Transcutaneous auricular vagus nerve stimulation regulates expression of growth differentiation factor 11 and activin-like kinase 5 in cerebral ischemia/reperfusion rats

J Neurol Sci. 2016 Oct 15;369:27-35. doi: 10.1016/j.jns.2016.08.004. Epub 2016 Aug 2.


Growth differentiation factor 11 (GDF11), as a rejuvenation factor in heterochronic parabiosis, can increase proliferation of primary brain capillary endothelial cells (ECs). However, the angiogenic role of GDF11 in ischemia-induced brain injury is still unclear. There are no previous reports on the spatiotemporal expression of GDF11 in cerebral ischemia/reperfusion (I/R) rats. Our recent work has strongly suggested that transcutaneous auricular vagus nerve stimulation (ta-VNS) reduces infarct size and induces angiogenesis in focal cerebral I/R rats. This study focused on expression of GDF11 and activin-like kinase 5 (ALK5) and the effects of ta-VNS in a rat cerebral I/R model. For ta-VNS, electrical stimulation of the left cavum concha (1h duration) using percutaneous needles was initiated 30min after induction of ischemia. Expression of GDF11 was analyzed by enzyme-linked immunosorbent assay, immunohistochemistry, real-time polymerase chain reaction, and western blot 24h, 3d, and 7d after reperfusion. In addition, neurobehavioral function, EC proliferation, and expression of ALK5 in ECs in the peri-infarct cortex were measured. Results showed that levels of GDF11 were significantly elevated after cerebral I/R, both in plasma and the peri-infarct cerebral cortex. Interestingly, splenic GDF11 levels decreased after ischemia. ALK5 was expressed in ECs in the peri-infarct cerebral cortex where active vessel remodeling was noted. ta-VNS improved neurobehavioral recovery, upregulated cerebral GDF11 and downregulated splenic GDF11, indicating a brain-spleen communication during stroke. ta-VNS also increased expression of ALK5 in ECs and stimulated proliferation of ECs. These results suggest that, after cerebral ischemia, GDF11 redistributes and participates in angiogenesis as an angiogenic factor that acts at least in part through ALK5. GDF11/ALK5 may represent a new potential therapy target for stroke.

Keywords: ALK5; Angiogenic factor; Cerebral ischemia/reperfusion; GDF11; Spleen; ta-VNS.

MeSH terms

  • Afferent Pathways / physiology
  • Animals
  • Antigens, CD / metabolism
  • Cerebral Cortex / metabolism*
  • Cerebral Infarction / etiology
  • Cerebral Infarction / therapy
  • Cerebrovascular Circulation / physiology
  • Disease Models, Animal
  • Functional Laterality
  • Gene Expression Regulation / physiology
  • Growth Differentiation Factors / genetics
  • Growth Differentiation Factors / metabolism*
  • Infarction, Middle Cerebral Artery / therapy*
  • Ki-67 Antigen / metabolism
  • Male
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Psychomotor Performance / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Reperfusion
  • Severity of Illness Index
  • Vagus Nerve Stimulation / methods*


  • Antigens, CD
  • Gdf11 protein, rat
  • Growth Differentiation Factors
  • Ki-67 Antigen
  • Receptors, Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • Tgfbr1 protein, rat