PPAR-γ Mediates Ta-VNS-Induced Angiogenesis and Subsequent Functional Recovery after Experimental Stroke in Rats

Abstract

Background. Neoangiogenesis after cerebral ischemia in mammals is insufficient to restore neurological function, illustrating the need to design better strategies for improving outcomes. Our previous study has suggested that transcutaneous auricular vagus nerve stimulation (ta-VNS) induced angiogenesis and improved neurological functions in a rat model of cerebral ischemia/reperfusion (I/R) injury. However, the mechanisms involved need further exploration. Peroxisome proliferator-activated receptor-γ (PPAR-γ), well known as a ligand-modulated nuclear transcription factor, plays a crucial role in the regulation of cerebrovascular structure and function. Hence, the present study was designed to explore the role of PPAR-γ in ta-VNS-mediated angiogenesis and uncover the possible molecular mechanisms against ischemic stroke. Methods. Adult male Sprague–Dawley rats were transfected with either PPAR-γ small interfering RNA (siRNA) or lentiviral vector without siRNA prior to surgery and subsequently received ta-VNS treatment. The expression and localization of PPAR-γ in the ischemic boundary after ta-VNS treatment were examined. Subsequently, neurological deficit scores, neuronal damage, and infarct volume were all evaluated. Additionally, microvessel density, endothelial cell proliferation condition, and the expression of angiogenesis-related molecules in the peri-infarct cortex were measured. Results. We found that the expression of PPAR-γ in the peri-infarct cortex increased at 14 d and reached normal levels at 28 d after reperfusion. Ta-VNS treatment further upregulated PPAR-γ expression in the ischemic cortex. PPAR-γ was mainly expressed in neurons and astrocytes. Furthermore, ta-VNS-treated I/R rats showed better neurobehavioral recovery, alleviated neuronal injury, reduced infarct volume, and increased angiogenesis, as indicated by the elevated levels of brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and phosphorylated endothelial nitric oxide synthase (P-eNOS). Surprisingly, the beneficial effects of ta-VNS were weakened after PPAR-γ silencing. Conclusions. Our results suggest that PPAR-γ is a potential mediator of ta-VNS-induced angiogenesis and neuroprotection against cerebral I/R injury.

Palmatine Protects against Cerebral Ischemia/Reperfusion Injury by Activation of the AMPK/Nrf2 Pathway

“…The brains were cut into four coronal sections and incubated with 2% TTC solution. All images were collected and analyzed using ImageJ (NIH, USA), as described previously [20].…”

Interleukin-22 Plays a Protective Role by Regulating the JAK2-STAT3 Pathway to Improve Inflammation, Oxidative Stress, and Neuronal Apoptosis following Cerebral Ischemia-Reperfusion Injury

“…The sections were fixed in 4% paraformaldehyde and photographed using an HD camera. The infarct area was analyzed using ImageJ, and the infarct volume was calculated as previously described [ 29 ].…”

Targeting the Autonomic Nervous System for Risk Stratification, Outcome Prediction and Neuromodulation in Ischemic Stroke

“…Meanwhile, high intensities of VNS would increase norepinephrine concentrations, promoting the recruitment of low-affinity β-adrenergic receptors and resulting in a pro-stability state [ 156 , 167 , 168 , 172 ]. Lastly, data suggest that activation of α7nAChR through invasive and non-invasive VNS upregulates the expression of neurotrophic and pro-angiogenic factors, such as brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF) and cerebral growth differentiation factor 11 (GDF11), in the ischemic penumbra [ 135 , 173 , 174 , 175 ]. However, to date, scanty data are available on the possible role of VNS in post-stroke neurogenesis and angiogenesis induction.…”

“…A single session of transcutaneous cervical vagus nerve stimulation (tcVNS) or tVNS, performed 30 min after the induction of ischemia, resulted in a significant difference in infarcted brain volume between the treated and the control groups and improved neurological functions [ 180 , 181 , 182 ]. In longer stimulation protocols (7 to 28 days), a continuous trend of neurofunctional restoration was observed in groups treated with tVNS [ 135 , 173 , 174 , 183 ].…”