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Neurochemical Research

, Volume 42, Issue 2, pp 625–633 | Cite as

Distinct Expression of Various Angiogenesis Factors in Mice Brain After Whole-Brain Irradiation by X-ray

  • Zhezhi Deng
  • Haiwei Huang
  • Xiaohong Wu
  • Mengmeng Wu
  • Guoyong He
  • Junjie Guo
Original Paper

Abstract

Radiation-induced brain injury (RBI) is the most serious complication after radiotherapy. However, the etiology of RBI remains elusive. In order to evaluate the effect of X-rays on normal brain tissue, adult male BALB/C mice were subjected to whole-brain exposure with a single dose of 10 Gy or sham radiation. The structure and number of mice brain vessels were investigated 1, 7, 30, 90 and 180 days after irradiation by H&E staining and immune-fluorescence staining. Compared with sham control mice, in addition to morphological changes, a significant reduction of microvascular density was detected in irradiated mice brains. Whole-brain irradiation also caused damage in tight junction (TJ). Increased expression of glial fibrillary acidic protein (GFAP) and vascular endothelial growth factor (VEGF) was observed in irradiated mouse brains showed by Western Blot. Immune-fluorescence staining results also verified the co-labeling of GFAP and VEGF after whole-brain irradiation. Furthermore, the protein expression levels of other angiogenesis factors, angiopoietin-1 (Ang-1), endothelial-specific receptor tyrosine kinase (Tie-2), and angiopoietin-2 (Ang-2) in brain were determined by Western Blot. Increased expression of Ang-2 was shown in irradiated mouse brains. In contrast, whole-brain irradiation significantly decreased Ang-1 and Tie-2 expression. Our data indicated that X-rays induced time-dependent microvascular injury and activation of astrocytes after whole-brain irradiation in mouse brain. Distinct regulation of VEGF/Ang2 and Ang-1/Tie-2 are closely associated with RBI, suggesting that angiogenesis interventions might be beneficial for patients with RBI.

Keywords

Radiation-induced brain injury Angiogenesis Mice 

Notes

Funding

The funding was provided by Guangzhou Science and Technology Program (CN) (Grant No. 2014Y2-00155) and National Natural Science Foundation of China (Grant No. 81271386).

Compliance with Ethical Standards

Conflict of interest

None.

Supplementary material

11064_2016_2118_MOESM1_ESM.docx (15 kb)
Supplementary material 1 (DOCX 14 KB)

References

  1. 1.
    Zhang Y et al (2016) Neuroprotective effects of Kukoamine a against radiation-induced rat brain injury through inhibition of oxidative stress and neuronal apoptosis. Neurochem Res 41(10):2549–2558CrossRefPubMedGoogle Scholar
  2. 2.
    Regal PJ et al (2014) Acute late-onset encephalopathy after radiotherapy: an unusual life-threatening complication. Neurology 82(12):1102CrossRefPubMedGoogle Scholar
  3. 3.
    Gupta M et al (2013) Comparative evaluation of brain neurometabolites and DTI indices following whole body and cranial irradiation: a magnetic resonance imaging and spectroscopy study. NMR Biomed 26(12):1733–1741CrossRefPubMedGoogle Scholar
  4. 4.
    Coderre JA et al (2006) Late effects of radiation on the central nervous system: role of vascular endothelial damage and glial stem cell survival. Radiat Res 166(3):495–503CrossRefPubMedGoogle Scholar
  5. 5.
    Liu Y et al (2010) An experimental study of acute radiation-induced cognitive dysfunction in a young rat model. AJNR Am J Neuroradiol 31:383–387CrossRefPubMedGoogle Scholar
  6. 6.
    Nonoguchi N et al (2011) The distribution of vascular endothelial growth factor-producing cells in clinical radiation necrosis of the brain: pathological consideration of their potential roles. J Neurooncol 105:423–431CrossRefPubMedGoogle Scholar
  7. 7.
    Wei M et al (2012) Increased expression of EMMPRIN and VEGF in the rat brain after gamma irradiation. J Korean Med Sci 27(3):291–299CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Lee SW et al (2009) Angiopoietin-1 reduces vascular endothelial growth factor-induced brain endothelial permeability via upregulation of ZO-2. Int J Mol Med 23(2):279–284PubMedGoogle Scholar
  9. 9.
    Ridet JL et al (1997) Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 20:570–577CrossRefPubMedGoogle Scholar
  10. 10.
    Augustin HG et al (2009) Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol 10(3):165–177CrossRefPubMedGoogle Scholar
  11. 11.
    Zhu Y, Lee C et al (2005) Angiopoietin-2 facilitates vascular endothelial growth factor-induced angiogenesis in the mature mouse brain. Stroke 36(7):1533–1537CrossRefPubMedGoogle Scholar
  12. 12.
    Zhou H et al (2011) Fractionated radiation-induced acute encephalopathy in a young rat model: cognitive dysfunction and histologic findings. Am J Neuroradiol 32(10):1795–1800CrossRefPubMedGoogle Scholar
  13. 13.
    Nordal RA et al (2004) Hypoxia and hypoxia-inducible factor-1 target genes in central nervous system radiation injury: a role for vascular endothelial growth factor. Clin Cancer Res 10(10):3342–3353CrossRefPubMedGoogle Scholar
  14. 14.
    Brown WR et al (2007) Capillary loss precedes the cognitive impairment induced by fractionated whole-brain irradiation: a potential rat model of vascular dementia. J Neurol Sci 257:67–71CrossRefPubMedGoogle Scholar
  15. 15.
    Tanino T et al (2013) Radiation-induced microbleeds after cranial irradiation: evaluation by phase-sensitive magnetic resonance imaging with 3.0 T. Yonago Acta Med 56(1):7–12PubMedPubMedCentralGoogle Scholar
  16. 16.
    Drigotas M et al (2013) Reactive oxygen species activation of MAPK pathway results in VEGF upregulation as an undesired irradiation response. J Oral Pathol Med 42(8):612–619CrossRefPubMedGoogle Scholar
  17. 17.
    Ferrara N (1999) Vascular endothelial growth factor: molecular and biological aspects. Curr Top Microbiol Immunol 237:1–30PubMedGoogle Scholar
  18. 18.
    Breier G et al (1992) Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. Development 114:521–532PubMedGoogle Scholar
  19. 19.
    Plate KH (1999) Mechanisms of angiogenesis in the brain. J Neuropathol Exp Neurol 58:313–320CrossRefPubMedGoogle Scholar
  20. 20.
    Yancopoulos GD et al (2000) Vascular-specific growth factors and blood vessel formation. Nature 407(6801):242–248CrossRefPubMedGoogle Scholar
  21. 21.
    Owen MR et al (2009) Angiogenesis and vascular remodelling in normal and cancerous tissues. J Math Biol 58(4–5):689–721CrossRefPubMedGoogle Scholar
  22. 22.
    Lau LT et al (2001) Astrocytes produce and release interleukin-1, interleukin-6, tumor necrosis factor alpha and interferon-gamma following traumatic and metabolic injury. J Neurotrauma 18:351–359CrossRefPubMedGoogle Scholar
  23. 23.
    Etoh T et al (2001) Angiopoietin-2 is related to tumor angiogenesis in gastric carcinoma: possible in vivo regulation via induction of proteases. Cancer Res 61(5):2145–2153PubMedGoogle Scholar
  24. 24.
    Kutryk MJ et al (2003) Angiogenesis of the heart. Microsc Res Tech 60(2):138–158CrossRefPubMedGoogle Scholar
  25. 25.
    Davis S et al (1996) Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87:1161–1169CrossRefPubMedGoogle Scholar
  26. 26.
    Cascone I et al (2003) Tie-2-dependent activation of RhoA and Rac1 participates in endothelial cell motility triggered by angiopoietin-1. Blood 102(7):2482–2490CrossRefPubMedGoogle Scholar
  27. 27.
    Zhang L et al (2003) Tumor-derived vascular endothelial growth factor up- regulates angiopoietin-2 in host endothelium and destabilizes host vasculature, supporting angiogenesis in ovarian cancer. Cancer Res 63(12):3403–3412PubMedGoogle Scholar
  28. 28.
    Maisonpierre PC et al (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277(5322):55–60CrossRefPubMedGoogle Scholar
  29. 29.
    Chae SS et al (2010) Angiopoietin-2 interferes with anti-VEGFR2-induced vessel normalization and survival benefit in mice bearing gliomas. Clin Cancer Res 16(14):3618–3627CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706):58–62CrossRefPubMedGoogle Scholar
  31. 31.
    Goel S et al (2011) Normailization of the vasculature for treatment of cancer and other diseases. Physiol Rev 91(3):1071–1121CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Lee WH et al (2011) Radiation attenuates physiological angiogenesis by differential expression of VEGF, ang-1, tie-2 and ang-2 in rat brain. Radiat Res 176(6):753–760CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Zhezhi Deng
    • 1
  • Haiwei Huang
    • 1
  • Xiaohong Wu
    • 1
  • Mengmeng Wu
    • 1
  • Guoyong He
    • 1
  • Junjie Guo
    • 1
  1. 1.Departments of NeurologyFirst Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina

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