From the Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands (P.J.H.K., T.T.P.S., L.B., D.L., H.W., V.d.W., E.L.).
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians University, Munich, Germany (T.T.P.S., D.L., H.W., N.G., E.L.).
Arterioscler Thromb Vasc Biol. 2018 May;38(5):1076-1085. doi: 10.1161/ATVBAHA.117.310640. Epub 2018 Mar 8.
The mechanisms underlying formation of arterial aneurysms remain incompletely understood. Because inflammation is a common feature during the progressive degeneration of the aortic wall, we studied the role of the costimulatory molecule CD40L, a major driver of inflammation, in aneurysm formation.
Transcriptomics data obtained from human abdominal aortic aneurysms and normal aortas revealed increased abundance of both CD40L and CD40 in media of thrombus-free and thrombus-covered human abdominal aortic aneurysms samples. To further unravel the role of CD40L in aneurysm formation, apolipoprotein E-deficient () and mice were infused with angiotensin II for 7 and 28 days. Only a minority of mice (33% and 17%) developed (dissecting) aneurysms compared with 75% and 67% of littermates after 7 and 28 days of infusion, respectively. Total vessel area of the aorta at the suprarenal level was 52% smaller in angiotensin II-infused mice compared with that in angiotensin II-infused mice. Chimeric mice repopulated with bone marrow afforded a similar protection against dissecting aneurysm formation. Moreover, lack of CD40L protected mice from fatal aneurysm rupture. T helper cell and macrophage accumulation in aneurysmal tissue was reduced in mice with a concomitant decrease in expression of proinflammatory chemo- and cytokines. In addition, aneurysms of mice displayed reduced abundance of matrix metalloproteinase-13 and an increase in tissue inhibitor of metalloproteinase-3 while activity of matrix metalloproteinase-2 and matrix metalloproteinase-9 was diminished.
Deficiency of (hematopoietic) CD40L protects against dissecting aneurysm formation and reduces the incidence of fatal rupture. This is associated with a decreased accumulation and activation of inflammatory cells and a dampened protease activity in the arterial wall.
动脉瘤形成的机制尚不完全清楚。由于炎症是主动脉壁进行性退化的一个共同特征，我们研究了共刺激分子 CD40L（炎症的主要驱动因素）在动脉瘤形成中的作用。
从人类腹主动脉瘤和正常主动脉获得的转录组学数据显示，血栓形成和未血栓形成的人类腹主动脉瘤样本的中膜中 CD40L 和 CD40 的丰度均增加。为了进一步阐明 CD40L 在动脉瘤形成中的作用，载脂蛋白 E 缺陷（）和 小鼠接受血管紧张素 II 输注 7 和 28 天。与血管紧张素 II 输注 7 和 28 天后的同窝对照相比，只有少数 小鼠（33%和 17%）发展为（夹层）动脉瘤，而 75%和 67%的 同窝对照发展为动脉瘤。与血管紧张素 II 输注的 小鼠相比，血管紧张素 II 输注的 小鼠的肾上主动脉总血管面积小 52%。用 骨髓重建的嵌合 小鼠提供了对夹层动脉瘤形成的类似保护。此外，缺乏 CD40L 可防止致命的动脉瘤破裂。与 小鼠相比， 小鼠动脉瘤组织中 T 辅助细胞和巨噬细胞的积累减少，同时促炎趋化因子和细胞因子的表达减少。此外， 小鼠的动脉瘤中基质金属蛋白酶-13 的丰度降低，组织金属蛋白酶抑制剂-3 的丰度增加，而基质金属蛋白酶-2 和基质金属蛋白酶-9 的活性降低。
（造血）CD40L 的缺乏可预防夹层动脉瘤的形成并降低致命性破裂的发生率。这与炎症细胞的积累和激活减少以及动脉壁中蛋白酶活性降低有关。
