Skip to main content

Advertisement

SpringerLink
Log in

Vascular Endothelial Growth Factor Increases Permeability of the Blood–Tumor Barrier via Caveolae-Mediated Transcellular Pathway

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

The first goal of this study was to determine the effect of vascular endothelial growth factor (VEGF) on permeability of the blood–tumor barrier (BTB). The second goal was to determine possible cellular mechanisms by which VEGF increases permeability of the BTB. In the rat C6 glioma model, the permeability of the BTB was significantly increased after VEGF injection at dose of 0.05 ng/g and reached its peak at 45 min. Meanwhile, we observed that the density of pinocytotic vesicles of brain microvascular endothelial cells (BMECs) in the BTB increased dramatically by transmission electron microscopy. The immunohistochemistry and western blot analysis revealed that the expression level of caveolae structure proteins caveolin-1 and caveolin-2 in BMECs was increased after VEGF injection, peaked at 45 min, and then decreased to the untreated level. The time peak of expression level of caveolin-1 and caveolin-2 was identical with the peak time of permeability of the BTB and the density of pinocytotic vesicles. All of these results strongly indicated that VEGF increased permeability of the BTB caused by enhancement of the density of pinocytotic vesicles, and the molecular mechanism might be associated with upregulated expression of caveolin-1 and caveolin-2.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Ali MM, Janic B, Babajani-Feremi A et al (2010) Changes in vascular permeability and expression of different angiogenic factors following anti-angiogenic treatment in rat glioma. PLoS ONE 5(1):e8727

    Article  PubMed  Google Scholar 

  • Brekken RA, Thorpe PE (2001) Vascular endothelial growth factor and vascular targeting of solid tumors. Anticancer Res 21(6B):4221–4229

    PubMed  CAS  Google Scholar 

  • Chang SH, Feng D, Nagy JA et al (2009) Vascular permeability and pathological angiogenesis in caveolin-1-null mice. Am J Pathol 175(4):1768–1776

    Article  PubMed  CAS  Google Scholar 

  • Chini B, Parenti M (2004) G-protein coupled receptors in lipid rafts and caveolae: how, when and why do they go there? J Mol Endocrinol 32(2):325–338

    Article  PubMed  CAS  Google Scholar 

  • Cogger VC, Arias IM, Warren A et al (2008) The response of fenestrations, actin, and caveolin-1 to vascular endothelial growth factor in SK Hep1 cells. Am J Physiol Gastrointest Liver Physiol 295(1):G137–G145

    Article  PubMed  CAS  Google Scholar 

  • Dobrogwska DH, Lossinsky AS, Tarnawski M et al (1998) Increased blood–brain barrier permeability and endothelial abnormalities induced by vascular endothelial growth factor. J Neurocytol 27(3):163–173

    Article  Google Scholar 

  • Dvorak AM (2005) Mast cell-derived mediators of enhanced microvascular permeability, vascular permeability factor/vascular endothelial growth factor, histamine, and serotonin, cause leakage of macromolecules through a new endothelial cell permeability organelle, the vesiculo-vacuolar organelle. Chem Immunol Allergy 85:185–204

    Article  PubMed  Google Scholar 

  • Dvorak HF, Brown LF, Detmar M et al (1995) Vascular permeability factor/ vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146(5):1926–1939

    Google Scholar 

  • Fukumura D, Gohongi T, Kadambi A et al (2001) Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proc Natl Acad Sci USA 98(5):2604–2609

    Article  PubMed  CAS  Google Scholar 

  • Grobben B, De Deyn PP, Slegers H (2002) Rat C6 glioma as experimental model system for the study of glioblastoma growth and invasion. Cell Tissue Res 310:257–270

    Article  PubMed  CAS  Google Scholar 

  • Hu G, Place AT, Minshall RD (2008) Regulation of endothelial permeability by Src kinase signaling: vascular leakage versus transcellular transport of drugs and macromolecules. Chem Biol Interact 171(2):177–189

    Article  PubMed  CAS  Google Scholar 

  • Idbaih A, Ducray F, Sierra D et al (2008) Therapeutic application of noncytotoxic molecular targeted therapy in gliomas: growth factor receptors and angiogenesis inhibitors. Oncologist 13(9):978–992

    Article  PubMed  CAS  Google Scholar 

  • Lajoie P, Nabi IR (2007) Regulation of raft-dependent endocytosis. J Cell Mol Med 11(4):644–653

    Article  PubMed  CAS  Google Scholar 

  • Leung DW, Cachianes G, Kuang WJ et al (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246(4935):1306–1309

    Article  PubMed  CAS  Google Scholar 

  • Lin ZX, Yang LJ, Huang Q et al (2008) Inhibition of tumor-induced edema by antisense VEGF is mediated by suppressive vesiculo-vacuolar organelles (VVO) formation. Cancer Sci 99(12):2540–2546

    Article  PubMed  CAS  Google Scholar 

  • Louis DN (2006) Molecular pathology of malignant gliomas. Annu Rev Pathol 1:97–117

    Article  PubMed  CAS  Google Scholar 

  • Matsunaga Y, Yamazaki Y, Suzuki H et al (2009) VEGF-A and VEGF-F evoke distinct changes in vascular ultrastructure. Biochem Biophys Res Commun 379(4):872–875

    Article  PubMed  CAS  Google Scholar 

  • Mayhan WG (1999) VEGF increases permeability of the blood-brain barrier via a nitric oxide synthase/cGMP-dependent pathway. Am J Physiol 276(5pt1):1148–1153

    Google Scholar 

  • Minshall RD, Sessa WC, Stan RV et al (2003) Caveolin regulation of endothelial function. Am J Physiol Lung Cell Mol Physiol 285(6):L1179–L1183

    PubMed  CAS  Google Scholar 

  • Miyake JA, Benadiba M, Colquhoun A (2009) Gamma-linolenic acid inhibits both tumour cell cycle progression and angiogenesis in the orthotopic C6 glioma model through changes in VEGF, Flt1, ERK1/2, MMP2, cyclin D1, pRb, p53 and p27 protein expression. Lipids Health Dis 8:8

    Article  PubMed  Google Scholar 

  • Nag S, Venugopalan R, Stewart DJ (2007) Increased caveolin-1 expression precedes decreased expression of occludin and claudin-5 during blood-brain barrier breakdown. Acta Neuropathol 114(5):459–469

    Article  PubMed  CAS  Google Scholar 

  • Nicolau M, Sirois MG, Bui M et al (1993) Plasma extravasation induced by neurokinins in conscious rats: receptor characterization with agonists and antagonists. Can J Physiol Pharmacol 71:217–221

    Article  PubMed  CAS  Google Scholar 

  • Ningaraj NS, Rao MK, Black KL (2003) Adenosine 5-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumor model. Cancer Res 63(24):8899–8911

    PubMed  CAS  Google Scholar 

  • Papadopoulos MC, Saadoun S, Binder DK et al (2004) Molecular mechanisms of brain tumor edema. Neuroscience 129(4):1011–1020

    Article  PubMed  CAS  Google Scholar 

  • Proescholdt MA, Heiss JD, Walbridge S et al (1999) Vascular endothelial growth factor (VEGF) modulates vascular permeability and inflammation in rat brain. J Neuropathol Exp Neurol 58(6):613–627

    Article  PubMed  CAS  Google Scholar 

  • Rite I, Machado A, Cano J et al (2007) Blood–brain barrier disruption induces in vivo degeneration of nigral dopaminergic neurons. J Neurochem 101(6):1567–1582

    Article  PubMed  CAS  Google Scholar 

  • Rogee S, Grellier E, Bernard C (2007) Intracellular trafficking of a fiber-modified adenovirus using lipid raft/caveolae endocytosis. Mol Ther 15(11):1963–1972

    Article  PubMed  CAS  Google Scholar 

  • Roseberry AG, Hosey MM (2001) Internalization of the M2 muscarinic acetylcholine receptor proceeds through an atypical pathway in HEK293 cells that is independent of clathrin and caveolae. J Cell Sci 114(Pt 4):739–746

    PubMed  CAS  Google Scholar 

  • Silva WI, Maldonado HM, Velazquez G et al (2007) Caveolins in glial cell model systems: from detection to significance. J Neurochem 103(1):101–112

    Article  PubMed  CAS  Google Scholar 

  • Stan RV (2005) Structure of caveolae. Biochim Biophys Acta 1746:334–348

    Article  PubMed  CAS  Google Scholar 

  • Toi M, Matsumoto T, Bando H (2001) Vascular endothelial growth factor: its prognostic, predictive, and therapeutic implications. Lancet Oncol 2(11):667–673

    Article  PubMed  CAS  Google Scholar 

  • Van Helmond ZK, Miners JS, Bednall E et al (2007) Caveolin-1 and -2 and their relationship to cerebral amyloid angiopathy in Alzheimer’s disease. Neuropathol Appl Neurobiol 33(3):317–327

    Article  PubMed  Google Scholar 

  • Yokomori H, Oda M, Yoshimura K et al (2009) Caveolin-1 and Rac regulate endothelial capillary-like tubular formation and fenestral contraction in sinusoidal endothelial cells. Liver Int 29(2):266–276

    Article  PubMed  CAS  Google Scholar 

  • Zhang ZB, Cai L, Zheng SG et al (2009) Overexpression of caveolin-1 in hepatocellular carcinoma with metastasis and worse prognosis: correlation with vascular endothelial growth factor, microvessel density and unpaired artery. Pathol Oncol Res 15(3):495–502

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This work was supported by the Natural Science Foundation of China, under contract Nos.30800451, 30872656, 30700861, 30670723, and 30973079; Scientific and Technological Research Projects in Colleges and Universities of Liaoning Province, No.2008850; the special fund for Scientific Research of Doctor-degree Subjects in Colleges and Universities, No. 20092104110015; and Scientific and Technological Planning Projects of Shenyang, Nos.1072033-1-00 and 1081266-9-00.

Author information

Authors and Affiliations

  1. Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, 110001, People’s Republic of China

    Li-ni Zhao, Zhi-hang Yang, Hua Zhang & Yi-xue Xue

  2. Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, 110004, People’s Republic of China

    Yun-hui Liu & Hao-qiang Ying

  3. Institute of Pathology and Pathophysiology, China Medical University, Shenyang, 110004, People’s Republic of China

    Hua Zhang & Yi-xue Xue

Authors
  1. Li-ni Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhi-hang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yun-hui Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hao-qiang Ying
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hua Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yi-xue Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yi-xue Xue.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhao, Ln., Yang, Zh., Liu, Yh. et al. Vascular Endothelial Growth Factor Increases Permeability of the Blood–Tumor Barrier via Caveolae-Mediated Transcellular Pathway. J Mol Neurosci 44, 122–129 (2011). https://doi.org/10.1007/s12031-010-9487-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-010-9487-x

Keywords

Search

Navigation