Cardiovascular disease is the major cause of morbidity and mortality in breast cancer survivors. Chemotherapy contributes to this risk. We aimed to define the mechanisms of long-term vascular dysfunction caused by neoadjuvant chemotherapy (NACT) and identify novel therapeutic targets. We studied arteries from postmenopausal women who had undergone breast cancer treatment using docetaxel, doxorubicin, and cyclophosphamide (NACT) and from women with no history of such treatment matched for key clinical parameters. We explored mechanisms in WT and Nox4^–/– mice and in human microvascular endothelial cells. Endothelium-dependent, NO-mediated vasodilatation was severely impaired in patients after NACT, while endothelium-independent responses remained normal. This was mimicked by a 24-hour exposure of arteries to NACT agents ex vivo. When applied individually, only docetaxel impaired endothelial function in human vessels. Mechanistic studies showed that NACT increased inhibitory eNOS phosphorylation of threonine 495 in a Rho-associated protein kinase–dependent (ROCK-dependent) manner and augmented vascular superoxide and hydrogen peroxide production and NADPH oxidase activity. Docetaxel increased expression of the NADPH oxidase NOX4 in endothelial and smooth muscle cells and NOX2 in the endothelium. A NOX4 increase in human arteries may be mediated epigenetically by diminished DNA methylation of the NOX4 promoter. Docetaxel induced endothelial dysfunction and hypertension in mice, and these were prevented in Nox4^–/– mice and by pharmacological inhibition of Nox4 or Rock. Commonly used chemotherapeutic agents and, in particular, docetaxel alter vascular function by promoting the inhibitory phosphorylation of eNOS and enhancing ROS production by NADPH oxidases.

中文翻译：

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乳腺癌化疗通过 NOX4 依赖机制诱导血管功能障碍和高血压

心血管疾病是乳腺癌幸存者发病率和死亡率的主要原因。化疗会增加这种风险。我们旨在确定由新辅助化疗 (NACT) 引起的长期血管功能障碍的机制，并确定新的治疗靶点。我们研究了使用多西紫杉醇、多柔比星和环磷酰胺 (NACT) 进行乳腺癌治疗的绝经后妇女的动脉，以及没有与关键临床参数匹配的此类治疗史的妇女的动脉。我们探索了 WT 和Nox4中的机制^–/–小鼠和人类微血管内皮细胞。NACT 后患者的内皮依赖性、NO 介导的血管舒张功能严重受损，而内皮非依赖性反应保持正常。这通过体外 24 小时动脉暴露于 NACT 剂来模拟。当单独应用时，只有多西紫杉醇会损害人体血管的内皮功能。机理研究表明，NACT 以 Rho 相关蛋白激酶依赖性（ROCK 依赖性）方式增加苏氨酸 495 的抑制性 eNOS 磷酸化，并增加血管超氧化物和过氧化氢的产生以及 NADPH 氧化酶活性。多西紫杉醇增加内皮细胞和平滑肌细胞中 NADPH 氧化酶 NOX4 的表达，以及内皮细胞中 NOX2 的表达。人类动脉中 NOX4 的增加可能是通过 NOX4 启动子的 DNA 甲基化减少来表观遗传介导的。多西紫杉醇诱导小鼠内皮功能障碍和高血压，这些在Nox4 ^–/–小鼠和通过药理学抑制 Nox4 或 Rock。常用的化学治疗剂，特别是多西他赛通过促进 eNOS 的抑制性磷酸化和增强 NADPH 氧化酶产生的 ROS 来改变血管功能。