-1 promotes wound healing through enhanced angiogenesis, lymphangiogenesis, and blood flow in a diabetic mouse model. Proc. Natl Acad. Sci. USA 103, 4946–4951 (2006).
Stratmann, A., Risau, W. & Plate, K. H. Cell type-specific expression of angiopoietin-1 and angiopoietin-2 suggests a role in glioblastoma angiogenesis. Am. J. Pathol. 153, 1459–1466 (1998).
Sugimachi, K. et al. Angiopoietin switching regulates angiogenesis and progression of human hepatocellular carcinoma. J. Clin. Pathol. 56, 854–860 (2003).
Xu, Y. & Yu, Q. Angiopoietin-1, unlike angiopoietin-2, is incorporated into the extracellular matrix via its linker peptide region. J. Biol. Chem. 276, 34990–34998 (2001).
Hackett, S. F. et al. Angiopoietin 2 expression in the retina: upregulation during physiologic and pathologic neovascularization. J. Cell. Physiol. 184, 275–284 (2000).
Holash, J., Wiegand, S. J. & Yancopoulos, G. D. New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. Oncogene 18, 5356–5362 (1999).
Huang, Y. Q., Li, J. J., Hu, L., Lee, M. & Karpatkin, S. Thrombin induces increased expression and secretion of angiopoietin-2 from human umbilical vein endothelial cells. Blood 99, 1646–1650 (2002).
Mandriota, S. J. & Pepper, M. S. Regulation of angiopoietin-2 mRNA levels in bovine microvascular endothelial cells by cytokines and hypoxia. Circ. Res. 83, 852–859 (1998).
Zhang, L. et al. Tumor-derived vascular endothelial growth factor up-regulates angiopoietin-2 in host endothelium and destabilizes host vasculature, supporting angiogenesis in ovarian cancer. Cancer Res. 63, 3403–3412 (2003).
Oh, H. et al. Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells. J. Biol. Chem. 274, 15732–15739 (1999).
Mandriota, S. J. et al. Hypoxia-inducible angiopoietin-2 expression is mimicked by iodonium compounds and occurs in the rat brain and skin in response to systemic hypoxia and tissue ischemia. Am. J. Pathol. 156, 2077–2089 (2000).
Parmar, K. M. et al. Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2. J. Clin. Invest. 116, 49–58 (2006).
Hegen, A. et al. Expression of angiopoietin-2 in endothelial cells is controlled by positive and negative regulatory promoter elements. Arterioscler. Thromb. Vasc. Biol. 24, 1803–1809 (2004).
Parikh, S. M. et al. Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans. PLoS Med. 3, e46 (2006).
Giuliano, J. S. Jr. et al. Admission angiopoietin levels in children with septic shock. Shock 28, 650–654 (2007).
Wang, B. et al. [Expression and significance of Ang1, Ang2 and receptor Tie2 in hemangioma]. Zhonghua Zheng Xing Wai Ke Za Zhi 23, 515–518 (2007) (in Chinese).
Fiedler, U. et al. The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel–Palade bodies. Blood 103, 4150–4156 (2004).
Fiedler, U. & Augustin, H. G. Angiopoietins: a link between angiogenesis and inflammation. Trends Immunol. 27, 552–558 (2006).
Kim, I. et al. Angiopoietin-1 induces endothelial cell sprouting through the activation of focal adhesion kinase and plasmin secretion. Circ. Res. 86, 952–959 (2000).
Papapetropoulos, A. et al. Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/survivin pathway. J. Biol. Chem. 275, 9102–9105 (2000).
Kontos, C. D., Cha, E. H., York, J. D. & Peters, K. G. The endothelial receptor tyrosine kinase Tie1 activates phosphatidylinositol 3-kinase and Akt to inhibit apoptosis. Mol. Cell. Biol. 22, 1704–1713 (2002).
DeBusk, L. M., Hallahan, D. E. & Lin, P. C. Akt is a major angiogenic mediator downstream of the Ang1/Tie2 signaling pathway. Exp. Cell Res. 298, 167–177 (2004).
Daly, C. et al. Angiopoietin-1 modulates endothelial cell function and gene expression via the transcription factor FKHR (FOXO1). Genes Dev. 18, 1060–1071 (2004). Unravels important TIE2 downstream mechanisms that transcriptionally drive a negative-feedback loop on ANG2 expression.
Tsigkos, S. et al. Regulation of Ang2 release by PTEN/PI3-kinase/Akt in lung microvascular endothelial cells. J. Cell. Physiol. 207, 506–511 (2006).
Graupera, M. et al. Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration. Nature 453, 662–666 (2008).
Kim, I. et al. Hepatic expression, synthesis and secretion of a novel fibrinogen/angiopoietin-related protein that prevents endothelial-cell apoptosis. Biochem. J. 346, 603–610 (2000).
Kanda, S., Miyata, Y., Mochizuki, Y., Matsuyama, T. & Kanetake, H. Angiopoietin 1 is mitogenic for cultured endothelial cells. Cancer Res. 65, 6820–6827 (2005).
Kim, I. et al. Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Circ. Res. 86, 24–29 (2000).
Master, Z. et al. Dok-R plays a pivotal role in angiopoietin-1-dependent cell migration through recruitment and activation of Pak. EMBO J. 20, 5919–5928 (2001).
Gavard, J., Patel, V. & Gutkind, J. S. Angiopoietin-1 prevents VEGF-induced endothelial permeability by sequestering Src through mDia. Dev. Cell 14, 25–36 (2008). Identifies the mechanisms of TIE2-signalling-dependent anti-permeability effects, which act through the sequestration of Src by mDia in a RhoA-dependent manner.
Tadros, A., Hughes, D. P., Dunmore, B. J. & Brindle, N. P. ABIN-2 protects endothelial cells from death and has a role in the antiapoptotic effect of angiopoietin-1. Blood 102, 4407–4409 (2003).
Hughes, D. P., Marron, M. B. & Brindle, N. P. The antiinflammatory endothelial tyrosine kinase Tie2 interacts with a novel nuclear factor-κB inhibitor ABIN-2. Circ. Res. 92, 630–636 (2003).
Iivanainen, E. et al. Angiopoietin-regulated recruitment of vascular smooth muscle cells by endothelial-derived heparin binding EGF-like growth factor. FASEB J. 17, 1609–1621 (2003).
Kobayashi, H., DeBusk, L. M., Babichev, Y. O., Dumont, D. J. & Lin, P. C. Hepatocyte growth factor mediates angiopoietin-induced smooth muscle cell recruitment. Blood 108, 1260–1266 (2006).
Sullivan, C. C. et al. Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway. Proc. Natl Acad. Sci. USA 100, 12331–12336 (2003).
Uemura, A. et al. Recombinant angiopoietin-1 restores higher-order architecture of growing blood vessels in mice in the absence of mural cells. J. Clin. Invest. 110, 1619–1628 (2002).
Saharinen, P. et al. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell–cell and cell–matrix contacts. Nature Cell Biol. 10, 527–537 (2008). Along with reference 125, this shows the context-dependent effects of TIE2. In resting ECs, TIE2 is translocated to cell junctions in a ligand-dependent manner to transduce survival signals, whereas TIE2 is translocated to focal adhesions in non-contacting ECs to affect the migratory behaviour of the cell.
Fukuhara, S. et al. Differential function of Tie2 at cell–cell contacts and cell–substratum contacts regulated by angiopoietin-1. Nature Cell Biol. 10, 513–526 (2008).
Fachinger, G., Deutsch, U. & Risau, W. Functional interaction of vascular endothelial-protein-tyrosine phosphatase with the angiopoietin receptor Tie-2. Oncogene 18, 5948–5953 (1999).
Chen-Konak, L. et al. Transcriptional and post-translation regulation of the Tie1 receptor by fluid shear stress changes in vascular endothelial cells. FASEB J. 17, 2121–2123 (2003).
Marron, M. B. et al. Regulated proteolytic processing of Tie1 modulates ligand responsiveness of the receptor-tyrosine kinase Tie2. J. Biol. Chem. 282, 30509–30517 (2007).
Yabkowitz, R. et al. Inflammatory cytokines and vascular endothelial growth factor stimulate the release of soluble tie receptor from human endothelial cells via metalloprotease activation. Blood 93, 1969–1979 (1999).
Yabkowitz, R. et al. Regulation of tie receptor expression on human endothelial cells by protein kinase C-mediated release of soluble tie. Blood 90, 706–715 (1997).
Yuan, H. T. et al. Activation of the orphan endothelial receptor Tie1 modifies Tie2-mediated intracellular signaling and cell survival. FASEB J. 21, 3171–3183 (2007).
Saharinen, P. et al. Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2. J. Cell Biol. 169, 239–243 (2005).
Scharpfenecker, M., Fiedler, U., Reiss, Y. & Augustin, H. G. The Tie-2 ligand angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism. J. Cell Sci. 118, 771–780 (2005).
Daly, C. et al. Angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cells. Proc. Natl Acad. Sci. USA 103, 15491–15496 (2006).
Lee, S. et al. Autocrine VEGF signaling is required for vascular homeostasis. Cell 130, 691–703 (2007).
Kim, I. et al. Angiopoietin-2 at high concentration can enhance endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Oncogene 19, 4549–4552 (2000).
Harfouche, R. & Hussain, S. N. Signaling and regulation of endothelial cell survival by angiopoietin-2. Am. J. Physiol. Heart Circ. Physiol. 291, H1635–H1645 (2006).
Teichert-Kuliszewska, K. et al. Biological action of angiopoietin-2 in a fibrin matrix model of angiogenesis is associated with activation of Tie2. Cardiovasc. Res. 49, 659–670 (2001).
Kim, I. et al. EphB ligand, ephrinB2, suppresses the VEGF- and angiopoietin 1-induced Ras/mitogen-activated protein kinase pathway in venous endothelial cells. FASEB J. 16, 1126–1128 (2002).
Arai, F. et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, 149–161 (2004). Provides evidence for a role of Ang–Tie signalling in maintaining the haematopoietic bone marrow stem cell niche.
Sacchetti, B. et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324–336 (2007).
Valable, S. et al. Angiopoietin-1-induced PI3-kinase activation prevents neuronal apoptosis. FASEB J. 17, 443–445 (2003).
Kosacka, J. et al. Angiopoietin-1 promotes neurite outgrowth from dorsal root ganglion cells positive for Tie-2 receptor. Cell Tissue Res. 320, 11–19 (2005).
Ward, N. L., Putoczki, T., Mearow, K., Ivanco, T. L. & Dumont, D. J. Vascular-specific growth factor angiopoietin 1 is involved in the organization of neuronal processes. J. Comp. Neurol. 482, 244–256 (2005).
Carlson, T. R., Feng, Y., Maisonpierre, P. C., Mrksich, M. & Morla, A. O. Direct cell adhesion to the angiopoietins mediated by integrins. J. Biol. Chem. 276, 26516–26525 (2001).
Dallabrida, S. M., Ismail, N., Oberle, J. R., Himes, B. E. & Rupnick, M. A. Angiopoietin-1 promotes cardiac and skeletal myocyte survival through integrins. Circ. Res. 96, e8–e24 (2005).
Imanishi, Y. et al. Angiopoietin-2 stimulates breast cancer metastasis through the α5 β1 integrin-mediated pathway. Cancer Res. 67, 4254–4263 (2007).
Morisada, T. et al. Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation. Blood 105, 4649–4656 (2005). Along with reference 152, this shows the activating effects of ANG1 on lymphangiogenesis.
Tammela, T. et al. Angiopoietin-1 promotes lymphatic sprouting and hyperplasia. Blood 105, 4642–4648 (2005).
Hirakawa, S. et al. Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells. Am. J. Pathol. 162, 575–586 (2003).
Huang, X. Z. et al. Fatal bilateral chylothorax in mice lacking the integrin α9β1. Mol. Cell. Biol. 20, 5208–5215 (2000).
Kidoya, H. et al. Spatial and temporal role of the apelin/APJ system in the caliber size regulation of blood vessels during angiogenesis. EMBO J. 27, 522–534 (2008).
The authors thank several colleagues and their students for assistance in collecting material for this review. We would like to particularly acknowledge A. Benest, M. Thomas and S. Bartels. The authors gratefully acknowledge M.O. Steinmetz (Paul Scherrer Institut, Villinge, Switzerland) for the rotary shadowing electron microscopic images shown in figure 3. We apologize to all those, whose work could not be cited owing to space limitations. Work in the authors' laboratories is supported by grants from the Deutsche Forschungsgemeinschaft, Finish Cancer Organizations, the Academy of Finland, Helsinki University Central Hospital, the Korea Science and Engineering Foundation (KOSEF), the Louis Jeantet Foundation, the Novo Nordisk Foundation, the Aventis Foundation, the German–Israel Foundation and the European Union and the National Institutes of Health.
H.G. Augustin, G.Y. Koh and K. Alitalo declare no competing financial interests. G. Thurston is an employee of Regeneron Pharmaceuticals.
Supplementary information S1 (table) | Expression and regulation of the angiopoietin ligands and Tie receptors (PDF 505 kb)
- Endothelial cell
A cell type that forms a single layer in the inner lining of blood and lymphatic vessels. Conceptually, the vascular endothelium can be considered to be a systemically disseminated organ system.
A precursor cell of endothelial cells that originates from a common lineage with haematopoietic precursor cells, or haemangioblasts.
- Angiogenic cascade
The sequential series of events that lead to the formation of new blood vessels: proteolysis, migration, proliferation, lumen formation and capillary network organization.
- Vessel quiescence
The non-proliferating, anti-thrombotic, anti-inflammatory and non-angiogenic default status of resting endothelial cells and the surrounding peri-endothelial cells.
A mesenchymal-like peri-endothelial cell in capillaries that controls the resting phenotype of adjacent endothelial cells. Pericyte markers are NG2 proteoglycan, desmin, platelet-derived growth factor-β (PDGFRβ), α-smooth muscle actin and RGS5.
- Chylous ascites
The presence of a milky fluid that contains suspended fat in the peritoneal cavity. Also called chyloperitoneum.
- Hyaloid vessel
One of several vessels that run through the vitreous humour of the eye during the fetal stage of development. These supply the fetal lens and regress during late embryonic and early postnatal development.
- Corpus luteum
Latin for yellow body, this temporary endocrine structure in the female ovary produces progesterone, which is required to maintain pregnancy.
The biological response programme of vascular tissues to harmful stimuli and irritants. The hallmarks of inflammation are pain, heat, redness, swelling and tissue damage.
- Vessel co-option
Describes the utilization of a pre-existing vasculature by a growing tumour.
A deficiency in oxygen. Hypoxia is a powerful regulator of vascular functions. Oxygen gradients have morphogenic properties during angiogenesis and vascular remodelling.
A substance that is used as an indicator of a biological state. Frequently analysed biomarkers in the circulation include growth factors, soluble adhesion molecules and soluble receptors. Also called a surrogate marker.
- Pericyte dropout
The loss of peri-endothelial pericyte coverage. This is a hallmark of vascular-destabilizing diseases, such as diabetic retinopathy.
- Soluble receptor
A receptor that has the extracellular domain of a membrane receptor that can bind to the ligand and prevent it from binding to the cell surface receptor. As such, soluble receptors act as decoys and inhibit signal transduction.
- Coiled-coil domain
A structural protein motif with multiple α-helices that coil together like the strands of a rope.
- Rotary shadowing
An electron microscopic technique that is based on the rapid freezing of a specimen, followed by the vacuuming off of ice crystals and rotary spraying with metal vapour. This yields a contrast in the electron micrograph after removal of the organic material.
- Shear stress
The biomechanical force that acts on the vessel wall as a consequence of the tangential force exerted by the flowing blood. This stabilizes the endothelial layer and prevents cell death.
- Weibel–Palade body
Named after its discoverers, this body is a storage granule of endothelial cells that contains von Willebrand Factor and a few other molecules, including P-selectin and angiopoietin 2.
- Von Willebrand Factor
A blood glycoprotein that is involved in haemostasis.
- Adherens junction
A junctional cell–cell contact that is composed of homotypic adhesion molecules of the cadherin family that associate with catenins.
- Tight junction
A junctional cell–cell contact that forms an essentially impermeable barrier. This is composed of molecules of the occludin and claudin families.
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Augustin, H., Young Koh, G., Thurston, G. et al. Control of vascular morphogenesis and homeostasis through the angiopoietin–Tie system. Nat Rev Mol Cell Biol 10, 165–177 (2009). https://doi.org/10.1038/nrm2639
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