DOI QR코드

DOI QR Code

Vascular endothelial growth factor-dependent and -independent regulation of angiogenesis

  • Shibuya, Masabumi (Department of Molecular Oncology, Tokyo Medical and Dental University)
  • Accepted : 2008.04.07
  • Published : 2008.04.30

Abstract

Angiogenesis, the formation of blood vessels, is essential for preparing a closed circulatory system in the body, and for supplying oxygen and nutrition to tissues. Major diseases such as cancer, rheumatoid arthritis, and atherosclerosis include pathological angiogenesis in their malignant processes, suggesting anti-angiogenic therapy to be a new strategy for suppression of diseases. However, until the 1970s, the molecular basis of angiogenesis was largely unknown. In recent decades, extensive studies have revealed a variety of angiogenic factors and their receptors, including vascular endothelial growth factor (VEGF)-VEGFRs, Angiopoietin-Tie, Ephrin-EphRs and Delta-Notch to be the major regulators of angiogenesis in vertebrates. VEGF and its receptors play a central role in physiological as well as pathological angiogenesis, and functional inhibitors of VEGF and VEGFRs such as anti-VEGF neutralizing antibody and small molecules that block the tyrosine kinase activity of VEGFRs have recently been approved for use to treat patients with colorectal, lung, renal and liver cancers. These drugs have opened a novel field of cancer therapy, i.e. anti-angiogenesis therapy. However, as yet they cannot completely cure patients, and cancer cells could become resistant to these drugs. Thus, it is important to understand further the molecular mechanisms underlying not only VEGF-VEGFR signaling but also the VEGF-independent regulation of angiogenesis, and to learn how to improve anti-angiogenesis therapy.

Keywords

References

  1. Hanahan, D. and Folkman, J. (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353-364 https://doi.org/10.1016/S0092-8674(00)80108-7
  2. Ferrara, N. and Davis-Smyth, T. (1997) The biology of vascular endothelial growth factor. Endocrine Rev. 18, 4-25 https://doi.org/10.1210/er.18.1.4
  3. Shibuya, M. and Claesson-Welsh, L. (2006) Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp. Cell. Res. 312, 549-560 https://doi.org/10.1016/j.yexcr.2005.11.012
  4. Dvorak, HF. (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 https://doi.org/10.1200/JCO.2002.10.088
  5. Takahashi, H. and Shibuya, M. (2005) The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin. Sci. (Lond). 109, 227-241 https://doi.org/10.1042/CS20040370
  6. 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 https://doi.org/10.1038/380435a0
  7. Ferrara, N., Carver-Moore, K., Chen, H., Dowd, M., Lu, L., O'Shea, KS., Powell-Braxton, L., Hillan, KJ. and Moore, MW. (1996) Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439-442 https://doi.org/10.1038/380439a0
  8. Ruhrberg, C., Gerhardt, H., Golding, M., Watson, R., Ioannidou, S., Fujisawa, H., Betsholtz, C. and Shima, DT. (2002) Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev. 16, 2684-2698 https://doi.org/10.1101/gad.242002
  9. Maes, C., Carmeliet, P., Moermans, K., Stockmans, I., Smets, N., Collen, D., Bouillon, R. and Carmeliet, G. (2002) Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Mech. Dev. 111, 61-73 https://doi.org/10.1016/S0925-4773(01)00601-3
  10. Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, JM., Lane, WS. and Kaelin, WG Jr. (2001) HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for $O_2$ sensing. Science 292, 464-468 https://doi.org/10.1126/science.1059817
  11. Jaakkola, P., Mole, DR., Tian, YM., Wilson, MI., Gielbert, J., Gaskell, SJ., Kriegsheim, Av., Hebestreit, HF., Mukherji, M., Schofield, CJ., Maxwell, PH., Pugh, CW. and Ratcliffe, PJ. (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by $O_2$-regulated prolyl hydroxylation. Science 292, 468-472 https://doi.org/10.1126/science.1059796
  12. Carmeliet, P., Moons, L., Luttun, A., Vincenti, V., Compernolle, V., De Mol, M., Wu, Y., Bono, F., Devy, L., Beck, H., Scholz, D., Acker, T., DiPalma, T., Dewerchin, M., Noel, A., Stalmans, I., Barra, A., Blacher, S., Vandendriessche, T., Ponten, A., Eriksson, U., Plate, KH., Foidart, JM., Schaper, W., Charnock-Jones, DS., Hicklin, DJ., Herbert, JM., Collen, D. and Persico, MG. (2001) Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat. Med. 7, 575-583 https://doi.org/10.1038/87904
  13. 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 https://doi.org/10.1016/S1535-6108(02)00153-8
  14. Luttun, A., Tjwa, M., Moons, L., Wu, Y., Angelillo-Scherrer, A., Liao, F., Nagy, JA., Hooper, A., Priller, J., De Klerck, B., Compernolle, V., Daci, E., Bohlen, P., Dewerchin, M., Herbert, JM., Fava, R., Matthys, P., Carmeliet, G., Collen, D., Dvorak, HF., Hicklin, DJ. and Carmeliet P. (2002) Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat. Med. 8, 831-840 https://doi.org/10.1038/nm731
  15. Murakami, M., Zheng, Y., Hirashima, M., Suda, T., Morita, Y., Ooehara, J., Ema, H., Fong, GH. and Shibuya, M. (2008) VEGFR1 tyrosine kinase signaling promotes lymphangiogenesis as well as angiogenesis indirectly via macrophage recruitment. Arterioscler. Thromb. Vasc. Biol. in press
  16. McColl, BK., Paavonen, K., Karnezis, T., Harris, NC., Davydova, N., Rothacker, J., Nice, EC., Harder, KW., Roufail, S., Hibbs, ML., Rogers, PA., Alitalo, K., Stacker, SA. and Achen, MG. (2007) Proprotein convertases promote processing of VEGF-D, a critical step for binding the angiogenic receptor VEGFR-2. FASEB J. 21, 1088-1098 https://doi.org/10.1096/fj.06-7060com
  17. Lyttle, DJ., Fraser, KM., Fleming, SB., Mercer, AA. and Robinson, AJ. (1994) Homologs of vascular endothelial growth factor are encoded by the poxvirus orf virus. J. Virol. 68, 84-92
  18. Meyer, M., Clauss, M., Lepple-Wienhues, A., Waltenberger, J., Augustin, HG., Ziche, M., Lanz, C., Buttner, M., Rziha, HJ. and Dehio, C. (1999) 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. 18, 363-374 https://doi.org/10.1093/emboj/18.2.363
  19. Ogawa, S., Oku, A., Sawano, A., Yamaguchi, S., Yazaki, Y. and Shibuya, M. (1998) A novel type of Vascular Endothelial Growth Factor: VEGF-E (NZ-7 VEGF) preferentially utilizes KDR/Flk-1 receptor and carries a potent mitotic activity without heparin-binding domain. J. Biol. Chem. 273, 31273-31282 https://doi.org/10.1074/jbc.273.47.31273
  20. Wise, LM., Veikkola, T., Mercer, AA., Savory, LJ., Fleming, SB., Caesar, C., Vitali, A., Makinen, T., Alitalo, K. and Stacker, SA. (1999) Vascular endothelial growth factor (VEGF)-like protein from orf virus NZ2 binds to VEGFR2 and neuropilin-1. Proc. Natl. Acad. Sci. U.S.A. 96, 3071-3076. https://doi.org/10.1073/pnas.96.6.3071
  21. Kiba, A., Sagara, H., Hara, T. and Shibuya, M. (2003a) VEGFR-2-specific ligand VEGF-E induces non-edematous hyper-vascularization in mice. Biochem. Biophys. Res. Commun. 301, 371-377 https://doi.org/10.1016/S0006-291X(02)03033-4
  22. Kunstfeld, R., Hirakawa, S., Hong, YK., Schacht, V., Lange-Asschenfeldt, B., Velasco, P., Lin, C., Fiebiger, E., Wei, X., Wu, Y., Hicklin, D., Bohlen, P. and Detmar, M. (2004) Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia. Blood 104, 1048-1057 https://doi.org/10.1182/blood-2003-08-2964
  23. Larcher, F., Murillas, R., Bolontrade, M., Conti, CJ. and Jorcano, JL. (1998) VEGF/VPF overexpression in skin of transgenic mice induces angiogenesis, vascular hyperpermeability and accelerated tumor development. Oncogene 17, 303-311 https://doi.org/10.1038/sj.onc.1201928
  24. Zheng, Y., Murakami, M., Takahashi, H., Yamauchi, M., Kiba, A., Yamaguchi, S., Yabana, N., Alitalo, K. and Shibuya, M. (2006) Chimeric VEGF-$E_{NZ7}$/PlGF promotes angiogenesis via VEGFR-2 without significant enhancement of vascular permeability and inflammation. Arterioscler. Thromb. Vasc. Biol. 26, 2019-2026 https://doi.org/10.1161/01.ATV.0000233336.53574.a1
  25. Inoue, N., Kondo, T., Kobayashi, K., Aoki, M., Numaguchi, Y., Shibuya, M. and Murohara, T. (2007) Therapeutic angiogenesis using novel Vascular Endothelial Growth Factor-E/human Placental Growth Factor chimera genes. Arterioscler. Thromb. Vasc. Biol. 27, 99-105 https://doi.org/10.1161/01.ATV.0000251504.61247.d5
  26. Kiba, A., Yabana, N. and Shibuya, M. (2003b) A set of loop-1 and -3 structures in the novel VEGF family member, VEGF-$E_{NZ-7}$, is essential for the activation of VEGFR-2 signaling. J. Biol. Chem. 278, 13453-13461 https://doi.org/10.1074/jbc.M210931200
  27. Zheng, Y., Watanabe, M., Kuraishi, T., Hattori, S., Kai, C. and Shibuya, M. (2007) Chimeric VEGF-$E_{NZ7}$/PlGF specifically binding to VEGFR-2 accelerates skin wound healing via enhancement of neovascularization. Arterioscler. Thromb. Vasc. Biol. 27, 503-511 https://doi.org/10.1161/01.ATV.0000256459.06671.3c
  28. Takahashi, H., Hattori, S., Iwamatsu, A., Takizawa, H. and Shibuya, M. (2004) A novel snake venom Vascular Endothelial Growth Factor (VEGF) predominantly induces vascular permeability through preferential signaling via VEGF Receptor-1. J. Biol. Chem. 279, 46304-46314 https://doi.org/10.1074/jbc.M403687200
  29. Matthews, W., Jordan, CT., Gavin, M., Jenkins, NA., Copeland, NG. and Lemischka, IR. (1991) A receptor tyrosine kinase cDNA isolated from a population of enriched primitive hematopoietic cells and exhibiting close genetic linkage to c-kit. Proc. Natl. Acad. Sci. U.S.A. 88, 9026-9030. https://doi.org/10.1073/pnas.88.20.9026
  30. 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
  31. Shibuya, M. (1995) Role of VEGF-Flt receptor system in normal and tumor angiogenesis. Adv. Cancer Res. 67, 281-316 https://doi.org/10.1016/S0065-230X(08)60716-2
  32. Terman, BI., Carrion, ME., Kovacs, E., Rasmussen, BA., Eddy, R. and Shows, TB. (1991) Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene 6, 1677-1683
  33. Alitalo, K. and Carmeliet, P. (2002) Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 1, 219-227 https://doi.org/10.1016/S1535-6108(02)00051-X
  34. Veikkola, T., Jussila, L., Makinen, T., Karpanen, T., Jeltsch, M., Petrova, TV., Kubo, H., Thurston, G., McDonald, DM., Achen, MG., Stacker, SA. and Alitalo, K. (2001) Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. EMBO J. 20, 1223-1231 https://doi.org/10.1093/emboj/20.6.1223
  35. 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
  36. Clauss, M., Weich, H., Breier, G., Knies, U., Rockl, W., Waltenberger, J. and Risau, W. (1996) The Vascular Endothelial Growth Factor Receptor Flt-1 madiates biological activities. J. Biol. Chem. 271, 17629-17634 https://doi.org/10.1074/jbc.271.30.17629
  37. Sawano, A., Iwai, S., Sakurai, Y., Ito, M., Shitara, K, Nakahata, T. and Shibuya, M. (2001) Vascular Endothelial Growth Factor Receptor-1 (Flt-1) is a novel cell surface marker for the lineage of monocyte-macrophages in humans. Blood 97, 785-791 https://doi.org/10.1182/blood.V97.3.785
  38. Lin, EY., Li, JF., Gnatovskiy, L., Deng, Y., Zhu, L., Grzesik, DA., Qian, H., Xue, XN. and Pollard, JW. (2006) Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 66, 11238-11246 https://doi.org/10.1158/0008-5472.CAN-06-1278
  39. Lyden, D., Hattori, K., Dias, S., Costa, C., Blaikie, P., Butros, L., Chadburn, A., Heissig, B., Marks, W., Witte, L., Wu, Y., Hicklin, D., Zhu, Z., Hackett, NR., Crystal, RG., Moore, MA., Hajjar, KA., Manova, K., Benezra, R., and Rafii, S. (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat. Med. 7, 1194-1201 https://doi.org/10.1038/nm1101-1194
  40. 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 https://doi.org/10.1182/blood-2006-04-016030
  41. Fong, GH., Rossant, J., Gertsentein, M. and Breitman, ML. (1995) Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376, 66-70 https://doi.org/10.1038/376066a0
  42. 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. https://doi.org/10.1073/pnas.95.16.9349
  43. Kaplan, RN., Riba, RD., Zacharoulis, S., Bramley, AH., Vincent, L., Costa, C., MacDonald, DD., Jin, DK., Shido, K., Kerns, SA., Zhu, Z., Hicklin, D., Wu, Y., Port, JL., Altorki, N., Port, ER., Ruggero, D., Shmelkov, SV., Jensen, KK., Rafii, S. and Lyden, D. (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the premetastatic niche. Nature 438, 820-827 https://doi.org/10.1038/nature04186
  44. Kendall, RL. and Thomas, KA. (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. https://doi.org/10.1073/pnas.90.22.10705
  45. Yamaguchi, S., Iwata, K. and Shibuya, M. (2002) Soluble Flt-1 (soluble VEGFR-1), a potent natural anti-angiogenic molecule in mammals, is phylogenetically conserved in avians. Biochem. Biophys. Res. Commun. 291, 554-559 https://doi.org/10.1006/bbrc.2002.6478
  46. 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 https://doi.org/10.1210/jc.2002-021942
  47. Levine, RJ., Maynard, SE., Qian, C., Lim, KH., England, LJ., Yu, KF., Schisterman, EF., Thadhani, R., Sachs, BP., Epstein, FH., Sibai, BM., Sukhatme, VP. and Karumanchi, SA. (2004) Circulating angiogenic factors and the risk of preeclampsia. N. Engl. J. Med. 350, 672-683 https://doi.org/10.1056/NEJMoa031884
  48. Maynard, SE., Min, JY., Merchan, J., Lim, KH., Li, J., Mondal, S., Libermann, TA., Morgan, JP., Sellke, FW., Stillman, IE., Epstein, FH., Sukhatme, VP. and Karumanchi, SA. (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 https://doi.org/10.1172/JCI17189
  49. Das, B., Yeger, H., Tsuchida, R., Torkin, R., Gee, MF., Thorner, PS., Shibuya, M., Malkin, D. and Baruchel, S. (2005) A hypoxia-driven vascular endothelial growth factor/ Flt1 autocrine loop interacts with hypoxia-inducible factor-1alpha through mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 pathway in neuroblastoma. Cancer Res. 65, 7267-7275 https://doi.org/10.1158/0008-5472.CAN-04-4575
  50. Tsuchida, R., Das, B., Yeger, H., Koren, G., Shibuya, M., Thorner, PS., Baruchel, S. and Malkin, D. (2008) Cisplatin treatment increases survival and expansion of a highly tumorigenic side-population fraction by upregulating VEGF/Flt1 autocrine signaling. Oncogene in press
  51. Shalaby, F., Rossant, J., Yamaguchi, TP., Gertsenstein, M., Wu, XF., Breitman, ML. and Schuh, AC. (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376, 62-66 https://doi.org/10.1038/376062a0
  52. 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 https://doi.org/10.1038/sj.onc.1202527
  53. Xia, P., Aiello, LP., Ishii, H., Jiang, ZY., Park, DJ., Robinson, GS., Takagi, H., Newsome, WP., Jirousek, MR. and King, GL. (1996) Characterization of vascular endothelial growth factor's effect on the activation of protein kinase C, its isoforms, and endothelial cell growth. J. Clin. Invest. 98, 2018-2026 https://doi.org/10.1172/JCI119006
  54. Takahashi, T., Yamaguchi, S., Chida, K. and Shibuya, M. (2001) 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. 20, 2768-2778 https://doi.org/10.1093/emboj/20.11.2768
  55. 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. https://doi.org/10.1073/pnas.0404984102
  56. Matsumoto, T., Bohman, S., Dixelius, J., Berge, T., Dimberg, A., Magnusson, P., Wang, L., Wikner, C., Qi, JH,, 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 https://doi.org/10.1038/sj.emboj.7600709
  57. Soker, S., Takashima, S., Miao, HQ., Neufeld, G. and Klagsbrun, M. (1998) Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92, 735-745 https://doi.org/10.1016/S0092-8674(00)81402-6
  58. Kopfstein, L., Veikkola, T., Djonov, VG., Baeriswyl, V., Schomber, T., Strittmatter, K., Stacker, SA., Achen, MG., Alitalo, K. and Christofori, G. (2007) Distinct roles of vascular endothelial growth factor-D in lymphangiogenesis and metastasis. Am. J. Pathol. 170, 1348-1361 https://doi.org/10.2353/ajpath.2007.060835
  59. Makinen, T., Veikkola, T., Mustjoki, S., Karpanen, T., Catimel, B., Nice, E.C., Wise, L., Mercer, A., Kowalski, H., Kerjaschki, D., Stacker, S.A., Achen, M.G., and Alitalo, K. (2001) Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J. 20, 4762-4773 https://doi.org/10.1093/emboj/20.17.4762
  60. Luo, JC., Yamaguchi, S., Shinkai, A., Shitara, K. and Shibuya, M. (1998) Significant expression of Vascular Endothelial Growth Factor/Vascular Permeability Factor in mouse ascites tumors. Cancer Res. 58, 2652-2660
  61. Kim, K. J., Li, B., Winer, J., Armanini, M., Gillett, N., Phillips, H. S. and Ferrara, N. (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362, 841-844 https://doi.org/10.1038/362841a0
  62. 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 https://doi.org/10.1056/NEJMoa032691
  63. Sandler, A., Gray, R., Perry, MC., Brahmer, J., Schiller, JH., Dowlati, A., Lilenbaum, R. and Johnson, DH. (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N. Engl. J. Med. 355, 2542-2550 https://doi.org/10.1056/NEJMoa061884
  64. Cohen, MH., 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 https://doi.org/10.1634/theoncologist.12-6-713
  65. Lee, S., Chen, TT., Barber, CL., Jordan, MC., Murdock, J., Desai, S., Ferrara, N., Nagy, A., Roos, KP. and Iruela-Arispe, ML. (2007) Autocrine VEGF signaling is required for vascular homeostasis. Cell 130, 691-703 https://doi.org/10.1016/j.cell.2007.06.054
  66. Fischer, C., Jonckx, B., Mazzone, M., Zacchigna, S., Loges, S., Pattarini, L., Chorianopoulos, E., Liesenborghs, L., Koch, M., De Mol, M., Autiero, M., Wyns, S., Plaisance, S., Moons, L., van Rooijen, N., Giacca, M., Stassen, JM., Dewerchin, M., Collen, D. and Carmeliet, P. (2007) Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131, 463-475 https://doi.org/10.1016/j.cell.2007.08.038
  67. Cho, CH., Kim, KE., Byun, J., Jang, HS., Kim, DK., Baluk, P., Baffert, F., Lee, GM., Mochizuki, N., Kim, J., Jeon, BH., McDonald, DM. and Koh, GY. (2005) Long-term and sustained COMP-Ang1 induces long-lasting vascular enlargement and enhanced blood flow. Circ. Res. 97, 86-94 https://doi.org/10.1161/01.RES.0000174093.64855.a6
  68. Uemura, A., Ogawa, M., Hirashima, M., Fujiwara, T., Koyama, S., Takagi, H., Honda, Y., Wiegand, SJ., Yancopoulos, GD. and Nishikawa, S. (2002) 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 https://doi.org/10.1172/JCI0215621
  69. Wang, HU., Chen, ZF. and Anderson, DJ. (1998) Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93, 741-753 https://doi.org/10.1016/S0092-8674(00)81436-1
  70. Gale, NW., Dominguez, MG., Noguera, I., Pan, L., Hughes, V., Valenzuela, DM., Murphy, AJ., Adams, NC., Lin, HC., Holash, J., Thurston, G. and Yancopoulos, GD. (2004) Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc. Natl. Acad. Sci. U.S.A. 101, 15949-15954. https://doi.org/10.1073/pnas.0407290101
  71. Noguera-Troise, I., Daly, C., Papadopoulos, NJ., Coetzee, S., Boland, P., Gale, NW., Lin, HC., Yancopoulos, GD. and Thurston, G. (2006) Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444, 1032-1037 https://doi.org/10.1038/nature05355
  72. Saito, M., Hamasaki, M. and Shibuya, M. (2003) Tubular formation by Angiopoietin-1 in endothelial cell/fibroblast co-culture is dependent on endogenous VEGF. Cancer Sci. 94, 782-790 https://doi.org/10.1111/j.1349-7006.2003.tb01519.x
  73. Yamauchi, M., Imajoh-Ohmi, S. and Shibuya, M. (2007) A novel anti-angiogenic pathway of thrombospondin-1 mediated by suppression of the cell cycle. Cancer Sci. 98, 1491-1497 https://doi.org/10.1111/j.1349-7006.2007.00534.x
  74. Kiyono, M. and Shibuya, M. (2003) Bone morphogenetic protein 4 mediates apoptosis of capillary endothelial cells during rat pupillary membrane regression. Mol. Cell. Biol. 23, 4627-4636 https://doi.org/10.1128/MCB.23.13.4627-4636.2003
  75. Kiyono, M. and Shibuya, M. (2006) Inhibitory Smad transcription factors protect arterial endothelial endothelial cells from apoptosis induced by BMP4. Oncogene 25, 7131-7137 https://doi.org/10.1038/sj.onc.1209700

Cited by

  1. Inhibition of vascular endothelial growth factor expression by Chinese medicine of Hedyotis diffusa Willd herbal compounds vol.5, pp.4, 2010, https://doi.org/10.1007/s11515-010-0033-6
  2. The endometrial lymphatic vasculature: Function and dysfunction vol.13, pp.4, 2012, https://doi.org/10.1007/s11154-012-9224-6
  3. A decrease in maternal plasma concentrations of sVEGFR-2 precedes the clinical diagnosis of preeclampsia vol.202, pp.6, 2010, https://doi.org/10.1016/j.ajog.2010.04.002
  4. Effect of vegf gene knockdown on growth of the murine sarcoma cell line MS-K vol.16, pp.6, 2011, https://doi.org/10.1111/j.1365-2443.2011.01513.x
  5. Breast cancer and spider telangiectasias at diagnosis and its relation to histopathology and prognosis: a population-based study vol.131, pp.1, 2012, https://doi.org/10.1007/s10549-011-1707-8
  6. Vascular Endothelial Growth Factor Receptor-1 Signaling Promotes Liver Repair through Restoration of Liver Microvasculature after Acetaminophen Hepatotoxicity vol.120, pp.1, 2011, https://doi.org/10.1093/toxsci/kfq366
  7. Unexplained fetal death is associated with increased concentrations of anti-angiogenic factors in amniotic fluid vol.23, pp.8, 2010, https://doi.org/10.3109/14767050903443467
  8. Oxidative stress in angiogenesis and vascular disease vol.123, pp.5, 2014, https://doi.org/10.1182/blood-2013-09-512749
  9. VEGF-A165 Potently Induces Human Blood–Nerve Barrier Endothelial Cell Proliferation, Angiogenesis, and Wound Healing In Vitro vol.33, pp.6, 2013, https://doi.org/10.1007/s10571-013-9946-3
  10. Effects of hyperglycemia on functional state of human umbilical vein endothelial cells in vitro vol.426, pp.1, 2009, https://doi.org/10.1134/S0012496609030053
  11. Antiangiogenic therapies: is VEGF-A inhibition alone enough? vol.11, pp.3, 2011, https://doi.org/10.1586/era.11.5
  12. Recurrent anaplastic meningioma treated by sunitinib based on results from quantitative proteomics vol.38, pp.1, 2012, https://doi.org/10.1111/j.1365-2990.2011.01197.x
  13. VEGFR1-Positive Macrophages Facilitate Liver Repair and Sinusoidal Reconstruction after Hepatic Ischemia/Reperfusion Injury vol.9, pp.8, 2014, https://doi.org/10.1371/journal.pone.0105533
  14. TWELVE-MONTH OUTCOME AFTER ONE INTRAVITREAL INJECTION OF BEVACIZUMAB TO TREAT MYOPIC CHOROIDAL NEOVASCULARIZATION vol.30, pp.10, 2010, https://doi.org/10.1097/IAE.0b013e3181e22659
  15. Mechanotransduction Drives Post Ischemic Revascularization Through KATPChannel Closure and Production of Reactive Oxygen Species vol.20, pp.6, 2014, https://doi.org/10.1089/ars.2012.4971
  16. Long Noncoding RNA JHDM1D-AS1 Promotes Tumor Growth by Regulating Angiogenesis in Response to Nutrient Starvation vol.37, pp.18, 2017, https://doi.org/10.1128/MCB.00125-17
  17. The Role of Vascular Endothelial Growth Factor Receptor-1 Signaling in the Recovery from Ischemia vol.10, pp.7, 2015, https://doi.org/10.1371/journal.pone.0131445
  18. The VEGF pathway in lung cancer vol.72, pp.6, 2013, https://doi.org/10.1007/s00280-013-2298-3
  19. Peritoneal fluid modifies the microRNA expression profile in endometrial and endometriotic cells from women with endometriosis vol.30, pp.10, 2015, https://doi.org/10.1093/humrep/dev204
  20. Serial serum VEGF-A, angiopoietin-2, and endostatin measurements in cirrhotic patients with hepatocellular carcinoma treated by transcatheter arterial chemoembolization vol.27, pp.8, 2011, https://doi.org/10.1016/j.kjms.2011.03.008
  21. ARTEMIN Promotes De Novo Angiogenesis in ER Negative Mammary Carcinoma through Activation of TWIST1-VEGF-A Signalling vol.7, pp.11, 2012, https://doi.org/10.1371/journal.pone.0050098
  22. The pan-deacetylase inhibitor panobinostat affects angiogenesis in hepatocellular carcinoma models via modulation of CTGF expression 2015, https://doi.org/10.3892/ijo.2015.3087
  23. Angiogenin and vascular endothelial growth factor expression in lungs of lung cancer patients vol.46, pp.4, 2012, https://doi.org/10.2478/v10019-012-0031-1
  24. Cantharidin inhibits angiogenesis by suppressing VEGF-induced JAK1/STAT3, ERK and AKT signaling pathways vol.38, pp.2, 2015, https://doi.org/10.1007/s12272-014-0383-8
  25. VEGF/VEGFR signaling in the liver repair from acetaminophen hepatotoxicity vol.33, pp.1, 2013, https://doi.org/10.2492/inflammregen.33.066
  26. Angiogenesis in rheumatoid arthritis vol.42, pp.7, 2009, https://doi.org/10.1080/08916930903143083
  27. Angiogenesis in the Developing Spinal Cord: Blood Vessel Exclusion from Neural Progenitor Region Is Mediated by VEGF and Its Antagonists vol.10, pp.1, 2015, https://doi.org/10.1371/journal.pone.0116119
  28. Angiogenesis and vasculogenesis in rheumatoid arthritis vol.22, pp.3, 2010, https://doi.org/10.1097/BOR.0b013e328337c95a
  29. Glial influence on the blood brain barrier vol.61, pp.12, 2013, https://doi.org/10.1002/glia.22575
  30. Suppression of Sproutys Has a Therapeutic Effect for a Mouse Model of Ischemia by Enhancing Angiogenesis vol.4, pp.5, 2009, https://doi.org/10.1371/journal.pone.0005467
  31. Fast rearrangement of the neuronal growth cone’s actin cytoskeleton following VEGF stimulation vol.139, pp.3, 2013, https://doi.org/10.1007/s00418-012-1036-y
  32. A Novel Approach for Studying Microcirculation in Bone Defects by Intravital Fluorescence Microscopy vol.17, pp.12, 2011, https://doi.org/10.1089/ten.tec.2011.0065
  33. Sprouty4deficiency potentiates Ras-independent angiogenic signals and tumor growth vol.100, pp.9, 2009, https://doi.org/10.1111/j.1349-7006.2009.01214.x
  34. Low-Dosage Inhibition of Dll4 Signaling Promotes Wound Healing by Inducing Functional Neo-Angiogenesis vol.7, pp.1, 2012, https://doi.org/10.1371/journal.pone.0029863
  35. Brain angiogenesis in developmental and pathological processes: therapeutic aspects of vascular endothelial growth factor vol.276, pp.17, 2009, https://doi.org/10.1111/j.1742-4658.2009.07175.x
  36. Morphological Plasticity of Emerging Purkinje Cells in Response to Exogenous VEGF vol.10, 2017, https://doi.org/10.3389/fnmol.2017.00002
  37. Angiogenesis and parasitic helminth-associated neovascularization vol.138, pp.04, 2011, https://doi.org/10.1017/S0031182010001642
  38. Pazopanib: an antiangiogenic drug in perspective vol.5, pp.9, 2009, https://doi.org/10.2217/fon.09.112
  39. Molecular Characteristics and Pathways of Avastin for the Treatment of Glioblastoma Multiforme vol.23, pp.3, 2012, https://doi.org/10.1016/j.nec.2012.05.002
  40. Assessment of Angiogenic Markers and Female Sex Hormone Receptors in Pregnancy Tumor of the Gingiva vol.71, pp.8, 2013, https://doi.org/10.1016/j.joms.2013.03.009
  41. Investigating the Influence of HUVECs in the Formation of Glioblastoma Spheroids in High-Throughput Three-Dimensional Microwells vol.14, pp.7, 2015, https://doi.org/10.1109/TNB.2015.2477818
  42. Controlling angiogenesis in breast cancer: A systematic review of anti-angiogenic trials vol.38, pp.6, 2012, https://doi.org/10.1016/j.ctrv.2011.12.002
  43. Fetal death: A condition with a dissociation in the concentrations of soluble vascular endothelial growth factor receptor-2 between the maternal and fetal compartments vol.23, pp.9, 2010, https://doi.org/10.3109/14767050903410664
  44. Copper promotion of angiogenesis in isolated rat aortic ring: role of vascular endothelial growth factor vol.25, pp.1, 2014, https://doi.org/10.1016/j.jnutbio.2013.08.013
  45. VEGF drives cancer-initiating stem cells through VEGFR-2/Stat3 signaling to upregulate Myc and Sox2 vol.34, pp.24, 2015, https://doi.org/10.1038/onc.2014.257
  46. Maternal cell-free messenger RNA in twin pregnancies: the effects of chorionicity and severe twin to twin transfusion syndrome (TTTS) vol.91, pp.10, 2012, https://doi.org/10.1111/j.1600-0412.2012.01507.x
  47. Valor pronóstico de la expresión del factor de crecimiento endotelial vascular A y del factor inducible por la hipoxia 1α en pacientes operados de cáncer de pulmón no microcítico vol.142, pp.10, 2014, https://doi.org/10.1016/j.medcli.2013.02.040
  48. Oxidized LDL-induced angiogenesis involves sphingosine 1-phosphate: prevention by anti-S1P antibody vol.172, pp.1, 2015, https://doi.org/10.1111/bph.12897
  49. Angiogenesis is a Link Between Atherosclerosis and Tumorigenesis: Role of LOX-1 vol.25, pp.5, 2011, https://doi.org/10.1007/s10557-011-6343-3
  50. Effect of Endostar combined with angiopoietin-2 inhibitor on malignant pleural effusion in mice vol.32, pp.1, 2015, https://doi.org/10.1007/s12032-014-0410-0
  51. Receptor tyrosine kinase inhibitors: Are they real tumor killers? vol.138, pp.3, 2016, https://doi.org/10.1002/ijc.29499
  52. Vascular Endothelial Growth Factor (VEGF) Receptors: Drugs and New Inhibitors vol.55, pp.24, 2012, https://doi.org/10.1021/jm301085w
  53. Development of radiotracers for oncology - the interface with pharmacology vol.163, pp.8, 2011, https://doi.org/10.1111/j.1476-5381.2010.01160.x
  54. BMP4/Thrombospondin-1 loop paracrinically inhibits tumor angiogenesis and suppresses the growth of solid tumors vol.33, pp.29, 2014, https://doi.org/10.1038/onc.2013.358
  55. A Digest on the Role of the Tumor Microenvironment in Gastrointestinal Cancers vol.3, pp.1, 2010, https://doi.org/10.1007/s12307-010-0040-9
  56. Cancer-associated fibroblasts up-regulate CCL2, CCL26, IL6 and LOXL2 genes related to promotion of cancer progression in hepatocellular carcinoma cells vol.66, pp.7, 2012, https://doi.org/10.1016/j.biopha.2012.02.001
  57. Pathways mediating VEGF-independent tumor angiogenesis vol.21, pp.1, 2010, https://doi.org/10.1016/j.cytogfr.2009.11.003
  58. Fe-MIL-101 exhibits selective cytotoxicity and inhibition of angiogenesis in ovarian cancer cells via downregulation of MMP vol.6, pp.1, 2016, https://doi.org/10.1038/srep26126
  59. Serum vascular endothelial growth factor levels in patients with non-small cell lung cancer and its relations to the micrometastasis in peripheral blood vol.29, pp.4, 2009, https://doi.org/10.1007/s11596-009-0414-8
  60. Extract of Cordyceps militaris inhibits angiogenesis and suppresses tumor growth of human malignant melanoma cells vol.45, pp.1, 2014, https://doi.org/10.3892/ijo.2014.2397
  61. KRN633, an Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinase, Induces Intrauterine Growth Restriction in Mice vol.98, pp.4, 2013, https://doi.org/10.1002/bdrb.21064
  62. Angiogenic, neurotrophic, and inflammatory system SNPs moderate the association between birth weight and ADHD symptom severity vol.165, pp.8, 2014, https://doi.org/10.1002/ajmg.b.32275
  63. Vascular endothelial growth factor expression along a circadian time span in intact adult mice liver vol.42, pp.2, 2011, https://doi.org/10.1080/09291016.2010.491241
  64. Ang II induces capillary formation from endothelial cells via the AT1R-dependent inositol requiring enzyme 1 pathway vol.434, pp.3, 2013, https://doi.org/10.1016/j.bbrc.2013.03.113
  65. Regulation of endometrial vascular remodelling: role of the vascular endothelial growth factor family and the angiopoietin-TIE signalling system vol.138, pp.6, 2009, https://doi.org/10.1530/REP-09-0147
  66. Vascular endothelial growth factor, basic fibroblast growth factor, insulin-like growth factor-I and platelet-derived growth factor levels in human milk of mothers with term and preterm neonates vol.50, pp.2, 2010, https://doi.org/10.1016/j.cyto.2010.02.008
  67. Morpholino-Mediated Isoform Modulation of Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) Reduces Colon Cancer Xenograft Growth vol.6, pp.4, 2014, https://doi.org/10.3390/cancers6042330
  68. Maternal plasma and amniotic fluid angiogenic factors and their receptors in monochorionic twin pregnancies complicated by twin-to-twin transfusion syndrome 2009, https://doi.org/10.1002/uog.7515
  69. Association of increased Treg and Th17 with pathogenesis of moyamoya disease vol.7, pp.1, 2017, https://doi.org/10.1038/s41598-017-03278-8
  70. Expression of angiogenic growth factors VEGF, bFGF and ANG1 in colon cancer after bevacizumab treatment in vitro: A potential self-regulating mechanism vol.37, pp.1, 2017, https://doi.org/10.3892/or.2016.5231
  71. Vascular Endothelial Growth Factor Receptor Type 1 Signaling Prevents Delayed Wound Healing in Diabetes by Attenuating the Production of IL-1β by Recruited Macrophages vol.186, pp.6, 2016, https://doi.org/10.1016/j.ajpath.2016.02.014
  72. VEGF as an activity marker in rheumatoid arthritis vol.5, pp.3, 2010, https://doi.org/10.2217/ijr.10.24
  73. Protein kinase inhibitors for the treatment of advanced and progressive radiorefractory thyroid tumors: From the clinical trials to the real life vol.31, pp.3, 2017, https://doi.org/10.1016/j.beem.2017.06.001
  74. Differential Expression of Vascular Endothelial Growth Factor, and Angiopoietin 1 and 2 in Functionally Divergent Experimental Rabbit Models of Bladder Hypertrophy vol.181, pp.6, 2009, https://doi.org/10.1016/j.juro.2009.01.100
  75. Rapid remodeling of airway vascular architecture at birth vol.239, pp.9, 2010, https://doi.org/10.1002/dvdy.22379
  76. 5′-(N-ethylcarboxamido) adenosine improves angiogenesis in transplanted human ovarian tissue vol.95, pp.8, 2011, https://doi.org/10.1016/j.fertnstert.2011.05.041
  77. Glial influences on BBB functions and molecular players in immune cell trafficking vol.1862, pp.3, 2016, https://doi.org/10.1016/j.bbadis.2015.10.004
  78. Tumor and stromal pathways mediating refractoriness/resistance to anti-angiogenic therapies vol.30, pp.12, 2009, https://doi.org/10.1016/j.tips.2009.09.004
  79. Pathophysiological Mechanisms of Carotid Plaque Vulnerability: Impact on Ischemic Stroke vol.60, pp.6, 2012, https://doi.org/10.1007/s00005-012-0192-z
  80. Expression Patterns of HIF-1α Under Hypoxia in Vascular Smooth Muscle Cells of Venous Malformations vol.75, pp.3, 2015, https://doi.org/10.1097/SAP.0000000000000015
  81. Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? vol.13, pp.1, 2010, https://doi.org/10.1007/s10456-009-9160-6
  82. Genetic Polymorphism in a VEGF-Independent Angiogenesis Gene ANGPT1 and Overall Survival of Colorectal Cancer Patients after Surgical Resection vol.7, pp.4, 2012, https://doi.org/10.1371/journal.pone.0034758
  83. Vascular Endothelial Growth Factor and Epidermal Growth Factor Signaling Pathways as Therapeutic Targets for Colorectal Cancer vol.138, pp.6, 2010, https://doi.org/10.1053/j.gastro.2010.02.005
  84. The possible mechanism for impaired angiogenesis after transient focal ischemia in type 2 diabetic GK rats: Different expressions of angiostatin and vascular endothelial growth factor vol.64, pp.3, 2010, https://doi.org/10.1016/j.biopha.2009.08.005
  85. Morphological and immunohistochemical characterization of angiogenic and apoptotic factors and the expression of thyroid receptors in the ovary of tilapia Oreochromis niloticus in captivity vol.35, pp.4, 2015, https://doi.org/10.1590/S0100-736X2015000400010
  86. Circulating CD14+ and CD14highCD16− classical monocytes are reduced in patients with signs of plaque neovascularization in the carotid artery vol.255, 2016, https://doi.org/10.1016/j.atherosclerosis.2016.10.004
  87. 4-Hydroxynonenal Contributes to Angiogenesis through a Redox-Dependent Sphingolipid Pathway: Prevention by Hydralazine Derivatives vol.2017, 2017, https://doi.org/10.1155/2017/9172741
  88. Role of endothelial progenitor cells in diabetes mellitus vol.4, pp.6, 2009, https://doi.org/10.1586/eem.09.49
  89. Upregulation of MicroRNA-210 Regulates Renal Angiogenesis Mediated by Activation of VEGF Signaling Pathway under Ischemia/Perfusion Injury in vivo and in vitro vol.35, pp.3, 2012, https://doi.org/10.1159/000331054
  90. Hepatocellular carcinoma cells cause different responses in expressions of cancer-promoting genes in different cancer-associated fibroblasts vol.29, pp.6, 2013, https://doi.org/10.1016/j.kjms.2012.08.012
  91. Zebrafish WNK Lysine Deficient Protein Kinase 1 (wnk1) Affects Angiogenesis Associated with VEGF Signaling vol.9, pp.8, 2014, https://doi.org/10.1371/journal.pone.0106129
  92. Maternal serum placental growth factor at 11-13 weeks' gestation and fetal cardiac defects vol.42, pp.2, 2013, https://doi.org/10.1002/uog.12346
  93. Tyrosine Kinase Inhibitor–Induced Thyroid Disorders: A Review and Hypothesis vol.23, pp.2, 2013, https://doi.org/10.1089/thy.2012.0456
  94. Antiangiogenic-Induced Hypertension: The Molecular Basis of Signaling Network vol.73, pp.2, 2012, https://doi.org/10.1159/000334458
  95. Expression Profile of MicroRNAs and mRNAs in Human Placentas From Pregnancies Complicated by Preeclampsia and Preterm Labor vol.18, pp.1, 2011, https://doi.org/10.1177/1933719110374115
  96. In VitroSelection of Multiple Libraries Created by Genetic Code Reprogramming To Discover Macrocyclic Peptides That Antagonize VEGFR2 Activity in Living Cells vol.8, pp.6, 2013, https://doi.org/10.1021/cb300697h
  97. Pre- and Perinatal Ischemia-Hypoxia, the Ischemia-Hypoxia Response Pathway, and ADHD Risk vol.46, pp.3, 2016, https://doi.org/10.1007/s10519-016-9784-4
  98. A subset of patients destined to develop spontaneous preterm labor has an abnormal angiogenic/anti-angiogenic profile in maternal plasma: Evidence in support of pathophysiologic heterogeneity of preterm labor derived from a longitudinal study vol.22, pp.12, 2009, https://doi.org/10.3109/14767050902994838
  99. Evidence in support of a role for anti-angiogenic factors in preterm prelabor rupture of membranes vol.23, pp.8, 2010, https://doi.org/10.3109/14767050903440471
  100. An electrochemical functional assay for the sensing of nitric oxide release induced by angiogenic factors vol.44, pp.11, 2011, https://doi.org/10.5483/BMBRep.2011.44.11.699
  101. The PKCβ/HuR/VEGF pathway in diabetic retinopathy vol.80, pp.8, 2010, https://doi.org/10.1016/j.bcp.2010.06.033
  102. The effect of VEGF on the myogenic differentiation of adipose tissue derived stem cells within thermosensitive hydrogel matrices vol.31, pp.6, 2010, https://doi.org/10.1016/j.biomaterials.2009.10.057
  103. Autocrine VEGF–VEGFR2–Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth vol.209, pp.3, 2012, https://doi.org/10.1084/jem.20111424
  104. Elucidating Novel Serum Biomarkers Associated with Pulmonary Tuberculosis Treatment vol.8, pp.4, 2013, https://doi.org/10.1371/journal.pone.0061002
  105. Modified rice bran hemicellulose inhibits vascular endothelial growth factor-induced angiogenesis in vitro via VEGFR2 and its downstream signaling pathways vol.36, pp.2, 2017, https://doi.org/10.12938/bmfh.16-016
  106. The ratio of VEGF/PEDF expression in bone marrow mesenchymal stem cells regulates neovascularization vol.81, pp.3, 2011, https://doi.org/10.1016/j.diff.2010.12.003
  107. Evidence of an imbalance of angiogenic/antiangiogenic factors in massive perivillous fibrin deposition (maternal floor infarction): a placental lesion associated with recurrent miscarriage and fetal death vol.208, pp.4, 2013, https://doi.org/10.1016/j.ajog.2013.01.017
  108. Future Prospects and Challenges of Antiangiogenic Cancer Gene Therapy vol.21, pp.4, 2010, https://doi.org/10.1089/hum.2010.017
  109. Decreased serum vascular endothelial growth factor-D levels in metastatic patients with differentiated thyroid carcinoma vol.76, pp.1, 2012, https://doi.org/10.1111/j.1365-2265.2011.04183.x
  110. The coffee diterpene kahweol inhibits metastasis by modulating expressions of MMPs and VEGF via STAT3 inactivation vol.133, pp.4, 2012, https://doi.org/10.1016/j.foodchem.2012.02.043
  111. Regulation of endothelial signaling and migration by v-ATPase vol.17, pp.3, 2014, https://doi.org/10.1007/s10456-013-9408-z
  112. Heme Oxygenase in the Regulation of Vascular Biology: From Molecular Mechanisms to Therapeutic Opportunities vol.14, pp.1, 2011, https://doi.org/10.1089/ars.2010.3153
  113. The Angiogenic Peptide Vascular Endothelial Growth Factor-Basic Fibroblast Growth Factor Signaling is Up-Regulated in a Rat Pressure Ulcer Model vol.296, pp.8, 2013, https://doi.org/10.1002/ar.22676
  114. The Role of Vascular Endothelial Growth Factor in Small-airway Remodelling in a Rat Model of Chronic Obstructive Pulmonary Disease vol.7, 2017, https://doi.org/10.1038/srep41202
  115. Soluble Tie2 fusion protein decreases peritoneal angiogenesis in uremic rats vol.8, pp.1, 2013, https://doi.org/10.3892/mmr.2013.1478
  116. The molecular profile of microglia under the influence of glioma vol.14, pp.8, 2012, https://doi.org/10.1093/neuonc/nos116
  117. Sp1 mediate hypoxia induced ephrinB2 expression via a hypoxia-inducible factor independent mechanism vol.391, pp.1, 2010, https://doi.org/10.1016/j.bbrc.2009.10.146
  118. Antiangiogenic-Like Properties of Fermented Extracts of Ayurvedic Medicinal Plants vol.18, pp.9, 2015, https://doi.org/10.1089/jmf.2014.0128
  119. Vascular endothelial growth factor A and cardiovascular disease in rheumatoid arthritis patients vol.77, pp.4, 2011, https://doi.org/10.1111/j.1399-0039.2010.01625.x
  120. Vascular Endothelial Growth Factor Gene Promoter Polymorphisms and Alzheimer's Disease Risk: A Meta-Analysis vol.19, pp.7, 2013, https://doi.org/10.1111/cns.12093
  121. Angiopoietin-1/Angiopoietin-2 Ratio for Prediction of Preeclampsia vol.22, pp.8, 2009, https://doi.org/10.1038/ajh.2009.97
  122. Role and Therapeutic Potential of VEGF in the Nervous System vol.89, pp.2, 2009, https://doi.org/10.1152/physrev.00031.2008
  123. Dual suppression of hemangiogenesis and lymphangiogenesis by splice-shifting morpholinos targeting vascular endothelial growth factor receptor 2 (KDR) vol.27, pp.1, 2013, https://doi.org/10.1096/fj.12-213835
  124. type-1 receptor signaling promotes liver repair after hepatic ischemia/reperfusion injury through the enhancement of macrophage recruitment vol.27, pp.8, 2013, https://doi.org/10.1096/fj.13-227421
  125. CD147 promotes the proliferation, invasiveness, migration and angiogenesis of human lung carcinoma cells vol.13, pp.2, 2017, https://doi.org/10.3892/ol.2016.5502
  126. Bone Marrow-Derived Endothelial Progenitor Cells Reduce Recurrent Miscarriage in Gestation vol.25, pp.12, 2016, https://doi.org/10.3727/096368916X692753
  127. Azithromycin effectively inhibits tumor angiogenesis by suppressing vascular endothelial growth factor receptor 2-mediated signaling pathways in lung cancer vol.14, pp.1, 2017, https://doi.org/10.3892/ol.2017.6103
  128. The role of tumor angiogenesis as a therapeutic target in colorectal cancer vol.18, pp.3, 2018, https://doi.org/10.1080/14737140.2018.1428092
  129. The evolution into personalized therapies in pancreatic ductal adenocarcinoma: challenges and opportunities vol.18, pp.2, 2018, https://doi.org/10.1080/14737140.2018.1417844
  130. Advances in the Ongoing Battle against the Consequences of Peripheral Nerve Injuries pp.19328486, 2018, https://doi.org/10.1002/ar.23936
  131. Topical axitinib is a potent inhibitor of corneal neovascularization pp.14426404, 2018, https://doi.org/10.1111/ceo.13333
  132. Haplotype-based association of Vascular Endothelial Growth Factor gene polymorphisms with urothelial bladder cancer risk in Tunisian population pp.08878013, 2018, https://doi.org/10.1002/jcla.22610
  133. Green tea prevents vascular disturbs and attenuates periodontal breakdown in long-term hyperglycaemia in T1D rats vol.45, pp.5, 2018, https://doi.org/10.1111/jcpe.12883
  134. Peritoneal morphologic changes in a peritoneal dialysis rat model correlate with angiopoietin/Tie-2 vol.24, pp.1, 2009, https://doi.org/10.1007/s00467-008-0944-5
  135. gene rs3025039C/T and rs833052C/A variants are associated with bladder cancer risk in Asian descendants pp.07302312, 2019, https://doi.org/10.1002/jcb.28324