p75 神经营养因子受体通过促进血管生成来减轻皮质梗死后的次级丘脑损伤。
The p75 neurotrophin receptor attenuates secondary thalamic damage after cortical infarction by promoting angiogenesis.
机构信息
Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
Department of Neurology, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
出版信息
CNS Neurosci Ther. 2024 Jul;30(7):e14875. doi: 10.1111/cns.14875.
BACKGROUND
Angiogenesis is crucial in neuroprotection of secondary thalamic injury after cortical infarction. The p75 neurotrophin receptor (p75) plays a key role in activating angiogenesis. However, the effects of p75 on angiogenesis in the thalamus after cortical infarction are largely unknown. Herein we investigate whether p75 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 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 and vessel density were decreased in ipsilateral thalamus after dMCAO. The p75-VHL interaction was reduced, which promoted the ubiquitination degradation of HIF-1α and reduced VEGF expression after dMCAO. Notably, p75 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-VHL interaction promoted angiogenesis in attenuating secondary thalamic damage after dMCAO.
背景
血管生成对于皮质梗死后次级丘脑损伤的神经保护至关重要。p75 神经营养素受体（p75）在激活血管生成中起关键作用。然而，p75 在皮质梗死后丘脑血管生成中的作用在很大程度上尚不清楚。在此，我们研究了 p75 是否通过激活缺氧诱导因子 1α（HIF-1α）/血管内皮生长因子（VEGF）途径来促进血管生成，从而减轻次级丘脑损伤，该途径由 Von Hippel-Lindau（VHL）介导，在大脑中动脉远端闭塞（dMCAO）后。
方法
建立雄性大鼠 dMCAO 模型。使用 RNA 测序、免疫组织化学、western blot、定量实时聚合酶链反应、磁共振成像、行为测试、病毒和药理学干预来评估 p75 对血管生成的影响。
结果
我们发现，dMCAO 后，同侧丘脑的 p75 和血管密度降低。p75-VHL 相互作用减少，这促进了 dMCAO 后 HIF-1α 的泛素化降解，降低了 VEGF 的表达。值得注意的是，p75 过表达通过抑制 VHL-HIF-1α 相互作用来抑制 HIF-1α 的泛素化降解，进一步促进了血管生成，增加了同侧丘脑的脑血流量，并改善了 dMCAO 后的神经功能。
结论
我们首次强调，增强 p75-VHL 相互作用可促进血管生成，从而减轻 dMCAO 后次级丘脑损伤。
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