Further Evidence Supporting a Protective Role of Transforming Growth Factor-β (TGFβ) in Aortic Aneurysm and Dissection

Tellides, George

doi:10.1161/atvbaha.117.310031

Cited by 18 publications

(13 citation statements)

References 29 publications

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“…Paradoxically, TGF‐β signalling seems to have a variable role depending on aortic developmental stage: critical for early normal aortic wall development, while pathologic when enhanced during late aneurysm formation . Multiple studies of compound mutant murine models combining Fbn1 mutations with knockout of TGF‐β signalling proteins have demonstrated that this dynamic role of TGF‐β seems to depend on developmental age, magnitude, receptor expression, aortic embryologic origin and disease state.…”

Section: Introductionmentioning

confidence: 99%

Divergent effects of canonical and non‐canonical TGF‐β signalling on mixed contractile‐synthetic smooth muscle cell phenotype in human Marfan syndrome aortic root aneurysms

Pedroza

Koyano

Trojan

et al. 2019

J Cellular Molecular Medi

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Aortic root aneurysm formation is a cardinal feature of Marfan syndrome (MFS) and likely TGF-β driven via Smad (canonical) and ERK (non-canonical) signalling. The current study assesses human MFS vascular smooth muscle cell (SMC) phenotype, focusing on individual contributions by Smad and ERK, with Notch3 signalling identified as a novel compensatory mechanism against TGF-β-driven pathology. Although significant ERK activation and mixed contractile gene expression patterns were observed by traditional analysis, this did not directly correlate with the anatomic site of the aneurysm. Smooth muscle cell phenotypic changes were TGF-β-dependent and opposed by ERK in vitro, implicating the canonical Smad pathway. Bulk SMC RNA sequencing after ERK inhibition showed that ERK modulates cell proliferation, apoptosis, inflammation, and Notch signalling via Notch3 in MFS. Reversing Notch3 overexpression with siRNA demonstrated that Notch3 promotes several protective remodelling pathways, including increased SMC proliferation, decreased apoptosis and reduced matrix metalloproteinase activity, in vitro. In conclusion, in human MFS aortic SMCs: (a) ERK activation is enhanced but not specific to the site of aneurysm formation; (b) ERK opposes TGF-β-dependent negative effects on SMC phenotype; (c) multiple distinct SMC subtypes contribute to a 'mixed' contractile-synthetic phenotype in MFS aortic aneurysm; and (d) ERK drives Notch3 overexpression, a potential pathway for tissue remodelling in response to aneurysm formation. K E Y W O R D S aortic aneurysm, Marfan syndrome, smooth muscle cell phenotype 1 | INTRODUC TI ON Marfan syndrome (MFS) is an inheritable connective tissue disorder resulting from fibrillin-1 (Fbn1) mutations with an incidence of 1 in 5000 individuals. 1,2 Aortic root aneurysm formation and ensuing dissection accounts for early mortality if not surgically repaired prophylactically. 3 Transforming growth factor-beta (TGF-β) signalling is central to MFS aortic aneurysm pathogenesis. 4 Despite enhanced S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Pedroza AJ, Koyano T, Trojan J, et al. Divergent effects of canonical and non-canonical TGF-β signalling on mixed contractile-synthetic smooth muscle cell phenotype in human Marfan syndrome aortic root aneurysms.

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Section: Introductionmentioning

confidence: 99%

Divergent effects of canonical and non‐canonical TGF‐β signalling on mixed contractile‐synthetic smooth muscle cell phenotype in human Marfan syndrome aortic root aneurysms

Pedroza

Koyano

Trojan

et al. 2019

J Cellular Molecular Medi

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“…We have already reported that CAM prevents atherosclerotic aortic aneurysm formation in mice by suppression of NF-kappa B activation, in ammatory cytokines, in ammatory macrophages accumulation and MMP-2 and -9 activation [7]. Some studies reported that cause of enlargement of dissected aortic aneurysm could be in ammatory cytokines activation including IL-6 [3,18], and decreasing TGF-β [6,19]. CAM redressed abnormalities of these cytokines and chemokines [20], so we thought that CAM might suppressed the enlargement of the dissected aortic aneurysm.…”

Section: Discussionmentioning

confidence: 99%

Clarithromycin Prevents the Progression of Dissected Aortic Aneurysm in the Experimental Study

Uchida¹,

Yamawaki-Ogata²,

Ito³

et al. 2021

Preprint

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Background The cause of enlarged aortic dissection (AD) is associated with increased inflammatory cytokines such as IL-6. Clarithromycin (CAM) has been reported to inhibit inflammatory cytokines via suppressing NF-κB. we investigated whether or not CAM could prevent the enlargement of dissected aortic aneurysm. Methods Male wild type mice (12 weeks of age) were infused with Angiotensin II and 3-aminopropinonitrile for two weeks for AD development. After two weeks, CAM (10 mg/kg/day) or saline was administered orally to the mice every day (CAM group: n=10, SAL group: n=10) with infusing Angiotensin II for more two weeks. After four weeks, the aortic diameter, macrophage infiltration, collagen and elastin quantities, and levels of inflammation related cytokines, were assessed. Results The aortic diameter was significantly suppressed in the CAM group (P < 0.01). No rupture death was observed in the CAM group in contrast to 3 (30%) in the SAL group (P = 0.07). Clarithromycin significantly increased the infiltration of anti-inflammatory macrophages (20.8% vs. 2.8%, P < 0.05). Compared with the controls, the levels of IL-1β (332 pg/mL vs. 800 pg/mL, P < 0.01) and IL-6 (344 pg/mL vs. 727 pg/mL: p < 0.05) were significantly decreased, and the levels of IL-4 (2519 pg/mL vs. 1397 pg/mL, P < 0.05) and TGF-β (1649 pg/mL vs. 1134 pg/mL, P < 0.05) was significantly increased in the CAM group. The collagen area was increased (10.1% vs. 4.2%, P < 0.05) and expression of α-SMA (9.5% vs. 2.8%, P < 0.05) and α-actinin (16.3% vs. 4.0%, P < 0.01) were increased in the CAM group compared with the SAL group. Conclusions CAM suppressed the progression of dissected aortic aneurysm through the anti-inflammatory and the existence of abundant collagen secreted including α-SMA, α-actinin positive cells.

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“…13 About the same time, it was also shown that systemic neutralization of TGF-β (transforming growth factor beta) activity exacerbated thoracic aortic disease in Ang IIinfused wild-type mice. 36 Although precise roles for the renin-angiotensin system and TGF-β remain unclear in the context of TAADs, [37][38][39] chronic Ang II infusion remains a convenient and reproducible model for studying potential mechanisms and time courses of particular thoracic aortopathies 22 even though direct translation to human pathology is limited. Indeed, lesions typically arise rapidly in the same anatomic location, within 3 to 5 days of Ang II infusion, and independent of hypercholesterolemia.…”

Section: Discussionmentioning

confidence: 99%

Evolving Mural Defects, Dilatation, and Biomechanical Dysfunction in Angiotensin II–Induced Thoracic Aortopathies

Weiss

Long

Tellides

et al. 2022

ATVB

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BACKGROUND: Thoracic aortopathy associates with extracellular matrix remodeling and altered biomechanical properties. We sought to quantify the natural history of thoracic aortopathy in a common mouse model and to correlate measures of wall remodeling such as aortic dilatation or localized mural defects with evolving microstructural composition and biomechanical properties of the wall. METHODS: We combined a high-resolution multimodality imaging approach (panoramic digital image correlation and optical coherence tomography) with histopathologic examinations and biaxial mechanical testing to correlate spatially, for the first time, macroscopic mural defects and medial degeneration within the ascending aorta with local changes in aortic wall composition and mechanical properties. RESULTS: Findings revealed strong correlations between local decreases in elastic energy storage and increases in circumferential material stiffness with increasing proximal aortic diameter and especially mural defect size. Mural defects tended to exhibit a pronounced biomechanical dysfunction that is driven by an altered organization of collagen and elastic fibers. CONCLUSIONS: While aneurysmal dilatation is often observed within particular segments of the aorta, dissection and rupture initiate as highly localized mechanical failures. We show that wall composition and material properties are compromised in regions of local mural defects, which further increases the dilatation and overall structural vulnerability of the wall. Identification of therapies focused on promoting robust collagen accumulation may protect the wall from these vulnerabilities and limit the incidence of dissection and rupture.

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Further Evidence Supporting a Protective Role of Transforming Growth Factor-β (TGFβ) in Aortic Aneurysm and Dissection

Cited by 18 publications

References 29 publications

Divergent effects of canonical and non‐canonical TGF‐β signalling on mixed contractile‐synthetic smooth muscle cell phenotype in human Marfan syndrome aortic root aneurysms

Divergent effects of canonical and non‐canonical TGF‐β signalling on mixed contractile‐synthetic smooth muscle cell phenotype in human Marfan syndrome aortic root aneurysms

Clarithromycin Prevents the Progression of Dissected Aortic Aneurysm in the Experimental Study

Evolving Mural Defects, Dilatation, and Biomechanical Dysfunction in Angiotensin II–Induced Thoracic Aortopathies

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