University of Antwerp, Faculty of Medicine and Health Sciences, Laboratory of Physiopharmacology, Campus Drie Eiken, Universiteitsplein 1, B-2610, Antwerp, Belgium.
University of Antwerp, Faculty of Medicine and Health Sciences, Laboratory of Physiopharmacology, Campus Drie Eiken, Universiteitsplein 1, B-2610, Antwerp, Belgium; University of Antwerp, Research Group Cardiovascular Diseases, GENCOR, Antwerp, Belgium; Ghent University, Faculty of Medicine and Health Sciences, Department of Internal Medicine, C. Heymanslaan 10, B-9000, Ghent, Belgium; Antwerp University Hospital (UZA), Department of Cardiology, Drie Eikenstraat 655, B-2650, Edegem, Belgium.
Toxicol Lett. 2021 Aug 1;346:23-33. doi: 10.1016/j.toxlet.2021.04.015. Epub 2021 Apr 22.
Arterial stiffness is an important predictor of cardiovascular risk. Clinical studies have demonstrated that arterial stiffness increases in cancer patients treated with the chemotherapeutic doxorubicin (DOX). However, the mechanisms of DOX-induced arterial stiffness remain largely unknown. This study aimed to evaluate artery stiffening in DOX-treated mice using in vivo and ex vivo techniques. Male C57BL/6J mice were treated for 2 weeks with 2 mg/kg (low dose) or 4 mg/kg (high dose) of DOX weekly. Arterial stiffness was assessed in vivo with ultrasound imaging (abdominal aorta pulse wave velocity (aaPWV)) and applanation tonometry (carotid-femoral PWV) combined with ex vivo vascular stiffness and reactivity evaluation. The high dose increased aaPWV, while cfPWV did not reach statistical significance. Phenylephrine (PE)-contracted aortic segments showed a higher Peterson's modulus (Ep) in the high dose group, while Ep did not differ when vascular smooth muscle cells (VSMCs) were relaxed by a NO donor (DEANO). In addition, aortic rings of DOX-treated mice showed increased PE contraction, decreased basal nitric oxide (NO) index and impaired acetylcholine-induced endothelium-dependent relaxation. DOX treatment contributed to endothelial cell loss and reduced endothelial nitric oxide synthase (eNOS) expression in the aorta. In conclusion, we have replicated DOX-induced arterial stiffness in a murine model and this aortic stiffness is driven by impaired endothelial function, contributing to increased vascular tone.
动脉僵硬度是心血管风险的一个重要预测指标。临床研究表明，接受化疗药物阿霉素（DOX）治疗的癌症患者的动脉僵硬度增加。然而，DOX 诱导的动脉僵硬度的机制在很大程度上仍然未知。本研究旨在使用体内和离体技术评估 DOX 处理的小鼠的动脉僵硬度。雄性 C57BL/6J 小鼠每周用 2 毫克/千克（低剂量）或 4 毫克/千克（高剂量）的 DOX 处理 2 周。通过超声成像（腹主动脉脉搏波速度（aaPWV））和平板测压法（颈动脉-股动脉 PWV）结合离体血管僵硬度和反应性评估来评估动脉僵硬度。高剂量组增加了 aaPWV，而 cfPWV 没有达到统计学意义。在高剂量组中，苯肾上腺素（PE）收缩的主动脉段显示出更高的彼得森模量（Ep），而当血管平滑肌细胞（VSMCs）被一氧化氮供体（DEANO）松弛时，Ep 没有差异。此外，DOX 处理的小鼠的主动脉环显示出增强的 PE 收缩、降低的基础一氧化氮（NO）指数和受损的乙酰胆碱诱导的内皮依赖性舒张。DOX 处理导致内皮细胞丢失和主动脉内皮型一氧化氮合酶（eNOS）表达减少。总之，我们在小鼠模型中复制了 DOX 诱导的动脉僵硬度，这种主动脉僵硬度是由受损的内皮功能驱动的，导致血管张力增加。
