Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Pathophysiological consequences of VEGF-induced vascular permeability

Abstract

Although vascular endothelial growth factor (VEGF) induces angiogenesis, it also disrupts vascular barrier function in diseased tissues. Accordingly, VEGF expression in cancer and ischaemic disease has unexpected pathophysiological consequences. By uncoupling endothelial cell–cell junctions VEGF causes vascular permeability and oedema, resulting in extensive injury to ischaemic tissues after stroke or myocardial infarction. In cancer, VEGF-mediated disruption of the vascular barrier may potentiate tumour cell extravasation, leading to widespread metastatic disease. Therefore, by blocking the vascular permeability promoting effects of VEGF it may be feasible to reduce tissue injury after ischaemic disease and minimize the invasive properties of circulating tumour cells.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Structural determinants of VEGF-induced leak.
Figure 2: VEGF induces vascular leak.
Figure 3: Signalling pathways implicated in VEGF-induced vascular permeability.
Figure 4: VEGF expression after myocardial infarction.

References

  1. Senger, D. R. et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219, 983–985 (1983)

    ADS  CAS  PubMed  Article  Google Scholar 

  2. Ferrara, N., Gerber, H. P. & LeCouter, J. The biology of VEGF and its receptors. Nature Med. 9, 669–676 (2003)

    CAS  PubMed  Article  Google Scholar 

  3. Carmeliet, P. et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435–439 (1996)

    ADS  CAS  PubMed  Article  Google Scholar 

  4. Ferrara, N. et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439–442 (1996)

    ADS  CAS  PubMed  Article  Google Scholar 

  5. Ferrara, N., Hillan, K. J., Gerber, H. P. & Novotny, W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nature Rev. Drug Discov. 3, 391–400 (2004)

    CAS  Article  Google Scholar 

  6. Eliceiri, B. P. et al. Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol. Cell 4, 915–924 (1999)

    CAS  PubMed  Article  Google Scholar 

  7. Brown, L. F., Dvorak, A. M. & Dvorak, H. F. Leaky vessels, fibrin deposition, and fibrosis: a sequence of events common to solid tumors and to many other types of disease. Am. Rev. Respir. Dis. 140, 1104–1107 (1989)

    CAS  PubMed  Article  Google Scholar 

  8. van Bruggen, N. et al. VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J. Clin. Invest. 104, 1613–1620 (1999)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. Weis, S. et al. Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction. J. Clin. Invest. 113, 885–894 (2004)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. Paul, R. et al. Src deficiency or blockade of Src activity in mice provides cerebral protection following stroke. Nature Med. 7, 222–227 (2001)

    CAS  PubMed  Article  Google Scholar 

  11. Jain, R. K. Transport of molecules across tumour vasculature. Cancer Metastasis Rev. 6, 559–593 (1987)

    CAS  PubMed  Article  Google Scholar 

  12. Dvorak, H. F. Leaky tumour vessels: consequences for tumour stroma generation and for solid tumour therapy. Prog. Clin. Biol. Res. 354A, 317–330 (1990)

    CAS  PubMed  Google Scholar 

  13. Roberts, W. G. & Palade, G. E. Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J. Cell Sci. 108, 2369–2379 (1995)

    CAS  PubMed  Article  Google Scholar 

  14. Esser, S. et al. Vascular endothelial growth factor induces endothelial fenestrations in vitro. J. Cell Biol. 140, 947–959 (1998)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Feng, D. et al. Pathways of macromolecular extravasation across microvascular endothelium in response to VPF/VEGF and other vasoactive mediators. Microcirculation 6, 23–44 (1999)

    CAS  PubMed  Article  Google Scholar 

  16. Hobbs, S. K. et al. Regulation of transport pathways in tumour vessels: role of tumour type and microenvironment. Proc. Natl Acad. Sci. USA 95, 4607–4612 (1998)

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. Monsky, W. L. et al. Augmentation of transvascular transport of macromolecules and nanoparticles in tumors using vascular endothelial growth factor. Cancer Res. 59, 4129–4135 (1999)

    CAS  PubMed  Google Scholar 

  18. Weis, S., Cui, J., Barnes, L. & Cheresh, D. Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumour cell extravasation and metastasis. J. Cell Biol. 167, 223–229 (2004)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Salgado, R. et al. Platelets and vascular endothelial growth factor (VEGF): a morphological and functional study. Angiogenesis 4, 37–43 (2001)

    CAS  PubMed  Article  Google Scholar 

  20. Cohen, A. W., Carbajal, J. M. & Schaeffer, R. C. Jr VEGF stimulates tyrosine phosphorylation of β-catenin and small-pore endothelial barrier dysfunction. Am. J. Physiol. 277, H2038–H2049 (1999)

    CAS  PubMed  Google Scholar 

  21. Moore, T. M. et al. Receptor-dependent activation of store-operated calcium entry increases endothelial cell permeability. Am. J. Physiol. Lung Cell. Mol. Physiol. 279, L691–L698 (2000)

    CAS  PubMed  Article  Google Scholar 

  22. Esser, S., Lampugnani, M. G., Corada, M., Dejana, E. & Risau, W. Vascular endothelial growth factor induces VE-cadherin tyrosine phosphorylation in endothelial cells. J. Cell Sci. 111, 1853–1865 (1998)

    CAS  PubMed  Article  Google Scholar 

  23. Fischer, S. et al. Hypoxia induces permeability in brain microvessel endothelial cells via VEGF and NO. Am. J. Physiol. 276, C812–C820 (1999)

    CAS  PubMed  Article  Google Scholar 

  24. Chang, Y. S. et al. Effect of vascular endothelial growth factor on cultured endothelial cell monolayer transport properties. Microvasc. Res. 59, 265–277 (2000)

    CAS  PubMed  Article  Google Scholar 

  25. Miles, A. A. & Miles, E. M. Vascular reactions to histamine, histamine-liberator and leukotaxine in the skin of guinea pigs. J. Physiol. (Lond.) 118, 228–257 (1952)

    CAS  Article  Google Scholar 

  26. Liao, F. et al. Selective targeting of angiogenic tumour vasculature by vascular endothelial-cadherin antibody inhibits tumour growth without affecting vascular permeability. Cancer Res. 62, 2567–2575 (2002)

    CAS  PubMed  Google Scholar 

  27. Bates, D. O., Lodwick, D. & Williams, B. Vascular endothelial growth factor and microvascular permeability. Microcirculation 6, 83–96 (1999)

    CAS  PubMed  Article  Google Scholar 

  28. McDonald, D. M., Thurston, G. & Baluk, P. Endothelial gaps as sites for plasma leakage in inflammation. Microcirculation 6, 7–22 (1999)

    CAS  PubMed  Article  Google Scholar 

  29. Feng, D., Nagy, J. A., Dvorak, A. M. & Dvorak, H. F. Different pathways of macromolecule extravasation from hyperpermeable tumour vessels. Microvasc. Res. 59, 24–37 (2000)

    CAS  PubMed  Article  Google Scholar 

  30. Ishida, A. et al. Expression of vascular endothelial growth factor receptors in smooth muscle cells. J. Cell. Physiol. 188, 359–368 (2001)

    CAS  PubMed  Article  Google Scholar 

  31. Deckers, M. M. et al. Expression of vascular endothelial growth factors and their receptors during osteoblast differentiation. Endocrinology 141, 1667–1674 (2000)

    CAS  PubMed  Article  Google Scholar 

  32. Takahashi, N. et al. Vascular endothelial growth factor induces activation and subcellular translocation of focal adhesion kinase (p125FAK) in cultured rat cardiac myocytes. Circ. Res. 84, 1194–1202 (1999)

    ADS  CAS  PubMed  Article  Google Scholar 

  33. Chintalgattu, V., Nair, D. M. & Katwa, L. C. Cardiac myofibroblasts: a novel source of vascular endothelial growth factor (VEGF) and its receptors Flt-1 and KDR. J. Mol. Cell. Cardiol. 35, 277–286 (2003)

    CAS  PubMed  Article  Google Scholar 

  34. Carmeliet, P. & Storkebaum, E. Vascular and neuronal effects of VEGF in the nervous system: implications for neurological disorders. Semin. Cell Dev. Biol. 13, 39–53 (2002)

    CAS  PubMed  Article  Google Scholar 

  35. Xie, K., Wei, D., Shi, Q. & Huang, S. Constitutive and inducible expression and regulation of vascular endothelial growth factor. Cytokine Growth Factor Rev. 15, 297–324 (2004)

    CAS  PubMed  Article  Google Scholar 

  36. Reynolds, L. E. et al. Enhanced pathological angiogenesis in mice lacking β3 integrin or β3 and β5 integrins. Nature Med. 8, 27–34 (2002)

    CAS  PubMed  Article  Google Scholar 

  37. Friedlander, M. et al. Definition of two angiogenic pathways by distinct αv integrins. Science 270, 1500–1502 (1995)

    ADS  CAS  PubMed  Article  Google Scholar 

  38. Eliceiri, B. P. et al. Src-mediated coupling of focal adhesion kinase to integrin αvβ5 in vascular endothelial growth factor signalling. J. Cell Biol. 157, 149–160 (2002)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Robinson, S. D., Reynolds, L. E., Wyder, L., Hicklin, D. J. & Hodivala-Dilke, K. M. β3-Integrin regulates vascular endothelial growth factor-A-dependent permeability. Thromb. Vasc. Biol. 24, 2108–2114 (2004)

    CAS  Article  Google Scholar 

  40. Borges, E., Jan, Y. & Ruoslahti, E. Platelet-derived growth factor receptor beta and vascular endothelial growth factor receptor 2 bind to the β3 integrin through its extracellular domain. J. Biol. Chem. 275, 39867–39873 (2000)

    CAS  PubMed  Article  Google Scholar 

  41. Reynolds, A. R. et al. Elevated Flk1 (vascular endothelial growth factor receptor 2) signalling mediates enhanced angiogenesis in β3-integrin-deficient mice. Cancer Res. 64, 8643–8650 (2004)

    CAS  PubMed  Article  Google Scholar 

  42. Dejana, E., Corada, M. & Lampugnani, M. G. Endothelial cell-to-cell junctions. FASEB J. 9, 910–918 (1995)

    CAS  PubMed  Article  Google Scholar 

  43. Suarez, S. & Ballmer-Hofer, K. VEGF transiently disrupts gap junctional communication in endothelial cells. J. Cell Sci. 114, 1229–1235 (2001)

    CAS  PubMed  Article  Google Scholar 

  44. Antonetti, D. A., Barber, A. J., Hollinger, L. A., Wolpert, E. B. & Gardner, T. W. Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors. J. Biol. Chem. 274, 23463–23467 (1999)

    CAS  PubMed  Article  Google Scholar 

  45. Pedram, A., Razandi, M. & Levin, E. R. Deciphering vascular endothelial cell growth factor/vascular permeability factor signalling to vascular permeability. Inhibition by atrial natriuretic peptide. J. Biol. Chem. 277, 44385–44398 (2002)

    CAS  PubMed  Article  Google Scholar 

  46. Corada, M. et al. Vascular endothelial-cadherin is an important determinant of microvascular integrity in vivo. Proc. Natl Acad. Sci. USA 96, 9815–9820 (1999)

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. Kevil, C. G., Okayama, N. & Alexander, J. S. H2O2-mediated permeability II: importance of tyrosine phosphatase and kinase activity. Am. J. Physiol. Cell Physiol. 281, C1940–C1947 (2001)

    CAS  PubMed  Article  Google Scholar 

  48. Nwariaku, F. E. et al. Tyrosine phosphorylation of vascular endothelial cadherin and the regulation of microvascular permeability. Surgery 132, 180–185 (2002)

    PubMed  Article  Google Scholar 

  49. Lambeng, N. et al. Vascular endothelial-cadherin tyrosine phosphorylation in angiogenic and quiescent adult tissues. Circ. Res. 96, 384–391 (2005)

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. Suyama, K., Shapiro, I., Guttman, M. & Hazan, R. B. A signalling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor. Cancer Cell 2, 301–314 (2002)

    CAS  PubMed  Article  Google Scholar 

  51. Fedor-Chaiken, M., Hein, P. W., Stewart, J. C., Brackenbury, R. & Kinch, M. S. E-cadherin binding modulates EGF receptor activation. Cell Commun. Adhes. 10, 105–118 (2003)

    CAS  PubMed  Article  Google Scholar 

  52. Avizienyte, E., Fincham, V. J., Brunton, V. G. & Frame, M. C. Src SH3/2 domain-mediated peripheral accumulation of Src and phospho-myosin is linked to de-regulation of E-cadherin and the epithelial-mesenchymal transition. Mol. Biol. Cell 15, 2794–2803 (2004)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. Roura, S., Miravet, S., Piedra, J., Garcia de Herreros, A. & Dunach, M. Regulation of E-cadherin/Catenin association by tyrosine phosphorylation. J. Biol. Chem. 274, 36734–36740 (1999)

    CAS  PubMed  Article  Google Scholar 

  54. Ozawa, M. & Ohkubo, T. Tyrosine phosphorylation of p120(ctn) in v-Src transfected L cells depends on its association with E-cadherin and reduces adhesion activity. J. Cell Sci. 114, 503–512 (2001)

    CAS  PubMed  Article  Google Scholar 

  55. Xu, Y. & Carpenter, G. Identification of cadherin tyrosine residues that are phosphorylated and mediate Shc association. J. Cell. Biochem. 75, 264–271 (1999)

    CAS  PubMed  Article  Google Scholar 

  56. Balsamo, J. et al. Regulated binding of PTP1B-like phosphatase to N-cadherin: control of cadherin-mediated adhesion by dephosphorylation of β-catenin. J. Cell Biol. 134, 801–813 (1996)

    CAS  PubMed  Article  Google Scholar 

  57. Brady-Kalnay, S. M. et al. Dynamic interaction of PTPµ with multiple cadherins in vivo. J. Cell Biol. 141, 287–296 (1998)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Nawroth, R. et al. VE-PTP and VE-cadherin ectodomains interact to facilitate regulation of phosphorylation and cell contacts. EMBO J. 21, 4885–4895 (2002)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Grazia Lampugnani, M. et al. Contact inhibition of VEGF-induced proliferation requires vascular endothelial cadherin, β-catenin, and the phosphatase DEP-1/CD148. J. Cell Biol. 161, 793–804 (2003)

    PubMed  Article  CAS  Google Scholar 

  60. Ukropec, J. A., Hollinger, M. K., Salva, S. M. & Woolkalis, M. J. SHP2 association with VE-cadherin complexes in human endothelial cells is regulated by thrombin. J. Biol. Chem. 275, 5983–5986 (2000)

    CAS  PubMed  Article  Google Scholar 

  61. Kroll, J. & Waltenberger, J. The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells. J. Biol. Chem. 272, 32521–32527 (1997)

    CAS  PubMed  Article  Google Scholar 

  62. Wu, H. M., Yuan, Y., Zawieja, D. C., Tinsley, J. & Granger, H. J. Role of phospholipase C, protein kinase C, and calcium in VEGF-induced venular hyperpermeability. Am. J. Physiol. 276, H535–H542 (1999)

    CAS  PubMed  Google Scholar 

  63. Behzadian, M. A. et al. VEGF-induced paracellular permeability in cultured endothelial cells involves urokinase and its receptor. FASEB J. 17, 752–754 (2003)

    CAS  PubMed  Article  Google Scholar 

  64. Langille, B. L. Morphologic responses of endothelium to shear stress: reorganization of the adherens junction. Microcirculation 8, 195–206 (2001)

    CAS  PubMed  Article  Google Scholar 

  65. Chen, K. D. et al. Mechanotransduction in response to shear stress. Roles of receptor tyrosine kinases, integrins, and Shc. J. Biol. Chem. 274, 18393–18400 (1999)

    CAS  PubMed  Article  Google Scholar 

  66. Stockton, R. A., Schaefer, E. & Schwartz, M. A. p21-activated kinase regulates endothelial permeability through modulation of contractility. J. Biol. Chem. 279, 46621–46630 (2004)

    CAS  PubMed  Article  Google Scholar 

  67. Wu, M. H., Guo, M., Yuan, S. Y. & Granger, H. J. Focal adhesion kinase mediates porcine venular hyperpermeability elicited by vascular endothelial growth factor. J. Physiol. (Lond.) 552, 691–699 (2003)

    CAS  Article  Google Scholar 

  68. Yue, X. & Tomanek, R. J. Stimulation of coronary vasculogenesis/angiogenesis by hypoxia in cultured embryonic hearts. Dev. Dyn. 216, 28–36 (1999)

    CAS  PubMed  Article  Google Scholar 

  69. Marti, H. J. et al. Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia. Am. J. Pathol. 156, 965–976 (2000)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. Li, J. et al. VEGF, flk-1, and flt-1 expression in a rat myocardial infarction model of angiogenesis. Am. J. Physiol. 270, H1803–H1811 (1996)

    CAS  PubMed  Google Scholar 

  71. Fukuda, S. et al. Angiogenic signal triggered by ischemic stress induces myocardial repair in rat during chronic infarction. J. Mol. Cell. Cardiol. 36, 547–559 (2004)

    CAS  PubMed  Article  Google Scholar 

  72. Sasaki, H. et al. Hypoxic preconditioning triggers myocardial angiogenesis: a novel approach to enhance contractile functional reserve in rat with myocardial infarction. J. Mol. Cell. Cardiol. 34, 335–348 (2002)

    CAS  PubMed  Article  Google Scholar 

  73. Shyu, K. G. et al. Intramyocardial injection of naked DNA encoding HIF-1α/VP16 hybrid to enhance angiogenesis in an acute myocardial infarction model in the rat. Cardiovasc. Res. 54, 576–583 (2002)

    CAS  PubMed  Article  Google Scholar 

  74. Kawamoto, A. et al. Intramyocardial transplantation of autologous endothelial progenitor cells for therapeutic neovascularization of myocardial ischemia. Circulation 107, 461–468 (2003)

    PubMed  Article  Google Scholar 

  75. Kawamoto, A. et al. Synergistic effect of bone marrow mobilization and vascular endothelial growth factor-2 gene therapy in myocardial ischemia. Circulation 110, 1398–1405 (2004)

    CAS  PubMed  Article  Google Scholar 

  76. Lee, R. J. et al. VEGF gene delivery to myocardium: deleterious effects of unregulated expression. Circulation 102, 898–901 (2000)

    CAS  PubMed  Article  Google Scholar 

  77. Tong, R. T. et al. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 64, 3731–3736 (2004)

    CAS  PubMed  Article  Google Scholar 

  78. Willett, C. G. et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nature Med. 10, 145–147 (2004)

    CAS  PubMed  Article  Google Scholar 

  79. Kuroi, K. & Toi, M. Circulating angiogenesis regulators in cancer patients. Int. J. Biol. Markers 16, 5–26 (2001)

    CAS  PubMed  Article  Google Scholar 

  80. Hormbrey, E. et al. A critical review of vascular endothelial growth factor (VEGF) analysis in peripheral blood: is the current literature meaningful? Clin. Exp. Metastasis 19, 651–663 (2002)

    CAS  PubMed  Article  Google Scholar 

  81. Yuan, F. et al. Time-dependent vascular regression and permeability changes in established human tumour xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proc. Natl Acad. Sci. USA 93, 14765–14770 (1996)

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335–2342 (2004)

    CAS  PubMed  Article  Google Scholar 

  83. Winkler, F. et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumour response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6, 553–563 (2004)

    CAS  PubMed  Google Scholar 

  84. Jain, R. K. Normalization of tumour vasculature: An emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005)

    ADS  CAS  PubMed  Article  Google Scholar 

  85. Mukhopadhyay, D., Tsiokas, L. & Sukhatme, V. P. Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res. 55, 6161–6165 (1995)

    CAS  PubMed  Google Scholar 

  86. Mukhopadhyay, D. & Datta, K. Multiple regulatory pathways of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) expression in tumors. Semin. Cancer Biol. 14, 123–130 (2004)

    CAS  PubMed  Article  Google Scholar 

  87. Izumi, Y., Xu, L., di Tomaso, E., Fukumura, D. & Jain, R. K. Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature 416, 279–280 (2002)

    ADS  CAS  PubMed  Article  Google Scholar 

  88. Baish, J. W., Netti, P. A. & Jain, R. K. Transmural coupling of fluid flow in microcirculatory network and interstitium in tumors. Microvasc. Res. 53, 128–141 (1997)

    CAS  PubMed  Article  Google Scholar 

  89. Tsuzuki, Y. et al. Vascular endothelial growth factor (VEGF) modulation by targeting hypoxia-inducible factor-1α → hypoxia response element → VEGF cascade differentially regulates vascular response and growth rate in tumors. Cancer Res. 60, 6248–6252 (2000)

    CAS  PubMed  Google Scholar 

  90. Akiyama, C. et al. Src family kinase inhibitor PP1 improves motor function by reducing edema after spinal cord contusion in rats. Acta Neurochir. Suppl. 86, 421–423 (2003)

    CAS  PubMed  Google Scholar 

  91. Mura, M., dos Santos, C. C., Stewart, D. & Liu, M. Vascular endothelial growth factor and related molecules in acute lung injury. J. Appl. Physiol. 97, 1605–1617 (2004)

    CAS  PubMed  Article  Google Scholar 

  92. Vaquero, J., Chung, C. & Blei, A. T. Brain edema in acute liver failure. A window to the pathogenesis of hepatic encephalopathy. Ann. Hepatol. 2, 12–22 (2003)

    PubMed  Article  Google Scholar 

  93. Caldwell, R. B. et al. Vascular endothelial growth factor and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives. Diabetes Metab. Res. Rev. 19, 442–455 (2003)

    MathSciNet  CAS  PubMed  Article  Google Scholar 

  94. Conklin, B. S., Zhao, W., Zhong, D. S. & Chen, C. Nicotine and cotinine up-regulate vascular endothelial growth factor expression in endothelial cells. Am. J. Pathol. 160, 413–418 (2002)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. Zhu, B. Q. et al. Second hand smoke stimulates tumour angiogenesis and growth. Cancer Cell 4, 191–196 (2003)

    CAS  PubMed  Article  Google Scholar 

  96. Liao, H. F. et al. Inhibitory effect of caffeic acid phenethyl ester on angiogenesis, tumour invasion, and metastasis. J. Agric. Food Chem. 51, 7907–7912 (2003)

    CAS  PubMed  Article  Google Scholar 

  97. Tang, F. Y., Nguyen, N. & Meydani, M. Green tea catechins inhibit VEGF-induced angiogenesis in vitro through suppression of VE-cadherin phosphorylation and inactivation of Akt molecule. Int. J. Cancer 106, 871–878 (2003)

    CAS  PubMed  Article  Google Scholar 

  98. Kimura, Y. & Okuda, H. Resveratrol isolated from Polygonum cuspidatum root prevents tumour growth and metastasis to lung and tumour-induced neovascularization in Lewis lung carcinoma-bearing mice. J. Nutr. 131, 1844–1849 (2001)

    CAS  PubMed  Article  Google Scholar 

  99. Cao, Z., Fang, J., Xia, C., Shi, X. & Jiang, B. H. trans-3,4,5′-Trihydroxystibene inhibits hypoxia-inducible factor 1α and vascular endothelial growth factor expression in human ovarian cancer cells. Clin. Cancer Res. 10, 5253–5263 (2004)

    CAS  PubMed  Article  Google Scholar 

  100. Lin, M. T., Yen, M. L., Lin, C. Y. & Kuo, M. L. Inhibition of vascular endothelial growth factor-induced angiogenesis by resveratrol through interruption of Src-dependent vascular endothelial cadherin tyrosine phosphorylation. Mol. Pharmacol. 64, 1029–1036 (2003)

    ADS  CAS  PubMed  Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David A. Cheresh.

Ethics declarations

Competing interests

D.A.C. receives consulting fees and owns stock in TargeGen, Inc., which has developed small molecule inhibitors of vascular permeability.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Weis, S., Cheresh, D. Pathophysiological consequences of VEGF-induced vascular permeability. Nature 437, 497–504 (2005). https://doi.org/10.1038/nature03987

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature03987

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing