Institut National de la Santé et de la Recherche Médicale U930, Team 4 (Affective disorders), Université François-Rabelais de Tours, Parc Grandmont, Batiment O, 37041 Tours Cedex 01, France.
Psychosom Med. 2012 Jan;74(1):63-72. doi: 10.1097/PSY.0b013e31823a43e0. Epub 2011 Dec 30.
Major depression is an independent risk factor for the development of cardiovascular diseases. However, the exact mechanism by which depression may induce cardiovascular events is unclear. Endothelial dysfunction has been reported as a possible link between depression and subsequent cardiovascular events as described in depressed subjects. The purpose of this study was to investigate endothelial dysfunction and atherosclerosis formation in the aorta of mice exposed to the unpredictable chronic mild stress (UCMS) procedure.
BALB/c mice were exposed to two 7-week UCMS procedures separated by 6 weeks. Treatments (fluoxetine 10 mg/kg; NaCl 0.9%) started at the third week until the end of the seventh week of each procedure. Endothelial function was evaluated by in vitro assessment of acetylcholine-induced vasorelaxation in aortic rings. By using specific inhibitors for nitric oxide (NO)- and prostacyclin-dependent relaxation, we assessed the part played by NO, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF)-like mediators in endothelium-dependent relaxation. Atherosclerosis was evaluated by histological examination.
Depression-like behavior was increased in the UCMS versus unstressed group and was reversed by chronic fluoxetine treatment. Vascular reactivity study indicated that UCMS induced a decrease in the NO-dependent relaxation that was partially compensated by an EDHF-like dependent relaxation. Because fluoxetine per se increased the NO-dependent relaxation, fluoxetine was able to reverse UCMS effect on the NO component and abolished the EDHF-like component. Atherosclerotic lesion was found in aorta of UCMS and nonstressed animals.
As an independent risk factor, UCMS reproduced the endothelial alterations observed in depression but was not sufficient to provoke morphological alterations.
重度抑郁症是心血管疾病发展的独立危险因素。然而，抑郁导致心血管事件的确切机制尚不清楚。已有研究报道，抑郁患者存在内皮功能障碍，这可能是抑郁与随后心血管事件之间的关联之一。本研究旨在探讨经历不可预测性慢性轻度应激（UCMS）程序的小鼠主动脉内皮功能障碍和动脉粥样硬化的形成。
BALB/c 小鼠接受了两次为期 7 周的 UCMS 处理，两次处理之间间隔 6 周。在第三次处理的第 3 周到第 7 周结束时，给予治疗（氟西汀 10mg/kg；生理盐水 0.9%）。通过体外评估乙酰胆碱诱导的主动脉环血管舒张来评估内皮功能。使用一氧化氮（NO）和前列环素依赖性舒张的特异性抑制剂，我们评估了 NO、前列环素和内皮源性超极化因子（EDHF）样介质在内皮依赖性舒张中的作用。通过组织学检查评估动脉粥样硬化。
与未应激组相比，UCMS 组出现了类似抑郁的行为，这种行为被慢性氟西汀治疗所逆转。血管反应性研究表明，UCMS 诱导了 NO 依赖性舒张的减少，这部分被 EDHF 样依赖性舒张所补偿。由于氟西汀本身增加了 NO 依赖性舒张，因此氟西汀能够逆转 UCMS 对 NO 成分的影响，并消除 EDHF 样成分。在 UCMS 和非应激动物的主动脉中发现了动脉粥样硬化病变。
作为一个独立的危险因素，UCMS 重现了抑郁患者中观察到的内皮改变，但不足以引起形态学改变。
