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

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.

Keywords: HIF‐1α; angiogenesis; cortical infarction; p75NTR; secondary damage; thalamus.