Mechanical factors direct mouse aortic remodelling during early maturation

Le, Victoria; Cheng, Jessica; Kim, Jungsil; Staiculescu, Marius C.; Ficker, Shawn W.; Sheth, Saahil; Bhayani, Siddharth; Mecham, Robert P.; Yanagisawa, Hiromi; Wagenseil, Jessica E.

doi:10.1098/rsif.2014.1350

Cited by 26 publications

(18 citation statements)

References 55 publications

(119 reference statements)

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“…Less severe mouse models of elastic fiber defects survive to adulthood and offer additional insight into the role of elastic fibers in arterial mechanics. Elastin haploinsufficient ( Eln +/− ) mice have 60% of the normal elastin levels (Faury et al 2003), while fibulin-5 knockout ( Fbln5 −/− ) mice have normal crosslinked elastin levels, but fragmented elastic fibers (Le et al 2015). Microstructurally-based constitutive modeling of biaxial mechanical test data suggests that collagen fiber structure or orientation are altered in Eln +/− and Fbln5 −/− arteries to maintain circumferential mechanical behavior near WT levels (Cheng et al 2013; Wan and Gleason 2013).…”

Section: Discussionmentioning

confidence: 99%

Crosslinked elastic fibers are necessary for low energy loss in the ascending aorta

Kim

Staiculescu

Cocciolone

et al. 2017

Journal of Biomechanics

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In the large arteries, it is believed that elastin provides the resistance to stretch at low pressure, while collagen provides the resistance to stretch at high pressure. It is also thought that elastin is responsible for the low energy loss observed with cyclic loading. These tenets are supported through experiments that alter component amounts through protease digestion, vessel remodeling, normal growth, or in different artery types. Genetic engineering provides the opportunity to revisit these tenets through the loss of expression of specific wall components. We used newborn mice lacking elastin (Eln−/−) or two key proteins (lysyl oxidase, Lox−/−, or fibulin-4, Fbln4−/−) that are necessary for the assembly of mechanically-functional elastic fibers to investigate the contributions of elastic fibers to large artery mechanics. We determined component content and organization and quantified the nonlinear and viscoelastic mechanical behavior of Eln−/−, Lox−/−, and Fbln4−/− ascending aorta and their respective controls. We confirmed that the lack of elastin, fibulin-4, or lysyl oxidase leads to absent or highly fragmented elastic fibers in the aortic wall and a 56 – 97% decrease in crosslinked elastin amounts. We found that the resistance to stretch at low pressure is decreased only in Eln−/− aorta, confirming the role of elastin in the nonlinear mechanical behavior of the aortic wall. Dissipated energy with cyclic loading and unloading is increased 53 – 387% in Eln−/−, Lox−/−, and Fbln4−/− aorta, indicating that not only elastin, but properly assembled and crosslinked elastic fibers, are necessary for low energy loss in the aorta.

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Section: Discussionmentioning

confidence: 99%

Crosslinked elastic fibers are necessary for low energy loss in the ascending aorta

Kim

Staiculescu

Cocciolone

et al. 2017

Journal of Biomechanics

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“…Images were taken with a digital camera mounted on a dissecting microscope. To visualize aortic wall structure, frozen section preparation and fluorescence staining were performed as previously described (26). Alexa fluor 633 hydrazide (0.6 M, Life Technologies) was used for elastin staining (8,40).…”

Section: Methodsmentioning

confidence: 99%

Mechanical behavior and matrisome gene expression in the aneurysm-prone thoracic aorta of newborn lysyl oxidase knockout mice

Staiculescu

Kim

Mecham

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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Mutations in lysyl oxidase (LOX) are associated with thoracic aortic aneurysm and dissection (TAAD). Mice that do not express ( ) die soon after birth and have 60% and 40% reductions in elastin- and collagen-specific cross-links, respectively. LOX inactivation could also change the expression of secreted factors, the structural matrix, and matrix-associated proteins that constitute the aortic matrisome. We hypothesized that absence of will change the mechanical behavior of the aortic wall because of reduced elastin and collagen cross-linking and alter the expression levels of matrisome and smooth muscle cell (SMC) genes in a vascular location-specific manner. Using fluorescence microscopy, pressure myography, and gene set enrichment analysis, we visualized the microarchitecture, quantified the mechanical behavior, and examined matrisome and SMC gene expression from ascending aortas (AAs) and descending aortas (DAs) from newborn and mice. Even though AAs and DAs have fragmented elastic laminae and disorganized SMCs, the unloaded outer diameter and wall thickness were similar to AAs and DAs. AAs and DAs have altered opening angles, circumferential stresses, and circumferential stretch ratios; however, only AAs have increased pressurized diameters and tangent moduli. Gene set enrichment analysis showed upregulation of the extracellular matrix (ECM) regulator gene set in AAs and DAs as well as differential expression of secreted factors, collagens, ECM-affiliated proteins, ECM glycoproteins, and SMC cell cycle gene sets that depend on the genotype and vascular location. These results provide insights into the local chemomechanical changes induced by inactivation that may be important for TAAD pathogenesis. Absence of lysyl oxidase () causes thoracic aortic aneurysms. The aortic mechanical behavior of mice is consistent with reduced elastin and collagen cross-linking but demonstrates vascular location-specific differences. aortas show upregulation of matrix remodeling genes and location-specific differential expression of other matrix and smooth muscle cell gene sets.

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“…The gross vascular phenotype exhibited by mice with a germline deletion of the Fbln5 gene includes elongated and tortuous elastic arteries [1]. Detailed studies of passive aortic properties in both young [2] and mature [3] Fbln5 À/À mice reveal further that the structural, but not material, stiffness is elevated in these mice, with altered wall mechanics manifesting similarly across different thoracic and abdominal regions independent of sex. Interestingly, Fbln5 À/À mice do not develop TAADs, even under induced hypertension (unpublished results), while other mouse models of compromised elastinassociated glycoproteins often present with dramatic thoracic lesions [4,5].…”

Section: Introductionmentioning

confidence: 97%

Reduced Biaxial Contractility in the Descending Thoracic Aorta of Fibulin-5 Deficient Mice

Murtada

Ferruzzi

Yanagisawa

et al. 2016

Journal of Biomechanical Engineering

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The precise role of smooth muscle cell contractility in elastic arteries remains unclear, but accumulating evidence suggests that smooth muscle dysfunction plays an important role in the development of thoracic aortic aneurysms and dissections (TAADs). Given the increasing availability of mouse models of these conditions, there is a special opportunity to study roles of contractility ex vivo in intact vessels subjected to different mechanical loads. In parallel, of course, there is a similar need to study smooth muscle contractility in models that do not predispose to TAADs, particularly in cases where disease might be expected. Multiple mouse models having compromised glycoproteins that normally associate with elastin to form medial elastic fibers present with TAADs, yet those with fibulin-5 deficiency do not. In this paper, we show that deletion of the fibulin-5 gene results in a significantly diminished contractility of the thoracic aorta in response to potassium loading despite otherwise preserved characteristic active behaviors, including axial force generation and rates of contraction and relaxation. Interestingly, this diminished response manifests around an altered passive state that is defined primarily by a reduced in vivo axial stretch. Given this significant coupling between passive and active properties, a lack of significant changes in passive material stiffness may help to offset the diminished contractility and thereby protect the wall from detrimental mechanosensing and its sequelae.

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Mechanical factors direct mouse aortic remodelling during early maturation

Cited by 26 publications

References 55 publications

Crosslinked elastic fibers are necessary for low energy loss in the ascending aorta

Crosslinked elastic fibers are necessary for low energy loss in the ascending aorta

Mechanical behavior and matrisome gene expression in the aneurysm-prone thoracic aorta of newborn lysyl oxidase knockout mice

Reduced Biaxial Contractility in the Descending Thoracic Aorta of Fibulin-5 Deficient Mice

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