Vegf-vegfr signals in health and disease

Biomolecules and Therapeutics

Volumn 22, Issue 1, 2014, Pages 1-9

  Shibuya, Masabumi ^a,b,c  

^a JOBU UNIVERSITY   (Japan)

^b TOKYO MEDICAL AND DENTAL UNIVERSITY   (Japan)

^c UNIVERSITY OF TOKYO   (Japan)

Author keywords

Angiogenic signals; Anti angiogenic therapy; Vegf; Vegf receptor

Indexed keywords

VASCULOTROPIN; VASCULOTROPIN ANTIBODY; VASCULOTROPIN INHIBITOR; VASCULOTROPIN RECEPTOR; VASCULOTROPIN RECEPTOR 1; VASCULOTROPIN RECEPTOR 2; VASCULOTROPIN RECEPTOR 3;

ANTIANGIOGENIC ACTIVITY; BINDING AFFINITY; CANCER PATIENT; CARCINOGENESIS; DISEASE ASSOCIATION; DRUG EFFICACY; DRUG USE; HUMAN; LYMPHANGIOGENESIS; NEOPLASM; NONHUMAN; PREECLAMPSIA; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN INTERACTION; PROTEIN PHOSPHORYLATION; REGULATORY MECHANISM; RETINA MACULA DEGENERATION; REVIEW; SIGNAL TRANSDUCTION;

EID: 84893148365     PISSN: 19769148     EISSN: 20054483     Source Type: Journal    
DOI: 10.4062/biomolther.2013.113     Document Type: Review

References (81)

1. Alitalo, K. and Carmeliet, P. (2002) Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 1, 219-227.
2. Ambati, B. K., Nozaki, M., Singh, N., Takeda, A., Jani, P. D., Suthar, T., Albuquerque, R. J., Richter, E., Sakurai, E., Newcomb, M. T., Kleinman, M. E., Caldwell, R. B., Lin, Q., Ogura, Y., Orecchia, A., Samuelson, D. A., Agnew, D. W., St Leger, J., Green, W. R., Mahasreshti, P. J., Curiel, D. T., Kwan, D., Marsh, H., Ikeda S, Leiper, L. J., Collinson, J. M., Bogdanovich, S., Khurana, T. S., Shibuya, M., Baldwin, M. E., Ferrara, N., Gerber, H. P., De Falco, S., Witta, J., Baffi, J. Z., Raisler, B. J. and Ambati, J. (2006) Corneal avascularity is due to soluble VEGF receptor-1. Nature 443, 993-997.
3. Barleon, B., Sozzani, S., Zhou, D., Weich, H. A., Martovani, A. and Marme, D. (1996) Migration of human monocytes in response to vascular endothelilal growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87, 3336-3343.
4. Beck, H., Raab, S., Copanaki, E., Heil, M., Scholz, A., Shibuya, M., Deller, T., Machein, M. and Plate, K. H. (2010) VEGFR-1 signaling regulates the homing of bone marrow derived cells in a mouse stroke model. J. Neuropathol. Exp. Neurol. 69,168-175.
5. Bellomo, D., Headrick, J. P., Silins, G. U., Paterson, C. A., Thomas, P. S., Gartside, M., Mould, A., Cahill, M. M., Tonks, I. D., Grimmond, S. M., Townson, S., Wells, C., Little, M., Cummings, M. C., Hayward, N. K. and Kay, G. F. (2000) Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. Circ. Res. 86, E29-E35.
6. Bry, M., Kivelä, R., Holopainen, T., Anisimov, A., Tammela, T., Soronen, J., Silvola, J., Saraste, A., Jeltsch, M., Korpisalo, P., Carmeliet, P., Lemström, K. B., Shibuya, M., Ylä-Herttuala, S., Alhonen, L., Mervaala, E., Andersson, L. C., Knuuti, J. and Alitalo, K. (2010) Vascular endothelial growth factor-B acts as a coronary growth factor in transgenic rats without inducing angiogenesis, vascular leak, or inflammation. Circulation 122,1725-1733.
7. Carmellet, P., Ferreira, V., Breier, G., Pollefeyt, S., Kleckens, L., Gertsenstein, M., Fahrig, M., Vandenhoeck, A., Harpal, K., Eberhardt, C., Declercq, C., Pawlling, J., Moons, L., Collen, D., Risau, W. and Nagy, A. (1996) Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435-439.
8. Clauss, M., Weich, H., Breier, G., Knies, U., Röckl, W., Waltenberger, J. and Risau, W. (1996) The vascular endothelial growth factor receptor Flt-1 mediates biological activities. J. Biol. Chem. 271, 17629-17634.
9. Cohen, M. H., Gootenberg, J., Keegan, P. and Pazdur, R. (2007) FDA drug approval summary: bevacizumab (Avastin) plus Carboplatin and Paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer. Oncologist 12, 713-718.
10. De Vries, C., Escobedo, J. A., Ueno, H., Houck, K., Ferrara, N. and Williams, L. T. (1992) The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255, 989-991
11. Dhondt, J., Peeraer, E., Verheyen, A., Nuydens, R., Buysschaert, I., Poesen, K., Van Geyte, K., Beerens, M., Shibuya, M., Haigh, J. J., Meert, T., Carmeliet, P. and Lambrechts, D. (2011) Neuronal FLT1 receptor and its selective ligand VEGF-B protect against retrograde degeneration of sensory neurons. FASEB J. 25, 1461-1473.
12. Dias, S., Shmelkov, S. V., Lam, G. and Rafii S. (2002) VEGF(165) promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2 expression and apoptosis inhibition. Blood 99, 2532-2540.
13. Dumont, D. J., Jussila, L., Taipale, J., Lymboussaki, A., Mustonen, T., Pajusola, K., Breitman, M. and Alitalo, K. (1998) Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282, 946-949.
14. Dvorak, H. F. (2002) Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J. Clin. Oncol. 20, 4368-4380.
15. Ferrara, N., Carver-Moore, K., Chen, H., Dowd, M., Lu, L., O'Shea, K. S., Powell-Braxton, L., Hillan, K. J. and Moore, M. W. (1996) Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439-442.
16. Ferrara, N. (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr. Rev. 25, 581-611.
17. Foidart, J. M., Schaaps, J. P., Chantraine, F., Munaut, C. and Lorquet, S. (2009) Dysregulation of anti-angiogenic agents (sFlt-1, PLGF, and sEndoglin) in preeclampsia-a step forward but not the definitive answer. J. Reprod. Immunol. 82, 106-111.
18. Fong, G. H., Rossant, J., Gertsentein, M. and Breitman, M. L. (1995) Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376, 66-70.
19. Freitas, C., Larrivée, B. and Eichmann, A. (2008) Netrins and UNC5 receptors in angiogenesis. Angiogenesis 11, 23-29.
20. Gilbert, J. S., Babcock, S. A. and Granger, J. P. (2007) Hypertension produced by reduced uterine perfusion in pregnant rats is associated with increased soluble Fms-like tyrosine kinase-1 expression. Hypertension 50, 1142-1147.
21. Hanahan, D. and Folkman, J. (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353-364.
22. Heldin, C. H. and Westermark, B. (1999) Mechanism of action and in vivo role of platelet-derived growth factor. Physiol. Rev. 79, 1283-1316.
23. Hida, K., Ohga, N., Akiyama, K., Maishi, N. and Hida, Y. (2013) Heterogeneity of tumor endothelial cells. Cancer Sci. Aug 12. doi: 10.1111/ cas.12251. [Epub ahead of print]
24. Hiratsuka, S., Minowa, O., Kuno, J., Noda, T. and Shibuya, M. (1998) Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc. Natl. Acad. Sci. U.S.A. 95, 9349-9354.
25. Hiratsuka, S., Nakamura, K., Iwai, S., Murakami, M., Itoh, T., Kijima, H., Shipley, J. M., Senior, R. M. and Shibuya, M. (2002) MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung specific metastasis. Cancer Cell 2, 289-300.
26. Hurwitz, H., Fehrenbacher, L., Novotny, W., Cartwright, T., Hainsworth, J., Heim, W., Berlin, J., Baron, A., Griffing, S., Holmgren, E., Ferrara, N., Fyfe, G., Rogers, B., Ross, R. and Kabbinavar, F. (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335-2342.
27. Huveldt, D., Lewis-Tuffin, L. J., Carlson, B. L., Schroeder, M. A., Rodriguez, F., Giannini, C., Galanis, E., Sarkaria, J. N. and Anastasiadis, P. Z. (2013) Targeting Src family kinases inhibits bevacizumab-induced glioma cell invasion. PLoS One. 8, e56505.
28. Jin, J., Sison, K., Li, C., Tian, R., Wnuk, M., Sung, H. K., Jeansson, M., Zhang, C., Tucholska, M., Jones, N., Kerjaschki, D., Shibuya, M., Fantus, I. G., Nagy, A., Gerber, H. P., Ferrara, N., Pawson, T., and Quaggin, S. E. (2012) Soluble FLT1 binds lipid microdomains in podocytes to control cell morphology and glomerular barrier function. Cell 151, 384-399.
29. Kaplan, R. N., Riba, R. D., Zacharoulis, S., Bramley, A. H., Vincent, L., Costa, C., MacDonald, D. D., Jin, D. K., Shido, K., Kerns, S. A., Zhu, Z., Hicklin, D., Wu, Y., Port, J. L., Altorki, N., Port, E. R., Ruggero, D., Shmelkov, S. V., Jensen, K. K., Rafii, S. and Lyden, D. (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820-827.
30. Kato, T., Ito, Y., Hosono, K., Suzsuki, T., Tamaki, H., Minamino, T., Kato, S., Sakagami, H., Shibuya, M. and Majima, M. (2011) Vascular endothelial growth factor receptor-1 signaling promotes liver repair through restoration of liver microvasculature after acetaminophen hepatotoxicity. Toxicol. Sci. 120, 218-229.
31. Kendall, R. L. and Thomas, K. A. (1993) Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc. Natl. Acad. Sci. U.S.A. 90, 10705-10709.
32. Kerber, M., Reiss, Y., Wickersheim, A., Jugold, M., Kiessling, F., Heil, M., Tchaikovski, V., Waltenberger, J., Shibuya, M., Plate, K.H. and Machein, M.R. (2008) Flt-1 signaling in macrophages promotes glioma growth in vivo. Cancer Res. 68, 7342-7351.
33. Keyt, B. A., Nguyen, H. V., Berleau, L. T., Duarte, C. M., Park, J., Chen, H. and Ferrara, N. (1996) Identification of vascular endothelial growth factor determinanats for binding KDR and FLT-1 receptors. Generation of receptor-selective VEGF variants by site-directed mutagenesis. J. Biol. Chem. 271, 5638-5646.
34. Kim, K. J., Li, B., Winer, J., Armanini, M., Gillett, N., Phillips, H. S. and Ferrara, N. (1993) Inhibition of vascular endothelial growth factorinduced angiogenesis suppresses tumour growth in vivo. Nature 362, 841-844.
35. Kim, M., Park, H. J., Seol, J. W., Jang, J. Y., Cho, Y. S., Kim, K. R., Choi, Y., Lydon, J. P., Demayo, F. J., Shibuya, M., Ferrara, N., Sung, H. K., Nagy, A., Alitalo, K. and Koh, G. Y. (2013) VEGF-A regulated by progesterone governs uterine angiogenesis and vascular remodeling during pregnancy. EMBO Mol. Med. 5, 1415-1430.
36. Koga, K., Osuga, Y., Yoshino, O., Hirota, Y., Ruimeng, X., Hirata, T., Takeda, S., Yano, T., Tsutsumi, O. and Taketani, Y. (2003) Elevated serum soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) levels in women with preeclampsia. J. Clin. Endocrinol. Metab. 88, 2348-2351.
37. Kumasawa, K., Ikawa, M., Kidoya, H., Hasuwa, H., Saito-Fujita, T., Morioka, Y., Takakura, N., Kimura, T. and Okabe, M. (2011) Pravastatin induces placental growth factor (PGF) and ameliorates preeclampsia in a mouse model. Proc. Natl. Acad. Sci. U.S.A. 108, 1451-1455.
38. Laurent, J., Hull, E. F., Touvrey, C., Kuonen, F., Lan, Q., Lorusso, G., Doucey, M. A., Ciarloni, L., Imaizumi, N., Alghisi, G.C., Fagiani, E., Zaman, K., Stupp, R., Shibuya, M., Delaloye, J. F., Christofori, G. and Ruegg, C. (2011) Proangiogenic factor PlGF programs CD11b(+) myelomonocytes in breast cancer during differentiation of their hematopoietic progenitors. Cancer Res. 71, 3781-3791.
39. Leung, D. W., Cachianes, G., Kuang, W. J., Goeddel, D. V. and Ferrara, N. (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246, 1306-1309.
40. Levine, R. J., Maynard, S. E., Qian, C., Lim, K. H., England, L. J., Yu, K. F., Schisterman, E. F., Thadhani, R., Sachs, B. P., Epstein, F. H., Sibai, B. M., Sukhatme, V. P. and Karumanchi, S. A. (2004) Circulating angiogenic factors and the risk of preeclampsia. N. Engl. J. Med. 350, 672-683.
41. Luo, L., Uehara, H., Zhang, X., Das, S. K., Olsen, T., Holt, D., Simonis, J. M., Jackman, K., Singh, N., Miya, T. R., Huang, W., Ahmed, F., Bastos-Carvalho, A., Le, Y. Z., Mamalis, C., Chiodo, V. A., Hauswirth, W. W., Baffi, J., Lacal, P. M., Orecchia, A., Ferrara, N., Gao, G., Young-Hee, K., Fu, Y., Owen, L., Albuquerque, R., Baehr, W., Thomas, K., Li, D. Y., Chalam, K. V., Shibuya, M., Grisanti, S., Wilson, D. J., Ambati, J. and Ambati, B. K. (2013) Photoreceptor avascular privilege is shielded by soluble VEGF receptor-1. Elife 2:e00324.
42. Matsumoto, T., Bohman, S., Dixelius, J., Berge, T., Dimberg, A., Magnusson, P., Wang, L., Wikner, C., Qi, J. H., Wernstedt, C., Wu, J., Bruheim, S., Mugishima, H., Mukhopadhyay, D., Spurkland, A. and Claesson-Welsh, L. (2005) VEGF receptor-2 Y951 signaling and a role for the adapter molecule TSAd in tumor angiogenesis. EMBO J. 24, 2342-2353.
43. Maynard, S. E., Min, J. Y., Merchan, J., Lim, K. H., Li, J., Mondal, S., Libermann, T. A., Morgan, J. P., Sellke, F. W., Stillman, I. E., Epstein, F. H., Sukhatme, V. P. and Karumanchi, S. A. (2003) Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J. Clin. Invest. 111, 649-658.
44. Mezquita, J., Mezquita, B., Pau, M. and Mezquita, C. (2003) Downregulation of Flt-1 gene expression by the proteasome inhibitor MG262. J. Cell. Biochem. 89, 1138-1147.
45. Minami, T., Horiuchi, K., Miura, M., Abid, M. R., Takabe, W., Noguchi, N., Kohro, T., Ge, X., Aburatani, H., Hamakubo, T., Kodama, T. and Aird, W. C. (2004) Vascular endothelial growth factor-and thrombin-induced termination factor, Down syndrome critical region-1, attenuates endothelial cell proliferation and angiogenesis. J. Biol. Chem. 279, 50537-50554.
46. Murakami, M., Iwai, S., Hiratsuka, S., Yamauchi, M., Nakamura, K., Iwakura, Y. and Shibuya, M. (2006) Signaling of vascular endothelial growth factor receptor-1 tyrosine kinase promotes rheumatoid arthritis through activation of monocyte/macrophages. Blood 108, 1849-1856.
47. Muramatsu, M., Yamamoto, S., Osawa, T. and Shibuya, M. (2010) Vascular endothelial growth factor receptor-1 signaling promotes mobilization of macrophage lineage cells from bone marrow and stimulates solid tumor growth. Cancer Res. 70, 8211-8221.
48. Nagamatsu, T., Fujii, T., Kusumi, M., Zou, L., Yamashita, T., Osuga, Y., Momoeda, M., Kozuma, S. and Taketani, Y. (2004) Cytotrophoblasts up-regulate soluble fms-like tyrosine kinase-1 expression under reduced oxygen: an implication for the placental vascular development and the pathophysiology of preeclampsia. Endocrinology 145, 4838-4845.
49. Niida, S., Kondo, T., Hiratsuka, S., Hayashi, S. I., Amizuka, N., Noda, T., Ikeda, K. and Shibuya, M. (2005) VEGF receptor 1 signaling is essential for osteoclast development and bone marrow formation in colony-stimulating factor 1-deficient mice. Proc. Natl. Acad. Sci. U.S.A. 102, 14016-14021.
50. Noguera-Troise, I., Daly, C., Papadopoulos, N. J., Coetzee, S., Boland, P., Gale, N. W., Lin, H. C., Yancopoulos, G. D. and Thurston, G. (2006) Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature. 444, 1032-1037.
51. Oosthuyse, B., Moons, L., Storkebaum, E., Beck, H., Nuyens, D., Brusselmans, K., Van Dorpe, J., Hellings, P., Gorselink, M., Heymans, S., Theilmeier, G., Dewerchin, M., Laudenbach, V., Vermylen, P., Raat, H., Acker, T., Vleminckx, V., Van Den Bosch, L., Cashman, N., Fujisawa, H., Drost, M. R., Sciot, R., Bruyninckx, F., Hicklin, D. J., Ince, C., Gressens, P., Lupu, F., Plate, K. H., Robberecht, W., Herbert, J. M., Collen, D. and Carmeliet, P. (2001) Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat. Genet. 28, 131-138.
52. Osawa, T., Tsuchida, R., Muramatsu, M., Shimamura, T., Wang, F., Suehiro, J. I., Kanki, Y., Wada, Y., Yuasa, Y., Aburatani, H., Miyano, S., Minami, T., Kodama, T. and Shibuya, M. (2013) Inhibition of histone demethylase JMJD1A improves anti-angiogenic therapy and reduces tumor associated macrophages. Cancer Res. 73, 3019-3028.
53. Pàez-Ribes, M., Allen, E., Hudock, J., Takeda, T., Okuyama, H., Viñals, F., Inoue, M., Bergers, G., Hanahan, D. and Casanovas, O. (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 15, 220-231.
54. Pritchard-Jones, R. O., Dunn, D. B., Qiu, Y., Varey, A. H., Orlando, A., Rigby, H., Harper, S. J. and Bates, D. O. (2007) Expression of VEGF(xxx)b, the inhibitory isoforms of VEGF, in malignant melanoma. Br. J. Cancer 97, 223-230.
55. Risau, W. (1997) Mechanisms of angiogenesis. Nature 386, 671-674.
56. Sakurai, Y., Ohgimoto, K., Kataoka, Y., Yoshida, N. and Shibuya, M. (2005) Essential role of Flk-1 (VEGF receptor 2) tyrosine residue 1173 in vasculogenesis in mice. Proc. Natl. Acad. Sci. U.S.A. 102, 1076-1081.
57. Sallinen, H., Anttila, M., Gröhn, O., Koponen, J., Hämäläinen, K., Kholova, I., Kosma, V.M., Heinonen, S., Alitalo, K. and Ylä-Herttuala S. (2011) Cotargeting of VEGFR-1 and -3 and angiopoietin receptor Tie2 reduces the growth of solid human ovarian cancer in mice. Cancer Gene Ther. 18, 100-109.
58. Sase, H., Watabe, T., Kawasaki, K., Miyazono, K. and Miyazawa, K. (2009) VEGFR2-PLCgamma1 axis is essential for endothelial specification of VEGFR2+ vascular progenitor cells. J. Cell Sci. 122, 3303-3311.
59. Sato, T., Amano, H., Ito, Y., Eshima, K., Minamino, T., Ae, T., Katada, C., Ohno, T., Hosono, K., Suzuki, T., Shibuya, M., Koizumi, W. and Majima M. (2013) NSAID, aspirin delays gastric ulcer healing with reduced accumulation of CXCR4+VEGFR1+ cells to the ulcer granulation tissues. Biomed Pharmacother. 67, 607-613.
60. Sato, Y. (2013) The vasohibin family: a novel family for angiogenesis regulation. J. Biochem. 153, 5-11.
61. Sawano, A., Takahashi, T., Yamaguchi, S., Aonuma, T. and Shibuya, M. (1996) Flt-1 but not KDR/Flk-1 tyrosine kinase is a receptor for placenta growth factor (PlGF), which is related to vascular endothelial growth factor (VEGF). Cell Growth Diff. 7, 213-221.
62. Schwartz, J. D., Rowinsky, E. K., Youssoufian, H., Pytowski, B. and Wu, Y. (2010) Vascular endothelial growth factor receptor-1 in human cancer: concise review and rationale for development of IMC-18F1 (Human antibody targeting vascular endothelial growth factor receptor-1). Cancer 116,1027-1032.
63. Shalaby, F., Rossant, J., Yamaguchi, T. P., Gertsenstein, M., Wu, X. F., Breitman, M. L. and Schuh, A. C. (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376, 62-66.
64. Shibuya, M., Yamaguchi, S., Yamane, A., Ikeda, T., Tojo, A., Matsushime, H. and Sato, M. (1990) Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. Oncogene 5, 519-524.
65. Shibuya, M. and Claesson-Welsh, L. (2006) Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp. Cell. Res. 312, 549-560.
66. Shibuya, M. (2006) Vascular endothelial growth factor receptor-1 (VEGFR1/Flt-1): a dual regulator for angiogenesis. Angiogenesis 9, 225-230
67. Shibuya, M. (2011) Involvement of Flt-1 (VEGFR-1) in cancer and preeclampsia. Proc. Jpn. Acad Ser. B. Phys. Biol. Sci. 87, 167-178.
68. Suri, C., Jones, P. F., Patan, S., Bartunkova, S., Maisonpierre, P. C., Davis, S., Sato, T. N. and Yancopoulos, G. D. (1996) Requisite role of Angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87, 1171-1180.
69. Takahashi, T., Ueno, H. and Shibuya, M. (1999) VEGF activates Protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells. Oncogene 18, 2221-2230.
70. Takahashi, T., Yamaguchi, S., Chida, K. and Shibuya, M. (2001) A single autophosphorylation site on KDR/Flk-1 is essential for VEGFA-dependent activation of PLC-γ and DNA synthesis in vascular endothelial cells. EMBO J. 20, 2768-2778.
71. Tammela, T., Zarkada, G., Wallgard, E., Murtomaki, A., Suchting, S., Wirzenius, M., Waltari, M., Hellstrom, M., Schomber, T., Peltonen, R., Freitas, C., Duarte, A., Isoniemi, H., Laakkonen, P., Christofori, G., Yla-Herttuala, S., Shibuya, M., Pytowski, B., Eichmann, A., Betsholtz, C. and Alitalo, K. (2008) Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454, 656-660.
72. Tanaka, K., Yamaguchi, S., Sawano, A. and Shibuya, M. (1997) Characterization of the extracellular domain in the vascular endothelial growth factor receptor-1 (Flt-1 tyrosine kinase). Jpn. J. Cancer Res. 88, 867-876.
73. Thadhani, R., Kisner, T., Hagmann, H., Bossung, V., Noack, S., Schaarschmidt, W., Jank, A., Kribs, A., Cornely, O. A., Kreyssig, C., Hemphill, L., Rigby, A. C., Khedkar, S., Lindner, T. H., Mallmann, P., Stepan, H., Karumanchi, S. A. and Benzing, T. (2011) Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia. Circulation 124, 940-950.
74. Verheyen, A., Peeraer, E., Nuydens, R., Dhondt, J., Poesen, K., Pintelon, I., Daniels, A., Timmermans, J. P., Meert, T., Carmeliet, P. and Lambrechts, D. (2012) Systemic anti-vascular endothelial growth factor therapies induce a painful sensory neuropathy. Brain 135, 2629-2641.
75. Wang, H. U., Chen, Z. F. and Anderson, D. J. (1998) Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93, 741-753.
76. Watnick, R. S., Cheng, Y. N., Rangarajan, A., Ince, T. A. and Weinberg, R. A. (2003) Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis. Cancer Cell 3, 219-231.
77. Wittko, I. M., Schänzer, A., Kuzmichev, A., Schneider, F. T., Shibuya, M., Raab, S. and Plate, K. H. (2009) VEGFR-1 regulates adult olfactory bulb neurogenesis and migration of neural progenitors in the rostral migratory stream in vivo. J. Neurosci. 29, 8704-8714.
78. Xiong, Y., Huo, Y., Chen, C., Zeng, H., Lu, X., Wei, C., Ruan, C., Zhang, X., Hu, Z., Shibuya, M. and Luo, J. (2009) Vascular endothelial growth factor (VEGF) receptor-2 tyrosine 1175 signaling controls VEGF-induced von Willebrand factor release from endothelial cells via phospholipase C-gamma 1-and protein kinase A-dependent pathways. J. Biol. Chem. 284, 23217-23224.
79. Yamauchi, M., Imajoh-Ohmi, S. and Shibuya, M. (2007) Novel anti-angiogenic pathway of thrombospondin-1 mediated by suppression of the cell cycle. Cancer Sci. 98, 1491-1497.
80. Yan, M., Callahan, C. A., Beyer, J. C., Allamneni, K. P., Zhang, G., Ridgway, J. B., Niessen, K. and Plowman, G. D. (2010) Chronic DLL4 blockade induces vascular neoplasms. Nature 463, E6-7.
81. Young, B. C., Levine, R. J. and Karumanchi, S. A. (2010) Pathogenesis of preeclampsia. Annu. Rev. Pathol. 5, 173-192.