SMAD3 deficiency promotes vessel wall remodeling, collagen fiber reorganization and leukocyte infiltration in an inflammatory abdominal aortic aneurysm mouse model

TGF-beta signaling plays critical roles in the pathogenesis of aneurysms; however, it is still unclear whether its role is protective or destructive. In this study, we investigate the role of SMAD(3) in the pathogenesis of calcium chloride (CaCl2)-induced abdominal aortic aneurysms (AAA) in Smad(3)(-/-), Smad(3)(+/-) and Smad(3)(+/+) mice. We find that loss of SMAD(3) drastically increases wall thickening of the abdominal aorta. Histological analyses show significant vessel wall remodeling with elastic fiber fragmentation. Remarkably, under polarized light, collagen fibers in the hyperplastic adventitia of Smad(3)(-/-) mice show extensive reorganization accompanied by loosely packed thin and radial collagen fibers. The expressions of matrix metalloproteinases including MMP2, MMP9, and MMP12 and infiltration of macrophage/T cells are drastically enhanced in the vascular wall of Smad(3)(-/-) mice. We also observe marked increase of NF-kappa B and ERK1/2 signaling as well as the expression of nuclear Smad(2), Smad(4) and TGF-beta 1 in the vessel wall of Smad(3)(-/-) mice. In addition, we find that SMAD(3) expression is reduced in the dedifferentiated medial smooth muscle-like cells of human AAA patients. These findings provide direct in vivo evidence to support the essential roles of SMAD(3) in protecting vessel wall integrity and suppressing inflammation in the pathogenesis of AAAs.