The p75 neurotrophin receptor attenuates secondary thalamic damage after cortical infarction by promoting angiogenesis
Linhui Peng, Kongping Li, Dan C. Li, Xialin Zuo, Lixuan Zhan, Meiyan Chen, Ming Gong, Weiwen Sun, En Xu
Abstract
Abstract Background Angiogenesis is crucial in neuroprotection of secondary thalamic injury after cortical infarction. The p75 neurotrophin receptor (p75 NTR ) plays a key role in activating angiogenesis. However, the effects of p75 NTR on angiogenesis in the thalamus after cortical infarction are largely unknown. Herein we investigate whether p75 NTR facilitates angiogenesis to attenuate secondary thalamic damage via activating hypoxia‐inducible factor 1α (HIF‐1α)/vascular endothelial growth factor (VEGF) pathway mediated by Von Hippel–Lindau (VHL) after distal middle cerebral artery occlusion (dMCAO). Methods The male rat model of dMCAO was established. The effects of p75 NTR on the angiogenesis was evaluated using RNA‐sequencing, immunohistochemistry, western blot, quantitative real‐time polymerase chain reaction, magnetic resonance imaging, behavior tests, viral and pharmacological interventions. Results We found that the p75 NTR and vessel density were decreased in ipsilateral thalamus after dMCAO. The p75 NTR ‐VHL interaction was reduced, which promoted the ubiquitination degradation of HIF‐1α and reduced VEGF expression after dMCAO. Notably, p75 NTR overexpression restrained the ubiquitination degradation of HIF‐1α by inhibiting VHL‐HIF‐1α interaction, further promoted angiogenesis, increased cerebral blood flow of ipsilateral thalamus and improved neurological function after dMCAO. Conclusion For the first time, we highlighted that the enhancement of p75 NTR ‐VHL interaction promoted angiogenesis in attenuating secondary thalamic damage after dMCAO.