Abstract 286: Loss of Smad3 Exacerbates Abdominal Aortic Aneurysm Formation With Enhanced Inflammation in an Experimental Mouse Model

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Xiaohua Dai ◽  
Anandita Arora ◽  
Jianbin Shen ◽  
Hong Jiang ◽  
Li Li
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Calcium Chloride ◽  
The United States ◽  
Protective Role ◽  
Elastic Fibers ◽  
Aneurysm Formation ◽  
Abdominal Aortic ◽  
The Media ◽  
Chloride Treatment

Introduction Abdominal aortic aneurysm (AAA) is a complex vascular disease that causes more than 10,000 deaths each year in the United States. Extensive studies have been performed in search of pharmaceutical treatment but surgical repair still remains the most effective treatment. TGF-β signaling is an important mechanism in the pathogenesis of aneurysms; however, there is debate as to whether its role is protective or destructive. Smad3 is a major intracellular mediator of the canonical pathway of TGF-β signaling. Hypothesis We hypothesize that Smad3-mediated TGF-β signal pathway plays important roles in the pathogenesis of AAA. Methods To test this hypothesis, we analyze the effects of loss of Smad3 on aneurysm formation in the calcium chloride induced AAA model using Smad3 knockout mice. Results Three weeks after calcium chloride treatment, the abdominal aorta displayed increased dilation, forming aneurysms. Histology and immunohistochemistry analyses show increased cell proliferation and enhanced inflammatory cell infiltration in the media and adventitia of the vessel wall. This was accompanied by elastic fibers degradation, increased MMPs expression and reduced expression of smooth muscle markers. Further analysis showed that the expression and nuclear localization of Smad2 and Smad4 was significantly increased. Conclusions These results demonstrate that Smad3-mediated TGF-β signaling plays a protective role in the pathogenesis of AAA and Smad2/Smad4 upregulation is not sufficient to compensate for the loss of Smad3 in this experimental model.

scholarly journals Basement membrane collagen IV deficiency promotes abdominal aortic aneurysm formation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
L. B. Steffensen ◽  
J. Stubbe ◽  
J. S. Lindholt ◽  
H. C. Beck ◽  
M. Overgaard ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Basement Membrane ◽  
Protective Factor ◽  
Complex Disease ◽  
Artery Bypass ◽  
Protective Role ◽  
Collagen Iv ◽  
Mammary Arteries ◽  
Abdominal Aortic

AbstractAbdominal aortic aneurysm (AAA) is a complex disease which is incompletely accounted for. Basement membrane (BM) Collagen IV (COL4A1/A2) is abundant in the artery wall, and several lines of evidence indicate a protective role of baseline COL4A1/A2 in AAA development. Using Col4a1/a2 hemizygous knockout mice (Col4a1/a2+/−, 129Svj background) we show that partial Col4a1/a2 deficiency augmented AAA formation. Although unchallenged aortas were morphometrically and biomechanically unaffected by genotype, explorative proteomic analyses of aortas revealed a clear reduction in BM components and contractile vascular smooth muscle cell (VSMC) proteins, suggesting a central effect of the BM in maintaining VSMCs in the contractile phenotype. These findings were translated to human arteries by showing that COL4A1/A2 correlated to BM proteins and VSMC markers in non-lesioned internal mammary arteries obtained from coronary artery bypass procedures. Moreover, in human AAA tissue, MYH11 (VSMC marker) was depleted in areas of reduced COL4 as assessed by immunohistochemistry. Finally, circulating COL4A1 degradation fragments correlated with AAA progression in the largest Danish AAA cohort, suggesting COL4A1/A2 proteolysis to be an important feature of AAA formation. In sum, we identify COL4A1/A2 as a critical regulator of VSMC phenotype and a protective factor in AAA formation.

Abstract 3718: MMP-12 Inhibitor Reduces Severity of ANGII-induced Aortic Abdominal Aneurysms in apoE−/− Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Dawn A Savio ◽  
Anita R Halpern ◽  
Yuchuan Wu ◽  
Wei Li ◽  
Joseph Sypek ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Vascular Wall ◽  
Inflammatory Disorder ◽  
Gene Markers ◽  
Genetic Ablation ◽  
Macrophage Recruitment ◽  
Aneurysm Formation ◽  
Abdominal Aortic

Abdominal aortic aneurysm (AAA) is an inflammatory disorder characterized by local connective tissue degradation, macrophage recruitment and infiltration leading to aortic dilation and rupture. Aneurysms of the abdominal aorta represent a significant cardiovascular risk for which inflammation plays an integral role in the defined pathology. Genetic ablation of metalloprotease-12 (MMP-12) eliminates metalloelastase activity and attenuates aneurysm formation in apoE−/− mice. In the current study, a selective MMP-12 inhibitor, WAY-644 was evaluated in the well-established murine model of ANGII-induced aneurysm formation. This inhibitor displays activity for murine MMP-12, IC50 = 6.3 nM by FRET analysis, with low crossreactivity for other MMPs (exception MMP-8), and has established in vivo efficacy in inflammation models. Coadministration of WAY-644 to hyperlipidemic apoE−/− mice during ANGII infusion (1.44 mg/kg) for 28d alters the severity of AngII-induced AAAs as measured by changes in abdominal aortic wet weights and typical AAA classification. As expected, plasma MMP-12 protease activity measured by FRET analysis was inhibited. RNA profiling of abdominal aortic aneurysm tissue characterizes ANGII-induced AAA expansion driven by macrophage infiltration, destructive MMP production and attenuation by MMP-12 inhibition. The transcription of a subset of proinflammatory genes activated with ANGII treatment was repressed by the inhibitor. These genes include quantitative markers of macrophage accumulation in the vessel wall, CD68, MCP1/CCL2, CCR2, MMP-12, and Csf1. Associated reductions in gene markers for inflammation and oxidative stress, ie., heme oxidase (HO), nitric oxide synthase (nos2), Ikbkb, and Stat3 also correlate with MMP-12 antagonism. These changes occur in the absence of lipid changes (TC or TG), or quantitative changes in aortic arch lesions in the ANGII-infused animals. The findings support a mechanism whereby MMP-12 metalloelastase inactivation reduces macrophage recruitment to aneurysmal lesion sites, to lessen activated-macrophage expression of proinflammatory cytokines that figure prominently in vascular wall destruction and the pathogenesis of AAAs.

scholarly journals Histochemical and immunohistochemical analysis of ruptured atherosclerotic abdominal aortic aneurysm wall

2010 ◽  
Vol 67 (12) ◽  
pp. 959-964 ◽  
Author(s):  
Irena Tanaskovic ◽  
Aleksandra Mladenovic-Mihailovic ◽  
Slavica Usaj-Knezevic ◽  
Vesna Stankovic ◽  
Aleksandar Aleksic ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Smooth Muscle Cells ◽  
Periodic Acid ◽  
Muscle Cells ◽  
Foam Cells ◽  
Abdominal Aortic ◽  
S 100 ◽  
The Media

Background/Aim. The main complication of the atherosclerotic abdominal aortic aneurism (AAA) is her rupture that begins with lesion in intima and rupture. The purpose of this work was to determine immunocytochemical and morphofunctional characteristics of the cells in aortic wall in ruptured atherosclerotic abdominal aortic aneurysm. Method. During the course of this study, 20 samples of atherosclerotic AAA were analyzed, all of them obtained during authopsy. The samples were fixed in 4% formalin and embedded in paraffin. Sections of 5 ?m thickness were stained histochemically (of Heidenhain azan stain and Periodic acid Schiff - PAS stain) and immunocytochemically using a DAKO LSAB+/HRP technique to identify ?-smooth muscle actin (?-SMA), vimentin, myosin heavy chains (MHC), desmin, S-100 protein, CD45 and CD68 (DAKO specification). Results. The results of our study showed that ruptured atherosclerotic AAA is characterized by a complete absence of endothelial cells, the disruption of basal membrane and internal elastic lamina, as well as a presence of the remains of hypocellular complicated atherosclerotic lesion in intima. On the plaque margins, as well as in the media, smooth muscle cells (SMCs) are present, which express a ?-SMA and vimentin (but without MHC or desmin expression), as well as leukocyte infiltration, and a large number of foam cells. Some of the foam cells show a CD68-immunoreactivity, while the others show vimentin- and S-100 protein-immunoreactivity. Media is thinned out with a disorganized elastic lamellas, while adventitia is characterized by inflammatory inflitrate (infection). Conclusion. Rupture of aneurysm occurs from the primary intimal disruption, which spreads into thinned out media and adventitia. Rupture is caused by unstable atherom, hypocellularity, loss of contractile characteristics of smooth muscle cells in intima and media, neovascularization of the media, as well as by the activity of the macrophages in the lesion.

Abstract 15228: Role of Sympathetic Innervation in the Pathogenesis of Abdominal Aortic Aneurysm

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Bin JIANG ◽  
Yugang Liu ◽  
Guillermo A Ameer
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Sympathetic Innervation ◽  
Nerve Fibers ◽  
Elastic Fibers ◽  
Surgical Removal ◽  
Infrarenal Aorta ◽  
Abdominal Aortic ◽  
Nerve Bundles

Introduction: The objective of this study is to understand the role of neurological factors, specifically those from the perivascular sympathetic nervous system (SNS), on the initiation and development of Abdominal Aortic Aneurysm (AAA). Hypothesis: We hypothesize that the formation of AAA is associated with the loss of perivascular SNS-induced vasoconstriction specific to the aneurysm region. Methods: We developed a rat Abdominal Aortic Denervation (AAD) model, where the infrarenal aorta of Spauge Dawley rats was denervated with surgical removal of nerve fibers and chemical denervation with 10% phenol ( Figure. A ). A sham control group was included where the infrarenal aorta was treated with PBS. The arteries were harvested at 1 month after the surgeries for histological assessment. Results: The denervated aortas exhibited significant thinning of the aortic wall including the media and the adventitia, compared to the sham controls ( Figure. B ). Moreover, degradation of elastin, demonstrated by the fragmentation of elastic fibers and the decreased number of lamellar units, was also observed in the dennervated aortas in comparison to the sham controls. While the control aortas were well innervated with perivascular nerve bundles adjacent to the adventitia, no nerves were found surrounding the denervated aortas, suggesting successful denervation. Conclusions: We generated an AAD model that could be used for mechanistic understanding and therapeutic development of AAA. The preliminary data suggest a direct link between the lack of aortic sympathetic innervation and AAA formation. Long-term studies are currently underway to further characterize changes in the aortic walls after sympathetic denervation. Figure. (A) Illustration of the denervated region on the rat infrarenal aorta. ( B ) Histological staining of control and denervated rat abdominal aortas at 1 month after surgery. Yellow stars: para-aortic nerve bundles. Scale bar = 200 μm.

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