Altered Integrin Signaling in Thoracic Aortopathy

Humphrey, Jay D.; Schwartz, Martin A.

doi:10.1161/atvbaha.123.319404

Cited by 2 publications

(4 citation statements)

References 21 publications

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“…At the tissue scale, it remains difficult to delineate the interplay between cellular mechanosensing and mechanoregulation, as seen in the correlations between the optimal insult parameters over multiple trials. Compromised mechanosensing has been conjectured based on the diverse mutations that predispose to TAAs [16] and is supported by the observed loss of intra- and inter-lamellar elastin [53] and recent studies showing altered integrin signalling in the Marfan aorta [37–39]. These diverse observational and experimental results are now supported by our computational results herein.…”

Section: Discussionsupporting

confidence: 85%

Section: Methodsmentioning

confidence: 99%

“…Hence, rates of turnover and mechanoregulation of newly deposited matrix become critical parameters [35,36]. Furthermore, increasing evidence for altered integrin signalling in Marfan syndrome suggests compromised actomyosin activity in vascular cells may play a major role in disease progression [37][38][39]. Motivated thus, in this paper we model progressive changes in aortic structure and function of the Marfan aorta in Fbn1 C1041G/+ and Fbn1 mgR/mgR mice.…”

Section: (B) Motivationmentioning

confidence: 99%

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Computational modelling distinguishes diverse contributors to aneurysmal progression in the Marfan aorta

Li,

Cavinato,

Latorre

et al. 2023

Proc. R. Soc. A.

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Thoracic aortic aneurysms are characterized by a progressive loss of biomechanical functionality resulting from degenerative changes in wall composition, microstructure, and mechanical properties. Among the many causes of these lesions, Marfan syndrome is the most common heritable condition, resulting from mutations to the gene that codes the elastin-associated glycoprotein fibrillin-1. Key histopathological features of the aneurysmal Marfan aorta include extensive degradation of elastic fibres, significant remodelling of fibrillar collagens and compromised smooth muscle cell function. Computational growth and remodelling models have confirmed the importance of compromised elastic fibre integrity in aneurysmal dilatation, but we show here that this contributor alone is not sufficient to describe biomechanical data collected from the two most common mouse models of Marfan syndrome. Rather, our simulations suggest that compromised mechanosensing and mechanoregulation of extracellular matrix by mural cells also play central roles in the natural history. Determination of optimal disease-contributing parameters further suggests a rapid reduction in cellular mechanosensing and mechanoregulation relative to diminished elastic fibre integrity, highlighting the importance of inter- and intra-lamellar elastin in the Marfan aorta. Aneurysmal dilatation in Marfan syndrome thus results from multiple contributors to progressive degeneration of the aortic wall, and computational mechanobiological models can help disentangle these contributions.

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Section: Discussionsupporting

confidence: 85%

Section: Methodsmentioning

confidence: 99%

Section: (B) Motivationmentioning

confidence: 99%

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Computational modelling distinguishes diverse contributors to aneurysmal progression in the Marfan aorta

Li,

Cavinato,

Latorre

et al. 2023

Proc. R. Soc. A.

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“…This can lead to thickening of the vessel wall with lumen constriction, as seen in peripheral arterial disease, or thinning of the vessel wall in the case of aneurysms [4]. These alterations exemplify maladaptive vessel wall remodeling, where ECM changes result in unregulated cellular behavior, leading to the shift of contractile vascular smooth muscle toward a proliferative or secretory phenotype, or triggering cell death [5,6].…”

Section: Introductionmentioning

confidence: 99%

Photochemical Modification of the Extracellular Matrix to Alter the Vascular Remodeling Process

Anderson,

Blair,

Huff

et al. 2023

JFB

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Therapeutic interventions for vascular diseases aim at achieving long-term patency by controlling vascular remodeling. The extracellular matrix (ECM) of the vessel wall plays a crucial role in regulating this process. This study introduces a novel photochemical treatment known as Natural Vascular Scaffolding, utilizing a 4-amino substituted 1,8-naphthimide (10-8-10 Dimer) and 450 nm light. This treatment induces structural changes in the ECM by forming covalent bonds between amino acids in ECM fibers without harming vascular cell survival, as evidenced by our results. To further investigate the mechanism of this treatment, porcine carotid artery segments were exposed to 10-8-10 Dimer and light activation. Subsequent experiments subjected these segments to enzymatic degradation through elastase or collagenase treatment and were analyzed using digital image analysis software (MIPAR) after histological processing. The results demonstrated significant preservation of collagen and elastin structures in the photochemically treated vascular wall, compared to controls. This suggests that photochemical treatment can effectively modulate vascular remodeling by enhancing the resistance of the ECM scaffold to degradation. This approach shows promise in scenarios where vascular segments experience significant hemodynamic fluctuations as it reinforces vascular wall integrity and preserves lumen patency. This can be valuable in treating veins prior to fistula creation and grafting or managing arterial aneurysm expansion.

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Altered Integrin Signaling in Thoracic Aortopathy

Cited by 2 publications

References 21 publications

Computational modelling distinguishes diverse contributors to aneurysmal progression in the Marfan aorta

Computational modelling distinguishes diverse contributors to aneurysmal progression in the Marfan aorta

Photochemical Modification of the Extracellular Matrix to Alter the Vascular Remodeling Process

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