Signal transduction induced in endothelial cells by growth factor receptors involved in angiogenesis

Summary

New vessel formation during development and in the adult is triggered by concerted signals of largely endothelial-specific receptors for ligands of the VEGF, angiopoietin and ephrin families. The signals and genes induced by these receptors operate in the context of additional signals transduced by non-endothelial specific growth factor receptors, inflammatory cytokine receptors as well as adhesion molecules. We summarize here available data on characteristic signaling of the VEGF receptor-2 and the current state of knowledge regarding the additional different receptor tyrosine kinases of the VEGF, Tie and Ephrin receptor families. Furthermore, the potential cross-talk with signals induced by other growth factors and inflammatory cytokines as well as the modulation by VE-cadherin is discussed.

Keywords

Angiogenesis and inhibitors - signal transduction - endothelial cells

• References

• 1 Coultas L, Chawengsaksophak K, Rossant J. Endothelial cells and VEGF in vascular development. Nature 2005; 438: 937-945.
• 2 Alitalo K, Tammela T, Petrova TV. Lymphangiogenesis in development and human disease. Nature 2005; 438: 946-953.
• 3 Carmeliet P. Angiogenesis in life, disease and medicine. Nature 2005; 438: 932-936.
• 4 Yancopoulos GD, Davis S, Gale NW. et al. Vascular- specific growth factors and blood vessel formation. Nature 2000; 407: 242-248.
• 5 Eklund L, Olsen BR. Tie receptors and their angiopoietin ligands are context-dependent regulators of vascular remodeling. Exp Cell Res 2006; 312: 630-641.
• 6 Heroult M, Schaffner F, Augustin HG. Eph receptor and ephrin ligand-mediated interactions during angiogenesis and tumor progression. Exp Cell Res 2006; 312: 642-650.
• 7 Carmeliet P. Angiogenesis in health and disease. Nat Med 2003; 9: 653-660.
• 8 Presta M, Dell'Era P, Mitola S. et al. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev 2005; 16: 159-178.
• 9 Compagni A, Wilgenbus P, Impagnatiello MA. et al. Fibroblast growth factors are required for efficient tumor angiogenesis. Cancer Res 2000; 60: 7163-7169.
• 10 Amin DN, Hida K, Bielenberg DR. et al. Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors. Cancer Res 2006; 66: 2173-2180.
• 11 Zeller PJ, Skalak TC, Ponce AM. et al. In vivo chemotactic properties and spatial expression of PDGF in developing mesenteric microvascular networks. Am J Physiol Heart Circ Physiol 2001; 280: H2116-2125.
• 12 Rolny C, Nilsson I, Magnusson P. et al. Platelet-derived growth factor receptor-beta promotes early endothelial cell differentiation. Blood 2006; 108: 1877-1886.
• 13 Goumans MJ, Lebrin F, Valdimarsdottir G. Controlling the angiogenic switch: a balance between two distinct TGF-b receptor signaling pathways. Trends Cardiovasc Med 2003; 13: 301-307.
• 14 Rajashekhar G, Willuweit A, Patterson CE. et al. Continuous endothelial cell activation increases angiogenesis: evidence for the direct role of endothelium linking angiogenesis and inflammation. J Vasc Res 2006; 43: 193-204.
• 15 Majno G. Chronic inflammation: links with angiogenesis and wound healing. Am J Pathol 1998; 153: 1035-1039.
• 16 Dejana E. Endothelial cell-cell junctions: happy together. Nat Rev Mol Cell Biol 2004; 5: 261-270.
• 17 Serini G, Valdembri D, Bussolino F. Integrins and angiogenesis: a sticky business. Exp Cell Res 2006; 312: 651-658.
• 18 Favier B, Alam A, Barron P. et al. Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration. Blood 2006; 108: 1243-1250.
• 19 Shibuya M, Yamaguchi S, Yamane A. et al. Nucleotide sequence and expression of a novel human receptor- type tyrosine kinase gene (flt) closely related to the fms family. Oncogene 1990; 5: 519-524.
• 20 Millauer B, Wizigmann-Voos S, Schnurch H. et al. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 1993; 72: 835-846.
• 21 Terman BI, Carrion ME, Kovacs E. et al. Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene 1991; 6: 1677-1683.
• 22 Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003; 9: 669-676.
• 23 Pajusola K, Aprelikova O, Korhonen J. et al. FLT4 receptor tyrosine kinase contains seven immunoglobulin- like loops and is expressed in multiple human tissues and cell lines. Cancer Res 1992; 52: 5738-5743.
• 24 de Vries C, Escobedo JA, Ueno H. et al. The fmslike tyrosine kinase, a receptor for vascular endothelial growth factor. Science 1992; 255: 989-991.
• 25 Maglione D, Guerriero V, Viglietto G. et al. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci USA 1991; 88: 9267-9271.
• 26 Terman BI, Dougher-Vermazen M, Carrion ME. et al. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun 1992; 187: 1579-1586.
• 27 Joukov V, Pajusola K, Kaipainen A. et al. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. Embo J 1996; 15: 1751
• 28 Ladomery MR, Harper SJ, Bates DO. Alternative splicing in angiogenesis: The vascular endothelial growth factor paradigm. Cancer Lett. 2006 e-pub
• 29 LeCouter J, Kowalski J, Foster J. et al. Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature 2001; 412: 877-884.
• 30 Lyttle DJ, Fraser KM, Fleming SB. et al. Homologs of vascular endothelial growth factor are encoded by the poxvirus orf virus. J Virol 1994; 68: 84-92.
• 31 Meyer M, Clauss M, Lepple-Wienhues A. et al. A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signalling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases. Embo J 1999; 18: 363-374.
• 32 Suto K, Yamazaki Y, Morita T. et al. Crystal structures of novel vascular endothelial growth factors (VEGF) from snake venoms: insight into selective VEGF binding to kinase insert domain-containing receptor but not to fms-like tyrosine kinase-1. J Biol Chem 2005; 280: 2126-2131.
• 33 Vajkoczy P, Farhadi M, Gaumann A. et al. Microtumor growth initiates angiogenic sprouting with simultaneous expression of VEGF, VEGF receptor-2, and angiopoietin- 2. J Clin Invest 2002; 109: 777-785.
• 34 Greenberg DA, Jin K. From angiogenesis to neuropathology. Nature 2005; 438: 954-959.
• 35 Deckers MM, Karperien M, van der Bent C. et al. Expression of vascular endothelial growth factors and their receptors during osteoblast differentiation. Endocrinology 2000; 141: 1667-1674.
• 36 Clauss M, Weich H, Breier G. et al. The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. J Biol Chem 1996; 271: 17629-17634.
• 37 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.
• 38 Clauss M, Gerlach M, Gerlach H. et al. Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J Exp Med 1990; 172: 1535-1545.
• 39 Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 2002; 20: 4368-4380.
• 40 Li XA, Everson W, Smart EJ. Nitric oxide, caveolae, and vascular pathology. Cardiovasc Toxicol 2006; 6: 1-13.
• 41 Matsumoto T, Bohman S, Dixelius J. et al. VEGF receptor-2 Y951 signaling and a role for the adapter molecule TSAd in tumor angiogenesis. Embo J 2005; 24: 2342-2353.
• 42 Kendall RL, Rutledge RZ, Mao X. et al. Vascular endothelial growth factor receptor KDR tyrosine kinase activity is increased by autophosphorylation of two activation loop tyrosine residues. J Biol Chem 1999; 274: 6453-6460.
• 43 Sakurai Y, Ohgimoto K, Kataoka Y. et al. Essential role of Flk-1 (VEGF receptor 2) tyrosine residue 1173 in vasculogenesis in mice. Proc Natl Acad Sci USA 2005; 102: 1076-1081.
• 44 Mechtcheriakova D, Clauss M, Hofer E. Specificity, diversity and convergence in angiogenic and inflammatory signaling in endothelial cells. In: Vascular Endothelium: Source and Target of Inflammatory mediators. Amsterdam: IOS Press; 2001: p. 211-226.
• 45 Mechtcheriakova D, Schabbauer G, Lucerna M. et al. Specificity, diversity, and convergence in VEGF and TNF-alpha signaling events leading to tissue factor upregulation via EGR-1 in endothelial cells. Faseb J 2001; 15: 230-242.
• 46 Mechtcheriakova D, Wlachos A, Holzmuller H. et al. Vascular endothelial cell growth factor-induced tissue factor expression in endothelial cells is mediated by EGR-1. Blood 1999; 93: 3811-3823.
• 47 Lucerna M, Mechtcheriakova D, Kadl A. et al. NAB2, a corepressor of EGR-1, inhibits vascular endothelial growth factor-mediated gene induction and angiogenic responses of endothelial cells. J Biol Chem 2003; 278: 11433-11440.
• 48 Fahmy RG, Dass CR, Sun LQ. et al. Transcription factor Egr-1 supports FGF-dependent angiogenesis during neovascularization and tumor growth. Nat Med 2003; 9: 1026-1032.
• 49 Khachigian LM. Early growth response-1 in cardiovascular pathobiology. Circ Res 2006; 98: 186-191.
• 50 Silverman ES, Collins T. Pathways of Egr-1-mediated gene transcription in vascular biology. Am J Pathol 1999; 154: 665-670.
• 51 Qu Z, Wolfraim LA, Svaren J. et al. The transcriptional corepressor NAB2 inhibits NGF-induced differentiation of PC12 cells. J Cell Biol 1998; 142: 1075-1082.
• 52 Shafarenko M, Liebermann DA, Hoffman B. Egr-1 abrogates the block imparted by c-Myc on terminal M1 myeloid differentiation. Blood 2005; 106: 871-878.
• 53 Minami T, Horiuchi K, Miura M. et al. Vascular endothelial growth factor- and thrombin-induced termination factor, Down syndrome critical region-1, attenuates endothelial cell proliferation and angiogenesis. J Biol Chem 2004; 279: 50537-50554.
• 54 Hesser BA, Liang XH, Camenisch G. et al. Down syndrome critical region protein 1 (DSCR1), a novel VEGF target gene that regulates expression of inflammatory markers on activated endothelial cells. Blood 2004; 104: 149-158.
• 55 Takahashi T, Yamaguchi S, Chida K. et al. A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells. Embo J 2001; 20: 2768-2778.
• 56 Dayanir V, Meyer RD, Lashkari K. et al. Identification of tyrosine residues in vascular endothelial growth factor receptor-2/FLK-1 involved in activation of phosphatidylinositol 3-kinase and cell proliferation. J Biol Chem 2001; 276: 17686-17692.
• 57 Holmqvist K, Cross MJ, Rolny C. et al. The adaptor protein shb binds to tyrosine 1175 in vascular endothelial growth factor (VEGF) receptor-2 and regulates VEGF-dependent cellular migration. J Biol Chem 2004; 279: 22267-22275.
• 58 Fujio Y, Walsh K. Akt mediates cytoprotection of endothelial cells by vascular endothelial growth factor in an anchorage-dependent manner. J Biol Chem 1999; 274: 16349-16354.
• 59 Bellacosa A, Kumar CC, Di Cristofano A. et al. Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res 2005; 94: 29-86.
• 60 Lee PC, Salyapongse AN, Bragdon GA. et al. Impaired wound healing and angiogenesis in eNOS-deficient mice. Am J Physiol 1999; 277: H1600-1608.
• 61 Dimmeler S, Fleming I, Fisslthaler B. et al. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 1999; 399: 601-605.
• 62 Le Boeuf F, Houle F, Huot J. Regulation of vascular endothelial growth factor receptor 2-mediated phosphorylation of focal adhesion kinase by heat shock protein 90 and Src kinase activities. J Biol Chem 2004; 279: 39175-39185.
• 63 Yamaoka-Tojo M, Ushio-Fukai M, Hilenski L. et al. IQGAP1, a novel vascular endothelial growth factor receptor binding protein, is involved in reactive oxygen species--dependent endothelial migration and proliferation. Circ Res 2004; 95: 276-283.
• 64 Bartoli M, Gu X, Tsai NT. et al. Vascular endothelial growth factor activates STAT proteins in aortic endothelial cells. J Biol Chem 2000; 275: 33189-33192.
• 65 Landgren E, Schiller P, Cao Y. et al. Placenta growth factor stimulates MAP kinase and mitogenicity but not phospholipase C-gamma and migration of endothelial cells expressing Flt 1. Oncogene 1998; 16: 359-367.
• 66 Sawano A, Takahashi T, Yamaguchi S. et al. The phosphorylated 1169-tyrosine containing region of flt-1 kinase (VEGFR-1) is a major binding site for PLCgamma. Biochem Biophys Res Commun 1997; 238: 487-491.
• 67 Fong GH, Rossant J, Gertsenstein M. et al. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 1995; 376: 66-70.
• 68 Hiratsuka S, Minowa O, Kuno J. et al. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci USA 1998; 95: 9349-9354.
• 69 Autiero M, Waltenberger J, Communi D. et al. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med 2003; 9: 936-943.
• 70 Oliver G, Detmar M. The rediscovery of the lymphatic system: old and new insights into the development and biological function of the lymphatic vasculature. Genes Dev 2002; 16: 773-783.
• 71 Dixelius J, Makinen T, Wirzenius M. et al. Ligandinduced vascular endothelial growth factor receptor-3 (VEGFR-3) heterodimerization with VEGFR-2 in primary lymphatic endothelial cells regulates tyrosine phosphorylation sites. J Biol Chem 2003; 278: 40973-40979.
• 72 Petrova TV, Karpanen T, Norrmen C. et al. Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nat Med 2004; 10: 974-981.
• 73 Hong YK, Detmar M. Prox1, master regulator of the lymphatic vasculature phenotype. Cell Tissue Res 2003; 314: 85-92.
• 74 Olsson AK, Dimberg A, Kreuger J. et al. VEGF receptor signalling – in control of vascular function. Nat Rev Mol Cell Biol 2006; 7: 359-371.
• 75 Dumont DJ, Yamaguchi TP, Conlon RA. et al. tek, a novel tyrosine kinase gene located on mouse chromosome 4, is expressed in endothelial cells and their presumptive precursors. Oncogene 1992; 7: 1471-1480.
• 76 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.
• 77 Yabkowitz R, Meyer S, Black T. et al. Inflammatory cytokines and vascular endothelial growth factor stimulate the release of soluble tie receptor from human endothelial cells via metalloprotease activation. Blood 1999; 93: 1969-1979.
• 78 Saharinen P, Kerkela K, Ekman N. et al. Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2. J Cell Biol 2005; 169: 239-243.
• 79 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.
• 80 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.
• 81 Fiedler U, Reiss Y, Scharpfenecker M. et al. Angiopoietin- 2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med 2006; 12: 235-239.
• 82 DeBusk LM, Hallahan DE, Lin PC. Akt is a major angiogenic mediator downstream of the Ang1/Tie2 signaling pathway. Exp Cell Res 2004; 298: 167-177.
• 83 Kim I, Kim HG, So JN. et al. Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3'-Kinase/Akt signal transduction pathway. Circ Res 2000; 86: 24-29.
• 84 Jones N, Dumont DJ. The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R. Oncogene 1998; 17: 1097-1108.
• 85 Huang L, Turck CW, Rao P. et al. GRB2 and SHPTP2: potentially important endothelial signaling molecules downstream of the TEK/TIE2 receptor tyrosine kinase. Oncogene 1995; 11: 2097-2103.
• 86 Jones N, Master Z, Jones J. et al. Identification of Tek/Tie2 binding partners. Binding to a multifunctional docking site mediates cell survival and migration. J Biol Chem 1999; 274: 30896-30905.
• 87 Audero E, Cascone I, Maniero F. et al. Adaptor ShcA protein binds tyrosine kinase Tie2 receptor and regulates migration and sprouting but not survival of endothelial cells. J Biol Chem 2004; 279: 13224-13233.
• 88 Hughes DP, Marron MB, Brindle NP. The antiinflammatory endothelial tyrosine kinase Tie2 interacts with a novel nuclear factor-kappaB inhibitor ABIN-2. Circ Res 2003; 92: 630-636.
• 89 Korpelainen EI, Karkkainen M, Gunji Y. et al. Endothelial receptor tyrosine kinases activate the STAT signaling pathway: mutant Tie-2 causing venous malformations signals a distinct STAT activation response. Oncogene 1999; 18: 1-8.
• 90 Yamaguchi Y, Pasquale EB. Eph receptors in the adult brain. Curr Opin Neurobiol 2004; 14: 288-296.
• 91 Poliakov A, Cotrina M, Wilkinson DG. Diverse roles of eph receptors and ephrins in the regulation of cell migration and tissue assembly. Dev Cell 2004; 7: 465-480.
• 92 Adams RH, Wilkinson GA, Weiss C. et al. Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev 1999; 13: 295-306.
• 93 Wang HU, Chen ZF, Anderson DJ. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 1998; 93: 741-753.
• 94 Adams RH, Diella F, Hennig S. et al. The cytoplasmic domain of the ligand ephrinB2 is required for vascular morphogenesis but not cranial neural crest migration. Cell 2001; 104: 57-69.
• 95 Fuller T, Korff T, Kilian A. et al. Forward EphB4 signaling in endothelial cells controls cellular repulsion and segregation from ephrinB2 positive cells. J Cell Sci 2003; 116: 2461-2470.
• 96 Carter N, Nakamoto T, Hirai H. et al. EphrinA1-induced cytoskeletal re-organization requires FAK and p130(cas). Nat Cell Biol 2002; 4: 565-573.
• 97 Huynh-Do U, Stein E, Lane AA. et al. Surface densities of ephrin-B1 determine EphB1-coupled activation of cell attachment through alphavbeta3 and alpha5beta1 integrins. Embo J 1999; 18: 2165-2173.
• 98 Schmucker D, Zipursky SL. Signaling downstream of Eph receptors and ephrin ligands. Cell 2001; 105: 701-704.
• 99 Powers CJ, McLeskey SW, Wellstein A. Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer 2000; 7: 165-197.
• 100 Auguste P, Javerzat S, Bikfalvi A. Regulation of vascular development by fibroblast growth factors. Cell Tissue Res 2003; 314: 157-166.
• 101 Tallquist M, Kazlauskas A. PDGF signaling in cells and mice. Cytokine Growth Factor Rev 2004; 15: 205-213.
• 102 Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 2006; 7: 505-516.
• 103 Oitzinger W, Hofer-Warbinek R, Schmid JA. et al. Adenovirus-mediated expression of a mutant IkappaB kinase 2 inhibits the response of endothelial cells to inflammatory stimuli. Blood 2001; 97: 1611-1617.
• 104 Wrighton CJ, Hofer-Warbinek R, Moll T. et al. Inhibition of endothelial cell activation by adenovirusmediated expression of I kappa B alpha, an inhibitor of the transcription factor NF-kappa B. J Exp Med 1996; 183: 1013-1022.
• 105 Versteeg HH, Ruf W. Emerging insights in tissue factor-dependent signaling events. Semin Thromb Hemost 2006; 32: 24-32.
• 106 Carmeliet P, Mackman N, Moons L. et al. Role of tissue factor in embryonic blood vessel development. Nature 1996; 383: 73-75.
• 107 Belting M, Dorrell MI, Sandgren S. et al. Regulation of angiogenesis by tissue factor cytoplasmic domain signaling. Nat Med 2004; 10: 502-509.
• 108 Grazia Lampugnani M, Zanetti A, Corada M. et al. Contact inhibition of VEGF-induced proliferation requires vascular endothelial cadherin, beta-catenin, and the phosphatase DEP-1/CD148. J Cell Biol 2003; 161: 793-804.
• 109 Lampugnani MG, Orsenigo F, Gagliani MC. et al. Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments. J Cell Biol 2006; 174: 593-604.
• 110 Esser S, Lampugnani MG, Corada M. et al. Vascular endothelial growth factor induces VE-cadherin tyrosine phosphorylation in endothelial cells. J Cell Sci 1998; 111: 1853-1865.
• 111 Nawroth R, Poell G, Ranft A. et al. VE-PTP and VE-cadherin ectodomains interact to facilitate regulation of phosphorylation and cell contacts. Embo J 2002; 21: 4885-4895.
• 112 Gavard J, Gutkind JS. VEGF controls endothelialcell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin. Nat Cell Biol 2006; 8: 1223-1234.
• 113 Huber AH, Weis WI. The structure of the betacatenin/ E-cadherin complex and the molecular basis of diverse ligand recognition by beta-catenin. Cell 2001; 105: 391-402.
• 114 Polakis P. Wnt signaling and cancer. Genes Dev 2000; 14: 1837-1851.
• 115 Issbrucker K, Marti HH, Hippenstiel S. et al. p38 MAP kinase--a molecular switch between VEGF-induced angiogenesis and vascular hyperpermeability. Faseb J 2003; 17: 262-264.