Adventitial remodeling protects against aortic rupture following late smooth muscle-specific disruption of TGFβ signaling

Kawamura, Yuki I.; Murtada, Sae‐Il; Gao, Feng; Liu, X.; Tellides, George; Humphrey, Jay D.

doi:10.1016/j.jmbbm.2020.104264

Cited by 15 publications

(25 citation statements)

References 49 publications

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“…Remarkably, we found that overall BAPN-related mortality was much greater in young littermate WT ( Fbn1 +/+ ) mice than in young MFS ( Fbn1 C1041G/+ ) mice, namely 45% vs. 8%, consistent with an early compensatory increase in accumulation and/or cross-linking of collagen in this MFS model 28 . We previously found increased adventitial collagen in another mouse model of thoracic aortic aneurysm and dissection (conditional Tgfbr1r2 knockout in adults) that appeared to protect against rupture in vivo even though this additional collagen differed in structure and function 46 . Most of the WT mice that died of an aortic rupture were young males: 27/35 (77%) males died whereas only 6/39 (15%) females died.…”

Section: Discussionmentioning

confidence: 99%

“…Area fractions were computed on a layer-specific basis using wall areas of elastin, cytoplasm, GAGs/PGs, and fibrin from MOV and wall areas of collagen from PSR. For TEM, aortic segments were fixed in 2.5% glutaraldehyde/2% paraformaldehyde in sodium cacodylate buffer at room temperature for 2 h at 4 o C. Samples were then rinsed in sodium cadodylate buffer before post-fixation in 1% osmium tetraoxide for 1 h and subsequent staining using 2% uranyl acetate for 1 h. Samples were washed and embedded in resin and viewed using a FEI Technai Biotwin electron microscope 46 .…”

Section: Histology and Transmission Electron Microscopy (Tem) -Sample...mentioning

confidence: 99%

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Compensatory aortic remodeling in Marfan syndrome protects against sexually dimorphic rupture during a BAPN challenge

Weiss

Rego

Cavinato

et al. 2022

Preprint

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Transmural rupture of the aorta is responsible for significant morbidity and mortality; it occurs when wall stress exceeds local wall strength. Amongst other conditions, the aortic root and ascending aorta become vulnerable to dissection and rupture in Marfan syndrome, a connective tissue disorder that results in a progressive fragmentation and degradation of the elastic fibers of the aortic wall. Whereas competent elastic fibers are critical for aortic functionality, cross-linked collagen fibers endow the aorta with its stiffness and strength. In this paper, we contrast progressive degeneration of the ascending aorta in male and female Marfan and wild-type mice, with and without chronic exposure to a potent inhibitor of lysyl oxidase (β-aminopropionitrile, or BAPN), to examine effects of extracellular matrix cross-linking in aortic dilatation and rupture. We found a strong sexual dimorphism in aortic dilatation in Marfan mice and aortic rupture in wild-type mice, but also a compensatory remodeling of the aorta that protected the Marfan aorta against lethal rupture despite a strong BAPN challenge. This compensation appears to be mediated via increased lysyl oxidase in the female and especially male Marfan aorta, resulting in improved collagen fiber stability and integrity, particularly of fibril bundles in the adventitia.

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Section: Discussionmentioning

confidence: 99%

Section: Histology and Transmission Electron Microscopy (Tem) -Sample...mentioning

confidence: 99%

Compensatory aortic remodeling in Marfan syndrome protects against sexually dimorphic rupture during a BAPN challenge

Weiss

Rego

Cavinato

et al. 2022

Preprint

Self Cite

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“…Mouse models of Ilk deletion present with thoracic aneurysms [ 42 , 43 ], perhaps suggesting yet another role of compromised mechanosensing and inappropriate maintenance or remodeling of ECM. Such changes in matrix turnover must be considered carefully, however, for structural functionality results not just from secretion, but also post-translational modifications and organization of matrix that affect fiber size, undulation, orientation, and cross-linking [ 44 , 45 ]. The present model cannot predict post-translational changes that include fibrillogenesis or cross-linking, hence highlighting one area of future need.…”

Section: Discussionmentioning

confidence: 99%

Roles of mTOR in thoracic aortopathy understood by complex intracellular signaling interactions

et al. 2021

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Thoracic aortopathy–aneurysm, dissection, and rupture–is increasingly responsible for significant morbidity and mortality. Advances in medical genetics and imaging have improved diagnosis and thus enabled earlier prophylactic surgical intervention in many cases. There remains a pressing need, however, to understand better the underlying molecular and cellular mechanisms with the hope of finding robust pharmacotherapies. Diverse studies in patients and mouse models of aortopathy have revealed critical changes in multiple smooth muscle cell signaling pathways that associate with disease, yet integrating information across studies and models has remained challenging. We present a new quantitative network model that includes many of the key smooth muscle cell signaling pathways and validate the model using a detailed data set that focuses on hyperactivation of the mechanistic target of rapamycin (mTOR) pathway and its inhibition using rapamycin. We show that the model can be parameterized to capture the primary experimental findings both qualitatively and quantitatively. We further show that simulating a population of cells by varying receptor reaction weights leads to distinct proteomic clusters within the population, and that these clusters emerge due to a bistable switch driven by positive feedback in the PI3K/AKT/mTOR signaling pathway.

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“…We focused on potential dissections and thus initial defects within the media, without consideration of differential properties of the media and adventitia. 24 The latter would be particularly important in simulations of transmural rupture, which were not considered herein. We also focused on energy-based calculations, not delineating possible effects of normal versus shear stresses in the damage process.…”

Section: Resultsmentioning

confidence: 99%

Critical Pressure of Intramural Delamination in Aortic Dissection

Ban

Cavinato

Humphrey

2021

Preprint

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Computational models of aortic dissection can provide novel insights into possible mechanisms by which this potentially lethal condition develops and propagates. We present results from a phase-field based finite element simulation of a classical experiment that had not previously been understood. Initial simulations agreed qualitatively and quantitatively with the experimental findings, but because of the complexity of the boundary value problem it was still difficult to build intuition. Hence, simplified analytical models were extended to gain further insight. Together, the simplified models and phase-field simulations revealed a power-law-based relation between the pressure required to initiate an intramural tear and key geometric and mechanical factors - area of the initial insult, stiffness of the wall, and characteristic energy of tearing. The degree of axial stretch and luminal pressure similarly influenced the value of the tearing pressure, which was ~70 kPa for a healthy aorta having a sub-millimeter-sized initial insult but even lower for larger tear sizes. Finally, the simulations showed that the direction a tear propagates can be altered by focal regions of weakening or strengthening, which can drive the tear towards the lumen (re-entry) or adventitia (rupture). Additional data are needed, however, on aortas having different predisposing disease conditions.

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Adventitial remodeling protects against aortic rupture following late smooth muscle-specific disruption of TGFβ signaling

Cited by 15 publications

References 49 publications

Compensatory aortic remodeling in Marfan syndrome protects against sexually dimorphic rupture during a BAPN challenge

Compensatory aortic remodeling in Marfan syndrome protects against sexually dimorphic rupture during a BAPN challenge

Roles of mTOR in thoracic aortopathy understood by complex intracellular signaling interactions

Critical Pressure of Intramural Delamination in Aortic Dissection

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