Cellular senescence assumes pivotal roles in various diseases through the secretion of proinflammatory factors. Despite extensive investigations into vascular senescence associated with aging and degenerative diseases, the molecular mechanisms governing microvascular endothelial cell senescence induced by traumatic stress, particularly its involvement in senescence-induced inflammation, remain insufficiently elucidated. In this study, we present a comprehensive demonstration and characterization of microvascular endothelial cell senescence induced by spinal cord injury (SCI). Lysine demethylase 6A (Kdm6a), commonly known as UTX, emerges as a crucial regulator of cell senescence in injured spinal cord microvascular endothelial cells (SCMECs). Upregulation of UTX induces senescence in SCMECs, leading to an amplified release of proinflammatory factors, specifically the senescence-associated secretory phenotype (SASP) components, thereby modulating the inflammatory microenvironment. Conversely, the deletion of UTX in endothelial cells shields SCMECs against senescence, mitigates the release of proinflammatory SASP factors, and promotes neurological functional recovery after SCI. UTX forms an epigenetic regulatory axis by binding to calponin 1 (CNN1), orchestrating trauma-induced SCMECs senescence and SASP secretion, thereby influencing neuroinflammation and neurological functional repair. Furthermore, local delivery of a senolytic drug reduces senescent SCMECs and suppresses proinflammatory SASP secretion, reinstating a local regenerative microenvironment and enhancing functional repair after SCI. In conclusion, targeting the UTX-CNN1 epigenetic axis to prevent trauma-induced SCMECs senescence holds the potential to inhibit SASP secretion, alleviate neuroinflammation, and provide a novel treatment strategy for SCI repair.

细胞衰老通过促炎因子的分泌在各种疾病中发挥关键作用。尽管对与衰老和退行性疾病相关的血管衰老进行了广泛的研究，但控制创伤应激诱导的微血管内皮细胞衰老的分子机制，特别是其参与衰老诱导的炎症的分子机制仍未得到充分阐明。在这项研究中，我们对脊髓损伤（SCI）引起的微血管内皮细胞衰老进行了全面的论证和表征。赖氨酸脱甲基酶 6A (Kdm6a)，通常称为 UTX，是受损脊髓微血管内皮细胞 (SCMEC) 细胞衰老的关键调节因子。 UTX 的上调会诱导 SCMEC 衰老，导致促炎因子，特别是衰老相关分泌表型 (SASP) 成分的放大释放，从而调节炎症微环境。相反，内皮细胞中 UTX 的缺失可以保护 SCMEC 免于衰老，减轻促炎 SASP 因子的释放，并促进 SCI 后神经功能的恢复。 UTX 通过与钙调蛋白 1 (CNN1) 结合形成表观遗传调控轴，协调创伤诱导的 SCMEC 衰老和 SASP 分泌，从而影响神经炎症和神经功能修复。此外，局部递送抗衰老药物可减少衰老的 SCMEC 并抑制促炎性 SASP 分泌，从而恢复局部再生微环境并增强 SCI 后的功能修复。总之，针对 UTX-CNN1 表观遗传轴来预防创伤引起的 SCMEC 衰老，有可能抑制 SASP 分泌，减轻神经炎症，并为 SCI 修复提供一种新的治疗策略。