Source data for all findings.

Background
Cellular senescence plays a critical role in regulating angiogenesis. While UTX has been implicated in vascular regeneration following spinal cord injury (SCI), its underlying mechanisms remain incompletely understood. This study investigates how senescence mediates UTX-regulated vascular responses after SCI.
Methods
We assessed p16INK4a (a senescence marker) and UTX expression in spinal cord endothelial cells at 3, 5, 7 and 14 days post-SCI. By breeding UTXflox/flox mice with heterozygous Tek-Cre mice, we generated endothelial-specific UTX knockout mice. Cellular senescence and proliferation were evaluated in primary spinal cord microvascular endothelial cells (SCMVECs). RNA sequencing and chromatin immunoprecipitation (ChIP)-seq were performed to identify UTX target genes.
Results
UTX and p16INK4a expression were both elevated post-SCI in a time-dependent manner. UTX deletion reduced endothelial senescence and enhanced proliferation both in vivo and in vitro. RNA-seq and ChIP-seq identified Top2β as a direct transcriptional target of UTX, negatively regulated through promoter binding. These findings were validated by ChIP-qPCR, western blotting, and immunofluorescence. Knockdown of Top2β reversed the anti-senescence and pro-proliferative effects induced by UTX deletion.
Conclusions
UTX deletion attenuates vascular endothelial senescence and promotes angiogenesis after SCI by upregulating Top2β expression. This newly defined UTX/Top2β axis regulates vascular regeneration and represents a potential therapeutic target for promoting vascular repair following SCI.

研究背景
细胞衰老在调控血管生成过程中发挥关键作用。尽管已有研究表明UTX与脊髓损伤（spinal cord injury, SCI）后的血管再生相关，但其具体分子机制仍未完全阐明。本研究旨在探究脊髓损伤后细胞衰老如何介导UTX调控的血管应答反应。

研究方法
我们检测了脊髓损伤后3、5、7及14天时脊髓内皮细胞中p16INK4a（细胞衰老标志物）与UTX的表达水平。通过将UTX flox/flox条件性敲除小鼠与杂合子Tek-Cre小鼠交配，成功构建了内皮细胞特异性UTX敲除小鼠。我们在原代脊髓微血管内皮细胞（spinal cord microvascular endothelial cells, SCMVECs）中评估了细胞衰老与细胞增殖情况。通过RNA测序（RNA sequencing）与染色质免疫共沉淀测序（ChIP-seq）鉴定UTX的靶基因。

研究结果
UTX与p16INK4a的表达在脊髓损伤后均呈时间依赖性升高。UTX敲除可在体内及体外降低内皮细胞衰老程度并增强其增殖活性。RNA测序与ChIP-seq鉴定发现Top2β是UTX的直接转录靶基因，UTX通过结合Top2β的启动子对其产生负向调控。上述研究结果通过ChIP-qPCR、蛋白质印迹（western blotting）与免疫荧光实验得到了验证。敲低Top2β可逆转UTX敲除所诱导的抗衰老与促增殖效应。

研究结论
UTX敲除可通过上调Top2β的表达，减轻脊髓损伤后血管内皮细胞的衰老并促进血管生成。本研究新揭示的UTX/Top2β信号轴可调控血管再生，有望成为促进脊髓损伤后血管修复的潜在治疗靶点。