Accumulation of senescent endothelial cells (ECs) with age is a pivotal driver of cardiovascular diseases in aging. However, little is known about the mechanisms and signaling pathways that regulate EC senescence. In this report, we delineate a previously unrecognized role of aquaporin 1 (AQP1) in orchestrating extracellular hydrogen peroxide (H2O2)-induced cellular senescence in aortic ECs. Our findings underscore AQP1's differential impact on senescence hallmarks, including cell-cycle arrest, senescence-associated secretory phenotype (SASP), and DNA damage responses, intricately regulating angiogenesis. In proliferating ECs, AQP1 is crucial for maintaining angiogenic capacity, whereas disruption of AQP1 induces morphological and mitochondrial alterations, culminating in senescence and impaired angiogenesis. Conversely, Aqp1 knockdown or selective blockade of AQP1 in senescent ECs rescues the excess H2O2-induced cellular senescence phenotype and metabolic dysfunction, thereby ameliorating intrinsic angiogenic incompetence. Mechanistically, AQP1 facilitates H2O2 transmembrane transport, exacerbating oxidant-sensitive kinases CaMKII-AMPK. This process suppresses HDAC4 translocation, consequently de-repressing Mef2A-eNOS signaling in proliferating ECs. However, in senescent ECs, AQP1 overexpression is linked to preserved HDAC4-Mef2A complex and downregulation of eNOS signaling. Together, our studies identify AQP1 as a novel epigenetic regulator of HDAC4-Mef2A-dependent EC senescence and angiogenic potential, highlighting its potential as a therapeutic target for antagonizing age-related cardiovascular diseases.

中文翻译：

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AQP1 差异协调内皮细胞衰老


衰老内皮细胞 （EC） 随年龄增长而积累是衰老中心血管疾病的关键驱动因素。然而，关于调节 EC 衰老的机制和信号通路知之甚少。在本报告中，我们描述了水通道蛋白 1 （AQP1） 在协调细胞外过氧化氢 （H 2 O 2） 诱导的主动脉 EC细胞衰老中以前未被认识的作用。我们的研究结果强调了 AQP1 对衰老标志物的不同影响，包括细胞周期停滞、衰老相关分泌表型 （SASP） 和 DNA 损伤反应，错综复杂地调节血管生成。在增殖的 ECs 中，AQP1 对于维持血管生成能力至关重要，而 AQP1 的破坏会诱导形态和线粒体改变，最终导致衰老和血管生成受损。相反，在衰老 EC 中敲低或选择性阻断 AQP1 可挽救过量的 H2O2 诱导的细胞衰老表型和代谢功能障碍，从而改善内在血管生成功能不全。从机制上讲，AQP1 促进 H2O2 跨膜转运，加剧氧化剂敏感激酶 CaMKII-AMPK。这个过程抑制了 HDAC4 易位，从而去抑制了增殖 ECs 中的 Mef2A-eNOS 信号传导。然而，在衰老的 ECs 中，AQP1 过表达与保留的 HDAC4-Mef2A 复合物和 eNOS 信号转导的下调有关。总之，我们的研究将 AQP1 确定为 HDAC4-Mef2A 依赖性 EC 衰老和血管生成潜力的新型表观遗传调节因子，突出了其作为拮抗年龄相关心血管疾病的治疗靶点的潜力。