The p75 neurotrophin receptor attenuates secondary thalamic damage after cortical infarction by promoting angiogenesis

Abstract

AbstractBackgroundAngiogenesis is crucial in neuroprotection of secondary thalamic injury after cortical infarction. The p75 neurotrophin receptor (p75NTR) plays a key role in activating angiogenesis. However, the effects of p75NTR on angiogenesis in the thalamus after cortical infarction are largely unknown. Herein we investigate whether p75NTR 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).MethodsThe male rat model of dMCAO was established. The effects of p75NTR 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.ResultsWe found that the p75NTR and vessel density were decreased in ipsilateral thalamus after dMCAO. The p75NTR‐VHL interaction was reduced, which promoted the ubiquitination degradation of HIF‐1α and reduced VEGF expression after dMCAO. Notably, p75NTR 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.ConclusionFor the first time, we highlighted that the enhancement of p75NTR‐VHL interaction promoted angiogenesis in attenuating secondary thalamic damage after dMCAO.