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Kusters, Pascal J. H.; Seijkens, Tom T. P.; Beckers, Linda; Lievens, Dirk; Winkels, Holger; Waard, Vivian de; Duijvestijn, Adriaan; Liljeqvist, Moritz Lindquist; Roy, Joy; Daugherty, Alan; Newby, Andrew; Gerdes, Norbert; Lutgens, Esther (2018): CD40L Deficiency Protects Against Aneurysm Formation. In: Arteriosclerosis Thrombosis and Vascular Biology, Vol. 38, No. 5: pp. 1076-1085
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Abstract

Objective 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. Approach and Results 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 (Apoe(-/-)) and Cd40l(-/-)Apoe(-/-) mice were infused with angiotensin II for 7 and 28 days. Only a minority of Cd40l(-/-)Apoe(-/-) mice (33% and 17%) developed (dissecting) aneurysms compared with 75% and 67% of Apoe(-/-) 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 Cd40l(-/-)Apoe(-/-) mice compared with that in angiotensin II-infused Apoe(-/-) mice. Chimeric Apoe(-/-) mice repopulated with Cd40l(-/-)Apoe(-/-) 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 Cd40l(-/-)Apoe(-/-) mice with a concomitant decrease in expression of proinflammatory chemo- and cytokines. In addition, aneurysms of Cd40l(-/-)Apoe(-/-) 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. Conclusions 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.