title: SMAD3 deficiency promotes vessel wall remodeling, collagen fiber reorganization and leukocyte infiltration in an inflammatory abdominal aortic aneurysm mouse model.
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.
authors.affiliation: 1] Department of Internal Medicine [2] Center for Molecular Medicine and Genetics.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Dai
authors.affiliation: 1] Department of Internal Medicine [2] Center for Molecular Medicine and Genetics [3] Cardiovascular Research Institute.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Biochemistry, Wayne State University, Detroit, MI 48201.
authors.forename: Neeraja Priyanka
authors.initials: NP
authors.lastname: Annam
authors.affiliation: Department of Internal Medicine.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Pathology, Veterans Affairs Medical Center, Detroit, MI 48201.
authors.forename: Edi
authors.initials: E
authors.lastname: Levi
authors.affiliation: The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA 17822.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Schworer
authors.affiliation: The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA 17822.
authors.forename: Gerard
authors.initials: G
authors.lastname: Tromp
authors.affiliation: Department of Internal Medicine.
authors.forename: Anandita
authors.initials: A
authors.lastname: Arora
authors.affiliation: Center for Molecular Medicine and Genetics.
authors.forename: Mary
authors.initials: M
authors.lastname: Higgins
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710.
authors.forename: Xiao-Fan
authors.initials: XF
authors.lastname: Wang
authors.affiliation: Bone and Joint Center, Henry Ford Hospital, Detroit, MI 48202.
authors.forename: Maozhou
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Medicine, University of Massachusetts, Worcester, MA 01655.
authors.forename: Hui J
authors.initials: HJ
authors.lastname: Li
authors.affiliation: Center for Molecular Medicine and Genetics.
authors.forename: Kezhong
authors.initials: K
authors.lastname: Zhang
authors.affiliation: The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA 17822.
authors.forename: Helena
authors.initials: H
authors.lastname: Kuivaniemi
authors.affiliation: 1] Department of Internal Medicine [2] Center for Molecular Medicine and Genetics [3] Cardiovascular Research Institute.
authors.forename: Li
authors.initials: L
authors.lastname: Li
mesh_terms: D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000209:etiology* / Q000473:pathology; D064752:Atrial Remodeling / Q000235:genetics*; D002122:Calcium Chloride / Q000494:pharmacology; D003094:Collagen / Q000378:metabolism*; D004195:Disease Models, Animal; D004549:Elastin; D005109:Extracellular Matrix / Q000378:metabolism; D005786:Gene Expression Regulation; D007249:Inflammation / Q000150:complications*; D007962:Leukocytes / Q000378:metabolism* / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000172:deficiency*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016328:NF-kappa B; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D003094:Collagen; D004549:Elastin; D020782:Matrix Metalloproteinases; D002122:Calcium Chloride