Molecular Neurobiology

, Volume 55, Issue 1, pp 567–582 | Cite as

Voluntary Physical Exercise Induces Expression and Epigenetic Remodeling of VegfA in the Rat Hippocampus

  • Christina A. E. Sølvsten
  • Frank de Paoli
  • Jane H. Christensen
  • Anders L. NielsenEmail author


A healthy lifestyle, including regular physical exercise, is generally believed to improve cognitive function and enhance neurogenesis. Such physical exercise-induced effects are associated with increased brain expression of neurotrophic and growth factors. In the present study, we investigated Bdnf, Igf-1, Fgf-2, Egf, and VegfA messenger RNA (mRNA) expression levels in the male rat hippocampus and frontal cortex after 2 weeks of voluntary physical exercise. Whereas the expression of Fgf-2 was upregulated in the hippocampus and prefrontal cortex by physical exercise, the expression levels of Bdnf transcript 1, Bdnf transcript 4, Igf-1, and VegfA were upregulated only in the hippocampus. We focused our subsequent analyses on the VegfA gene, which encodes vascular endothelial growth factor, a signaling molecule important for angiogenesis, vasculogenesis, and neurogenesis. To study the epigenetic mechanisms involved in the physical exercise-mediated induction of VegfA expression, we used oxidative and non-oxidative bisulfite pyrosequencing to analyze VegfA promoter DNA methylation and DNA hydroxymethylation. We observed discrete DNA hypomethylation at specific CpG sites in rats that engaged in physical exercise relative to sedentary rats. This is exemplified by a CpG site located within a VegfA promoter Sp1/Sp3 transcription factor recognition element. DNA hydroxymethylation was present at the VegfA promoter, but no differences in DNA hydroxymethylation were observed in rats that engaged in physical exercise relative to sedentary rats. Moreover, we observed increased Tet1 and decreased Dnmt3b mRNA expression in the hippocampi of rats that engaged in physical exercise. The presented results substantiate the involvement of epigenetics as a mediator of the beneficial effects of physical exercise and point to the importance of analyzing factors beyond Bdnf to delineate the mechanisms behind the functional impacts of physical exercise in mediating benefits to the brain.


Physical exercise Neurotrophic factors Epigenetics Bdnf Gene regulation 



Brain-derived neurotrophic factor


Chromatin immunoprecipitation


CpG island


DNA methyltransferases


Nerve growth factor






Hypoxia-inducible factor 1


Insulin-like growth factor-1


Fibroblast growth factor-2


Vascular endothelial growth factor A


Standard of mean



This work was supported by the Toyota Foundation and the Lundbeck Foundation (R100-A9606). We thank Tina Fuglsang Daugaard for excellent technical assistance.

Author Contributions

CS, FDP, JHC, and ALN conceived and designed the study. CS performed the biological experiments. All authors contributed to the writing of the manuscript and approved the final version of the manuscript.

Compliance with Ethical Standards

Conflict of Interest

The authors declare no conflicts of interest.

Supplementary material

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Table S1 (DOCX 17 kb)
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Table S2 (DOCX 16 kb)
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Table S3 (DOCX 17 kb)
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Table S4 (DOCX 15 kb)
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Table S5 (DOCX 19 kb)
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Fig S1

Schematic illustration of the structure of the rat Bdnf gene. Nine Bdnf promoters are identified with promoters 1 to 8 driving the transcription of Bdnf mRNA containing one of the eight alternative non-coding 5′ exons (exons 1–8) all spliced to the common protein coding 3′ exon 9. In addition, transcription can be initiated upstream of exon 9 with a resulting exon 9a which includes a 5′ sequence extension of the exon 9 sequence. (GIF 4 kb)

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Fig S2

Grouping of exercised animals according to cumulative running distance. The rats from the exercised group were subdivided into three groups with four rats in each group. Rats in group 1 (G1) had run between 7.25 and 9.16 km in total, rats in group 2 (G2) had run between 14.44 and 26.84 km, and rats in group 3 (G3) had run between 46.31 and 55.92 km. To the right are illustrated G1, G2, and G3 classification according to the cumulative running distance. (GIF 9 kb)

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High resolution image (EPS 639 kb)
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Fig S3

Neurotrophic factor mRNA expression analysis in hippocampus of physically exercised animals subgrouped accordingly to cumulative running distance. The mean mRNA expression level in the sedentary group was tested against the mean expression level in each of the three exercise subgroups G1, G2, and G3. Expression data were normalized to the expression of the reference genes Ppia and Rpl13A, and the expression level in sedentary rats normalized to value one. Values represent the mean + SEM. Expression differences between the exercised subgroups of rats and the sedentary rats were analyzed by one-way ANOVA followed by Bonferroni’s multiple comparison test with *P ≤ 0.05 and **P ≤ 0.01. (GIF 36 kb)

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Fig S4

Neurotrophic factor mRNA expression analysis in frontal cortex of exercised rats grouped accordingly to cumulative running distance. See legend to Fig. S3 for details. (GIF 34 kb)

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High resolution image (EPS 1753 kb)
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Fig S5

Expression analysis of growth factors Igf-1, VegfA, Fgf-2, and Egf mRNA in hippocampus of exercised rats grouped accordingly to cumulative running distance. See legend to Fig. S3 for details. (GIF 18 kb)

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High resolution image (EPS 994 kb)
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Fig S6

Expression analysis of growth factors Igf-1, VegfA, Fgf-2, and Egf mRNA in frontal cortex of exercised rats grouped accordingly to cumulative running distance. See legend to Fig. S3 for details. (GIF 18 kb)

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Fig S7

Expression analysis of Dnmt3a, Dnmt3b, Dnmt1, and Tet1 mRNA in hippocampus of exercised rats grouped accordingly to cumulative running distance. See legend to Fig. S3 for details. (GIF 18 kb)

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Fig S8

Immunohistochemical staining with hematoxylin (blue) and VegfA-antibody (brown) of the dentate gyrus of physically exercised rat number 10 (19.6 km in total) (a, b) and a control sedentary rat (c, d). Immunohistochemistry was performed on hippocampus cryosections. Five-micrometer-thick sections were mounted on coated glass slides. The tissue sections were fixed in Lillies fixative. The slides were treated with peroxidase block (DAKO) for 5 min and blocked with bovine serum albumin for 30 min. Immunohistochemical detection of VegfA was performed using the EnVision+ System-HRP. To detect VegfA protein, rabbit anti-rat VegfA antibody (ab46157) was used in a dilution of 1:600 and incubated ON at 4 °C. The sections were counterstained with Mayer’s hematoxylin solution. The slides were finally cover slipped with mounting medium (DAKO) and analyzed by a Leica DM 2500 microscope using Leica IM50 4.0 software. Magnification is ×10 (a, c) and ×40 (b, d) with the latter representing the red squared boxes (a, c) (GIF 145 kb)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of BiomedicineAarhus UniversityAarhus CDenmark
  2. 2.The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCHAarhus CDenmark
  3. 3.Centre for Integrative Sequencing, iSEQAarhus UniversityAarhus CDenmark

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