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Elevated Expression of VEGF-C and Its Receptors, VEGFR-2 and VEGFR-3, in Patients with Mesial Temporal Lobe Epilepsy

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Abstract

Mesial temporal lobe epilepsy (MTLE) is a frequent form of focal intractable epilepsy in adults. We previously reported overexpression of vascular endothelial growth factor C (VEGF-C) and its receptors, VEGFR-2 and VEGFR-3, in epilepsy-associated tuberous sclerosis complex. To identify whether VEGF-C and its receptors are involved in epileptogenesis of MTLE, we investigated the levels and expression pattern of VEGF-C and its receptors in temporal neocortex and hippocampus (HPC) from 28 patients with MTLE and ten control (CTX) subjects. Real-time quantitative polymerase chain reaction and Western blotting results revealed upregulated mRNA and immunoreactive protein levels of VEGF-C, VEGFR-2, and VEGFR-3 in the MTLE group compared to the control groups. Immunohistochemistry and double-labeled immunofluorescence showed that VEGF-C was highly expressed in neurons and astrocytes, including reactive astrocytes and vascular endothelial cells, VEGFR-2 was expressed at a high level in reactive astrocytes and vascular endothelial cells, but not in neurons, whereas VEGFR-3 was only overexpressed in reactive astrocytes. Taken together, these findings suggest that VEGF-C and its receptors, VEGFR-2 and VEGFR-3, may contribute to the epileptogenesis of MTLE.

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References

  • Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ (2010) Structure and function of the blood-brain barrier. Neurobiol Dis 37(1):13–25

    Article  CAS  PubMed  Google Scholar 

  • Bae EK, Jung KH, Chu K, et al. (2010) Neuropathologic and clinical features of human medial temporal lobe epilepsy. J Clin Neurol 6(2):73–80

    Article  PubMed  PubMed Central  Google Scholar 

  • Ballabh P, Braun A, Nedergaard M (2004) The blood-brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis 16(1):1–13

    Article  CAS  PubMed  Google Scholar 

  • Calvo CF, Fontaine RH, Soueid J, et al. (2011) Vascular endothelial growth factor receptor 3 directly regulates murine neurogenesis. Genes Dev 25(8):831–844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cammalleri M, Martini D, Ristori C, Timperio AM, Bagnoli P (2011) Vascular endothelial growth factor up-regulation in the mouse hippocampus and its role in the control of epileptiform activity. Eur J Neurosci 33(3):482–498

    Article  PubMed  Google Scholar 

  • Crino PB, Nathanson KL, Henske EP (2006) The tuberous sclerosis complex. N Engl J Med 355(13):1345–1356

    Article  CAS  PubMed  Google Scholar 

  • Dreier JP, Jurkat-Rott K, Petzold GC, et al. (2005) Opening of the blood-brain barrier preceding cortical edema in a severe attack of FHM type II. Neurology 64(12):2145–2147

    Article  CAS  PubMed  Google Scholar 

  • Engel J Jr (2001) Mesial temporal lobe epilepsy: what have we learned? Neuroscientist 7(4):340–352

  • Heinrich C, Lahteinen S, Suzuki F, et al. (2011) Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy. Neurobiol Dis 42(1):35–47

    Article  CAS  PubMed  Google Scholar 

  • Jenny B, Harrison JA, Baetens D, et al. (2006) Expression and localization of VEGF-C and VEGFR-3 in glioblastomas and haemangioblastomas. J Pathol 209(1):34–43

    Article  CAS  PubMed  Google Scholar 

  • Kandratavicius L, Monteiro MR, Assirati JA Jr, Carlotti Jr CG, Hallak JE, Leite JP (2013) Neurotrophins in mesial temporal lobe epilepsy with and without psychiatric comorbidities. J Neuropathol Exp Neurol 72(11):1029–1042

  • Karkkainen MJ, Haiko P, Sainio K, et al. (2004) Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol 5(1):74–80

    Article  CAS  PubMed  Google Scholar 

  • Korn A, Golan H, Melamed I, Pascual-Marqui R, Friedman A (2005) Focal cortical dysfunction and blood-brain barrier disruption in patients with postconcussion syndrome. J Clin Neurophysiol 22(1):1–9

    Article  PubMed  Google Scholar 

  • Le Bras B, Barallobre MJ, Homman-Ludiye J, et al. (2006) VEGF-C is a trophic factor for neural progenitors in the vertebrate embryonic brain. Nat Neurosci 9(3):340–348

    Article  PubMed  Google Scholar 

  • Liimatainen S, Lehtimaki K, Palmio J, Alapirtti T, Peltola J (2013) Immunological perspectives of temporal lobe seizures. J Neuroimmunol 263(1–2):1–7

    Article  CAS  PubMed  Google Scholar 

  • Liu YW, Mee EW, Bergin P, et al. (2007) Adult neurogenesis in mesial temporal lobe epilepsy: a review of recent animal and human studies. Curr Pharm Biotechnol 8(3):187–194

    Article  CAS  PubMed  Google Scholar 

  • Lohela M, Helotera H, Haiko P, Dumont DJ, Alitalo K (2008) Transgenic induction of vascular endothelial growth factor-C is strongly angiogenic in mouse embryos but leads to persistent lymphatic hyperplasia in adult tissues. Am J Pathol 173(6):1891–1901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malikova H, Kramska L, Vojtech Z, et al. (2014) Different surgical approaches for mesial temporal epilepsy: resection extent, seizure, and neuropsychological outcomes. Stereotact Funct Neurosurg 92(6):372–380

    Article  PubMed  Google Scholar 

  • Morin-Brureau M, Lebrun A, Rousset MC, et al. (2011) Epileptiform activity induces vascular remodeling and zonula occludens 1 downregulation in organotypic hippocampal cultures: role of VEGF signaling pathways. J Neurosci 31(29):10677–10688

    Article  CAS  PubMed  Google Scholar 

  • Morin-Brureau M, Rigau V, Lerner-Natoli M (2012) Why and how to target angiogenesis in focal epilepsies. Epilepsia 53(Suppl 6):64–68

    Article  CAS  PubMed  Google Scholar 

  • Park JM, Shin YJ, Cho JM, et al. (2013) Upregulation of vascular endothelial growth factor receptor-3 in the spinal cord of Lewis rats with experimental autoimmune encephalomyelitis. J Histochem Cytochem 61(1):31–44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Piltonen M, Planken A, Leskela O, et al. (2011) Vascular endothelial growth factor C acts as a neurotrophic factor for dopamine neurons in vitro and in vivo. Neuroscience 192:550–563

    Article  CAS  PubMed  Google Scholar 

  • Raab S, Plate KH (2007) Different networks, common growth factors: shared growth factors and receptors of the vascular and the nervous system. Acta Neuropathol 113(6):607–626

    Article  CAS  PubMed  Google Scholar 

  • Rigau V, Morin M, Rousset MC, et al. (2007) Angiogenesis is associated with blood-brain barrier permeability in temporal lobe epilepsy. Brain 130(Pt 7):1942–1956

    Article  PubMed  Google Scholar 

  • Roy H, Bhardwaj S, Yla-Herttuala S (2006) Biology of vascular endothelial growth factors. FEBS Lett 580(12):2879–2887

    Article  CAS  PubMed  Google Scholar 

  • Shin YJ, Choi JS, Lee JY, et al. (2008) Differential regulation of vascular endothelial growth factor-C and its receptor in the rat hippocampus following transient forebrain ischemia. Acta Neuropathol 116(5):517–527

    Article  CAS  PubMed  Google Scholar 

  • Shin YJ, Riew TR, Park JH, Pak HJ, Lee MY (2015) Expression of vascular endothelial growth factor-C (VEGF-C) and its receptor (VEGFR-3) in the glial reaction elicited by human mesenchymal stem cell engraftment in the normal rat brain. J Histochem Cytochem 63(3):170–180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van Vliet EA, Aronica E, Gorter JA (2015) Blood-brain barrier dysfunction, seizures and epilepsy. Semin Cell Dev Biol 38:26–34

    Article  PubMed  Google Scholar 

  • van Vliet EA, da Costa Araujo S, Redeker S, van Schaik R, Aronica E, Gorter JA (2007) Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain 130(Pt 2):521–534

    Article  PubMed  Google Scholar 

  • Vezzani A, Friedman A (2011) Brain inflammation as a biomarker in epilepsy. Biomark Med 5(5):607–614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vezzani A, Maroso M, Balosso S, Sanchez MA, Bartfai T (2011) IL-1 receptor/toll-like receptor signaling in infection, inflammation, stress and neurodegeneration couples hyperexcitability and seizures. Brain Behav Immun 25(7):1281–1289

    Article  CAS  PubMed  Google Scholar 

  • Ward MC, Cunningham AM (2015) Developmental expression of vascular endothelial growth factor receptor 3 and vascular endothelial growth factor C in forebrain. Neuroscience 303:544–557

    Article  CAS  PubMed  Google Scholar 

  • Zhang CQ, Shu HF, Yin Q, et al. (2012) Expression and cellular distribution of vascular endothelial growth factor-C system in cortical tubers of the tuberous sclerosis complex. Brain Pathol 22(2):205–218

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (No. 81370028), the Natural Science Foundation Project of Chongqing CSTC (No. 2012 jjB10019), and the Gansu Natural Science Foundation (No.145RJYA301).

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Authors and Affiliations

  1. Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, 2-V Xinqiao Street, Chongqing, 400037, China

    Fei-Ji Sun, Yu-Jia Wei, Song Li, Xin Chen, Shi-Yong Liu, Hui Yang & Chun-Qing Zhang

  2. Department of Rehabilitation Department, Xinqiao Hospital, Third Military Medical University, Chongqing, China

    Qing Yin

  3. Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xian, China

    Wei Guo

  4. Department of Neurosurgery, Lanzhou General Hospital of Chinese People’s Liberation Army, Lanzhou, China

    Jiao-Jiang He

Authors
  1. Fei-Ji Sun
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  2. Yu-Jia Wei
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  3. Song Li
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  4. Wei Guo
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  5. Xin Chen
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  7. Jiao-Jiang He
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  8. Qing Yin
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  9. Hui Yang
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  10. Chun-Qing Zhang
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Correspondence to Hui Yang or Chun-Qing Zhang.

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Informed consent and written permission for all procedures were obtained before surgery. All procedures and experiments were conducted under the guidelines approved by the Ethics Committee of the Third Military University (Chongqing, China).

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The authors declare that they have no competing interests.

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Sun, FJ., Wei, YJ., Li, S. et al. Elevated Expression of VEGF-C and Its Receptors, VEGFR-2 and VEGFR-3, in Patients with Mesial Temporal Lobe Epilepsy. J Mol Neurosci 59, 241–250 (2016). https://doi.org/10.1007/s12031-016-0714-y

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  • DOI: https://doi.org/10.1007/s12031-016-0714-y

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