Abstract
TGF-β 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 SMAD3 in the pathogenesis of calcium chloride (CaCl2)-induced abdominal aortic aneurysms (AAA) in Smad3−/−, Smad3+/− and Smad3+/+ mice. We find that loss of SMAD3 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 Smad3−/− 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 Smad3−/− mice. We also observe marked increase of NF-κB and ERK1/2 signaling as well as the expression of nuclear Smad2, Smad4 and TGF-β1 in the vessel wall of Smad3−/− mice. In addition, we find that SMAD3 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 SMAD3 in protecting vessel wall integrity and suppressing inflammation in the pathogenesis of AAAs.
Highlights
Laboratory studies have provided insights into the pathogenesis of AAA2,5, the underlying molecular mechanisms remain elusive
Mutations in TGF-β receptors and SMAD3 occur in patients with aneurysms associated with Loeys–Dietz syndrome (LDS), Marfan syndrome (MFS), aneurysm-osteoarthritis syndrome (AOS) and familial thoracic aortic aneurysms and dissections (FTAAD)[11,12,13]: these discoveries point to the complexity of the role(s) of TGF-β signaling in the pathogenesis of aneurysms[6,8]
Western blot (WB) analyses confirm that the expression of SMAD3 in the resulting Smad3−/− mice is abolished (Supplemental Fig. S1B)
Summary
Laboratory studies have provided insights into the pathogenesis of AAA2,5, the underlying molecular mechanisms remain elusive. Mutations in TGF-β receptors and SMAD3 (a key component of TGF-β canonical signal pathways) occur in patients with aneurysms associated with Loeys–Dietz syndrome (LDS), MFS, aneurysm-osteoarthritis syndrome (AOS) and familial thoracic aortic aneurysms and dissections (FTAAD)[11,12,13]: these discoveries point to the complexity of the role(s) of TGF-β signaling in the pathogenesis of aneurysms[6,8] Such complexity, context-dependence, and apparent inconsistencies are not surprising in view of the multifaceted critical role that TGF-β signaling plays in cell migration, proliferation, and differentiation and in maintaining extracellular matrix (ECM) integrity[14]. Since there is a subgroup of human AAAs showing significant wall thickening and tremendous inflammatory cell infiltration, our CaCl2-treated Smad[3] knockout mice can be used as a new valuable pro-inflammatory AAA mouse model
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