UMMS Affiliation

Department of Medicine

Publication Date

5-18-2015

Document Type

Article

Subjects

Animals; Aortic Aneurysm, Abdominal; Atrial Remodeling; Calcium Chloride; Collagen; Disease Models, Animal; Elastin; Extracellular Matrix; Gene Expression Regulation; Inflammation; Leukocytes; Matrix Metalloproteinases; Mice; Mice, Knockout; NF-kappa B; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta

Disciplines

Cardiovascular Diseases | Molecular Biology

Abstract

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 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-kappaB and ERK1/2 signaling as well as the expression of nuclear Smad2, Smad4 and TGF-beta1 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.

Rights and Permissions

Citation: Sci Rep. 2015 May 18;5:10180. doi: 10.1038/srep10180. Link to article on publisher's site

DOI of Published Version

10.1038/srep10180

Comments

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Related Resources

Link to Article in PubMed

Keywords

Molecular biology, Pathogenesis

Journal/Book/Conference Title

Scientific reports

PubMed ID

25985281

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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