CD40L Deficiency Protects Against Aneurysm Formation.

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.

KEYWORDS: {{ getKeywords(articleDetailText.words) }}