Skip to main content
SpringerLink
Log in

RETRACTED ARTICLE: Gold nanoparticles inhibit vascular endothelial growth factor-induced angiogenesis and vascular permeability via Src dependent pathway in retinal endothelial cells

  • Original Paper
  • Published:
Angiogenesis Aims and scope Submit manuscript

This article was retracted on 17 July 2011

Abstract

The purpose of this study was to investigate the effect of gold nanoparticles on the signaling cascade related to angiogenesis and vascular permeability induced by Vascular Endothelial Growth Factor (VEGF) in Bovine retinal endothelial cells (BRECs). The effect of VEGF and gold nanoparticles on cell viability, migration and tubule formation was assessed. PP2 (Src Tyrosine Kinase inhibitor) was used as the positive control and the inhibitor assay was performed to compare the effect of AuNPs on VEGF induced angiogenesis. The transient transfection assay was performed to study the VEGFR2/Src activity during experimental conditions and was confirmed using western blot analysis. Treatment of BRECs with VEGF significantly increased the cell proliferation, migration and tube formation. Furthermore, gold nanoparticles (500 nM) significantly inhibited the proliferation, migration and tube formation, in the presence of VEGF in BRECs. The gold nanoparticles also inhibited VEGF induced Src phosphorylation through which their mode of action in inhibiting angiogenic pathways is revealed. The fate of the gold nanoparticles within the cells is being analyzed using the TEM images obtained. The potential of AuNPs to inhibit the VEGF165-induced VEGFR-2 phosphorylation is also being confirmed through the receptor assay which elucidates one of the possible mechanism by which AuNPs inhibit VEGF induced angiogenesis. These results indicate that gold nanoparticles can block VEGF activation of important signaling pathways, specifically Src in BRECs and hence modulation of these pathways may contribute to gold nanoparticles ability to block VEGF-induced retinal neovascularization.

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
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Carmeliet P (2000) VEGF gene therapy: stimulating angiogenesis or angioma-genesis? Nat Med 6:1102–1103

    Article  PubMed  CAS  Google Scholar 

  2. Cross MJ, Claesson-Welsh L (2001) FGF and VEGF function in angiogenesis: signaling pathways, biological responses and therapeutic inhibition. Trends Pharmacol Sci 22:201–207

    Article  PubMed  CAS  Google Scholar 

  3. Aiello LP, Avery RL, Arrigg PG, Bruce AK, Henry DJ, Sabera TS (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487

    Article  PubMed  CAS  Google Scholar 

  4. Hata Y, Nakagawa K, Ishibashi T, Inomata H, Ueno H, Sueishi K (1995) Hypoxia-induced expression of vascular endothelial growth factor by retinal glial cells promotes in vitro angiogenesis. Virchows Arch 426:479–486

    Article  PubMed  CAS  Google Scholar 

  5. Ferrara N (2002) VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2:795–803

    Article  PubMed  CAS  Google Scholar 

  6. Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18:4–25

    Article  PubMed  CAS  Google Scholar 

  7. Millauer B, Wizigmann-Voos S, Schnurch H, Martinez R, Moller NP, Risau W (1993) High-affinity VEGF binding and developmental expression suggests Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 72:835–846

    Article  PubMed  CAS  Google Scholar 

  8. Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376:62–66

    Article  PubMed  CAS  Google Scholar 

  9. Shen BQ, Lee DY, Zioncheck TF (1999) Vascular endothelial growth factor governs endothelial nitric-oxide synthase expression via a KDR/Flk-1 receptor and a protein kinase C signaling pathway. J Biol Chem 274:33057–33063

    Article  PubMed  CAS  Google Scholar 

  10. Bashshur ZF, Bazarbachi A, Schakal A, Haddad ZA, El Haibi CP, Noureddin BN (2006) Intravitreal bevacizumab for the management of choroidal neovascularization in age-related macular degeneration. Am J Ophthalmol 142:1–9

    Article  PubMed  CAS  Google Scholar 

  11. Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR (2004) VEGF inhibition study in ocular neovascularization clinical trial group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 351:2805–2816

    Article  PubMed  CAS  Google Scholar 

  12. Economopoulou M, Bdeir K, Cines DB, Franz F, Yasmina B (2005) Inhibition of pathologic retinal neovascularization by alpha-defensins. Blood 106:3831–3838

    Article  PubMed  CAS  Google Scholar 

  13. Konopatskaya O, Churchill AJ, Harper SJ, Bates DO, Gardiner TA (2006) VEGF165b, an endogenous C-terminal splice variant of VEGF, inhibits retinal neovascularization in mice. Mol Vis 12:626–632

    PubMed  CAS  Google Scholar 

  14. Ojima T, Takagi H, Suzuma K, Oh H, Suzuma I, Ohashi H (2006) Ephrin A1 inhibits vascular endothelial growth factor-induced intracellular signaling and suppresses retinal neovascularization and blood-retinal barrier breakdown. Am J Pathol 168:331–339

    Article  PubMed  CAS  Google Scholar 

  15. Shen J, Yang X, Xiao WH, Hackett SF, Sato Y, Campochiaro PA (2006) Vasohibin is up-regulated by VEGF in the retina and suppresses VEGF receptor 2 and retinal neovascularization. FASEB J 20:723–725

    PubMed  CAS  Google Scholar 

  16. Xia X, Xiong S, Song W, Luo J, Wang Y, Zhou R (2008) Inhibition of retinal neovascularization by siRNA targeting VEGF165. Mol Vis 14:1965–1973

    PubMed  CAS  Google Scholar 

  17. Ghosh P, Han G, Mrinmoy De, Kim CK, Rotello VM (2008) Gold nanoparticles in delivery applications. Adv Drug Deliv Rev 60:1307–1315

    Article  PubMed  CAS  Google Scholar 

  18. Paciotti GF, Myer L, Weinreich D, Goia D, Pavel N, McLaughlin RE, Tamarkin L (2004) Colloidal gold: a novel nanoparticle vector for tumor directed drug delivery. Drug Deliv 11:169–183

    Article  PubMed  CAS  Google Scholar 

  19. Davda J, Labhasetwar V (2002) Characterization of nanoparticle uptake by endothelial cells. Int J Pharm 233:51–59

    Article  PubMed  CAS  Google Scholar 

  20. Kalishwaralal K, Banumathi E, Pandian SRK, Deepak V, Muniyandi J, Eom SH, Gurunathan S (2009) Silver nanoparticles inhibit VEGF-induced cell proliferation and migration in bovine retinal endothelial cells. Colloid Surf B 73:51–57

    Article  CAS  Google Scholar 

  21. Kalimuthu K, Babu RS, Venkataraman D, Bilal M, Gurunathan S (2008) Biosynthesis of silver nanocrystals by Bacillus licheniformis. Colloids Surf B 65:150–153

    Article  CAS  Google Scholar 

  22. Kalishwaralal K, Deepak V, Ram Kumar Pandian S, Gurunathan S (2009) Biological synthesis of gold nanocubes from Bacillus licheniformis. Bioresour Technol 100:5356–5358

    Article  PubMed  CAS  Google Scholar 

  23. Liu X, Atwater M, Wang J, Huo Q (2007) Extinction coefficient of gold nanoparticles with different sizes and different capping ligands. Colloids Surf B 58:3–7

    Article  CAS  Google Scholar 

  24. Banumathi E, Haribalaganesh R, Babu SSP, Kumar NS, Sangiliyandi G (2009) High-yielding enzymatic method for isolation and culture of microvascular endothelial cells from bovine retinal blood vessels. Microvasc Res 77:377–381

    Article  PubMed  CAS  Google Scholar 

  25. Gurunathan S, Lee KJ, Kalishwaralal K, Sheikpranbabu S, Vaidyanathan R, Eom SH (2009) Antiangiogenic properties of silver nanoparticles. Biomaterials 31:6341–6350

    Article  Google Scholar 

  26. Sheikpranbabu S, Kalishwaralal K, Venkataraman D, Eom SH, Park J, Gurunathan S (2009) Silver nanoparticles inhibit VEGF-and IL-1β-induced vascular permeability via Src dependent pathway in porcine retinal endothelial cells. J Nanobiotechnol 7:8

    Article  Google Scholar 

  27. Kumar SA, Peter YA, Nadeau JL (2008) Facile biosynthesis, separation and conjugation of gold nanoparticles to doxorubicin. Nanotechnology 19:495101

    Article  PubMed  Google Scholar 

  28. Sastry M, Patil V, Sainkar SRJ (1998) Electrostatically controlled diffusion of carboxylic acid derivatized silver colloidal particles in thermally evaporated fatty amine films. Phys Chem B 102:1404–1410

    Article  CAS  Google Scholar 

  29. Eliceiri BP, Paul R, Schwartzberg PL, Hood JD, Leng J, Cheresh DA et al (1999) Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol Cell 4:915–924

    Article  PubMed  CAS  Google Scholar 

  30. Liu F, Verin AD, Wang P, Day R, Wersto RP, Chrest FJ et al (2001) Differential regulation of sphingosine-1-phosphate and VEGF-induced endothelial cell chemotaxis: involvement of G (ialpha2)-linked Rho kinase activity. Am J Respir Cell Mol Biol 24:711–719

    PubMed  CAS  Google Scholar 

  31. Paul R, Zhang ZG, Eliceiri BP, Jiang Q, Boccia AD, Zhang RL (2001) Src deficiency or blockade of Src activity in mice provides cerebral protection following stroke. Nat Med 7:222–227

    Article  PubMed  CAS  Google Scholar 

  32. Patan S (2004) Vasculogenesis and angiogenesis. Cancer Treat Res 117:3–32

    Article  PubMed  CAS  Google Scholar 

  33. Harhaj NS, Antonetti DA (2004) Regulation of tight junctions and loss of barrier function in pathophysiology. Int J Biochem Cell Biol 36:1206–1237

    Article  PubMed  CAS  Google Scholar 

  34. Parsons JT, Parsons SJ (1997) Src family protein tyrosine kinases: cooperating with growth factor and adhesion signaling pathways. Curr Opin Cell Biol 9:187–192

    Article  PubMed  CAS  Google Scholar 

  35. Mukherjee P, Bhattacharya R, Wang P, Wang L, Basu S, Nagy JA (2005) Antiangiogenic properties of gold nanoparticles. Clin Cancer Res 11:3530–3534

    Article  PubMed  CAS  Google Scholar 

  36. Murugesan S, Mousa SA, O’Connor LJ, Lincoln DW II, Linhardt RJ (2007) Carbon inhibits vascular endothelial growth factor- and fibroblast growth factor promoted angiogenesis. FEBS Lett 581:1157–1160

    Article  PubMed  CAS  Google Scholar 

  37. Nakashio A, Fujita N, Tsuruo T (2002) Topotecan inhibits VEGF- and bFGF-induced vascular endothelial cell migration via downregulation of the PI3 K-Akt signaling pathway. Int J Cancer 98:36–41

    Article  PubMed  CAS  Google Scholar 

  38. Favot L, Keravis T, Holl V, Le Bec A, Lugnier C (2003) VEGF-induced HUVEC migration and proliferation are decreased by PDE2 and PDE4 inhibitors. Thromb Haemost 90:334–343

    PubMed  CAS  Google Scholar 

  39. Thomas SM, Brugge JS (1997) Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol 13:513–609

    Article  PubMed  CAS  Google Scholar 

  40. Nam JS, Ino Y, Sakamoto M, Hirohashi S (2002) Src family kinase inhibitor PP2 restores the E cadherin/catenin cell adhesion system in human cancer cells and reduces cancer metastasis. Clin Cancer Res 8:2430–2436

    PubMed  CAS  Google Scholar 

  41. Boyer B, Bourgeois Y, Poupon MF (2002) Src kinase contributes to the metastatic spread of carcinoma cells. Oncogene 21:2347–2356

    Article  PubMed  CAS  Google Scholar 

  42. Thurston G, Suri C, Smith K, McClain J, Sato TN, Yancopoulos GD, McDonald DM (1999) Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286:2511–2514

    Article  PubMed  CAS  Google Scholar 

  43. He H, Venema VJ, Gu X, Venema RC, Marrero MB, Caldwell RB (1999) Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c-Src. J Biol Chem 274:25130–25135

    Article  PubMed  CAS  Google Scholar 

  44. Irby RB, Mao W, Coppola D, Kang J, Loubeau JM, Trudeau W (1999) Activating SRC mutation in a subset of advanced human colon cancers. Nat Genet 21:187–190

    Article  PubMed  CAS  Google Scholar 

  45. Simeonova PP, Wang S, Hulderman T, Luster MI (2002) c-Src-dependent activation of the epidermal growth factor receptor and mitogen-activated protein kinase pathway by arsenic: role in carcinogenesis. J Biol Chem 277:2945–2950

    Article  PubMed  CAS  Google Scholar 

  46. Brown MT, Cooper JA (1996) Regulation, substrates and functions of src. Biochi Biophys Acta 1287:121–149

    Google Scholar 

  47. Abram CL, Courtneidge SA (2000) Src family tyrosine kinases and growth factor signaling. Exp Cell Res 254:1–13

    Article  PubMed  CAS  Google Scholar 

  48. Priyabrata M, Resham B, Nancy B, Yean KL, Chitta Ranjan P, Shanfeng W, Lichun L, Charla S, Pataki CB, Michael JY, Neil EK (2007) Potential therapeutic application of gold nanoparticles in B-chronic lymphocytic leukemia (BCLL): enhancing apoptosis. J Nanobiotechnol 5:4

    Article  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge Kyung Jin Lee, Department of Life Science, Cell Dynamics Research Centre, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea for performing western blot analysis. The authors also wish to acknowledge the support of Dr. Puspha Viswanathan, Professor, Cancer Institute (WIA), Chennai, who helped us with TEM analysis. Prof G. Sangiliyandi was supported by grants from Council of Scientific and Industrial Research (CSIR), New Delhi (Project No. 37/0347) and Department of Science and Technology (DST), New Delhi (Project No. SR/NM/NS-31/2010), India. Mr. Kalishwaralal was supported by the grant for Senior Research Fellowship from Council of Scientific and Industrial Research (CSIR), New Delhi (Grant No. 9/1012(0003)2K10EMR-I), India.

Author information

Authors and Affiliations

  1. Department of Biotechnology, Division of Molecular and Cellular Biology, Kalasalingam University (Kalasalingam Academy of Research and Education), Anand Nagar, Krishnankoil, Tamilnadu, 626 190, India

    Kalimuthu Kalishwaralal, Sardarpasha Sheikpranbabu, Selvaraj BarathManiKanth, Ravinarayanan Haribalaganesh, Sureshbabu Ramkumarpandian & Sangiliyandi Gurunathan

Authors
  1. Kalimuthu Kalishwaralal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sardarpasha Sheikpranbabu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Selvaraj BarathManiKanth
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ravinarayanan Haribalaganesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sureshbabu Ramkumarpandian
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sangiliyandi Gurunathan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sangiliyandi Gurunathan.

Additional information

This article has been retracted at the request of the editors in chief as the authors have manipulated images included in the article with the result being an altered representation of the data.

The authors Kalimuthu Kalishwaralal and Sardarpasha Sheikpranbabu contributed equally to this manuscript.

An erratum to this article can be found at http://dx.doi.org/10.1007/s10456-011-9225-1

About this article

Cite this article

Kalishwaralal, K., Sheikpranbabu, S., BarathManiKanth, S. et al. RETRACTED ARTICLE: Gold nanoparticles inhibit vascular endothelial growth factor-induced angiogenesis and vascular permeability via Src dependent pathway in retinal endothelial cells. Angiogenesis 14, 29–45 (2011). https://doi.org/10.1007/s10456-010-9193-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10456-010-9193-x

Keywords

Search

Navigation