Differences in genetic signaling, and not mechanical properties of the wall, are linked to ascending aortic aneurysms in fibulin-4 knockout mice

Kim, Jungsil; Procknow, Jesse D.; Yanagisawa, Hiromi; Wagenseil, Jessica E.

doi:10.1152/ajpheart.00178.2015

Cited by 13 publications

(16 citation statements)

References 88 publications

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“…The microscopy images suggest changes in cellular organization, but do not show any obvious changes in cell or collagen amount or collagen organization for the KO AAs. The fluorescence microscopy results are consistent with previous data on the aortic microstructure in these mice (Wagenseil et al 2009; Mäki et al 2002; Huang et al 2010; Kim et al 2015). …”

Section: Discussionsupporting

confidence: 91%

“…The AA was mounted in a 37°C Myograph 110P (Danish Myotechnology) bath filled with physiologic saline solution, stretched axially to 1.05 times the unloaded length, and preconditioned by pressurizing for three cycles from 0 – 60 mmHg at a constant rate (4 mmHg/sec). Average AA axial stretch values are 1.17 in newborn Fbln4 −/− and Fbln4 +/+ mice, but are highly variable across individual samples (Kim et al 2015). Axial stretch at or below the physiologic value provides similar pressure-diameter curves (Wagenseil et al 2005) and we have noted that newborn aorta is susceptible to axial stretch induced damage, hence we conservatively applied 1.05 axial stretch.…”

Section: Methodsmentioning

confidence: 99%

“…Cross-sectional rings were cut after testing and imaged to determine the AA unloaded thickness. The raw pressure-outer diameter data for loading of Lox +/+ , Lox −/− , Fbln4 +/+ , and Fbln4 −/− AA have been previously published (Kim et al 2015; Staiculescu et al 2017). …”

Section: Methodsmentioning

confidence: 99%

“…Two of the proteins associated with elastic fibers, lysyl oxidase (LOX) and fibulin-4 (FBLN4), are critical for elastic fiber assembly and are necessary for postnatal survival in mice. Lox −/− and Fbln4 −/− mice die soon after birth with arterial tortuosity, aneurysms, and have highly disrupted elastic fibers in the aortic walls (Hornstra et al 2003; Mäki et al 2002; Huang et al 2010; Kim et al 2015; McLaughlin et al 2006). LOX crosslinks elastic and collagen fibers, hence Lox −/− mice represent a model where the mechanical contribution of these two major components is altered.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…Mice with smooth-muscle-specific loss of fibulin-4 expression show altered fibrillar collagen localization with larger, poorly organized fibrils in aortic walls (Papke et al, 2015) and fibulin-4 knockout mice show upregulation of the neutrophil collagenase matrix metalloprotease-8 in aortic walls (Kim et al, 2015). It is possible that impaired collagen assembly or homeostasis might contribute to the aortic phenotype in Ltbp4S −/− ; Fibulin-4 R/R mice, which is under current investigation.…”

Section: Discussionmentioning

confidence: 99%

Function of Ltbp‑4L and fibulin‑4 in survival and elastogenesis

Bultmann-Mellin

Essers

Heijingen

et al. 2016

Disease Models &Amp; Mechanisms

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LTBP-4L and LTBP-4S are two isoforms of the extracellular matrix protein latent-transforming growth factor beta-binding protein 4 (LTBP-4). The mutational inactivation of both isoforms causes autosomal recessive cutis laxa type 1C (ARCL1C) in humans and an ARCL1C-like phenotype in Ltbp4−/− mice, both characterized by high postnatal mortality and severely affected elastogenesis. However, genetic data in mice suggest isoform-specific functions for Ltbp-4 because Ltbp4S−/− mice, solely expressing Ltbp-4L, survive to adulthood. This clearly suggests a requirement of Ltbp-4L for postnatal survival. A major difference between Ltbp4S−/− and Ltbp4−/− mice is the matrix incorporation of fibulin-4 (a key factor for elastogenesis; encoded by the Efemp2 gene), which is normal in Ltbp4S−/− mice, whereas it is defective in Ltbp4−/− mice, suggesting that the presence of Ltbp-4L might be required for this process. To investigate the existence of a functional interaction between Ltbp-4L and fibulin-4, we studied the consequences of fibulin-4 deficiency in mice only expressing Ltbp-4L. Resulting Ltbp4S−/−;Fibulin-4R/R mice showed a dramatically reduced lifespan compared to Ltbp4S−/− or Fibulin-4R/R mice, which survive to adulthood. This dramatic reduction in survival of Ltbp4S−/−;Fibulin-4R/R mice correlates with severely impaired elastogenesis resulting in defective alveolar septation and distal airspace enlargement in lung, and increased aortic wall thickness with severely fragmented elastic lamellae. Additionally, Ltbp4S−/−;Fibulin-4R/R mice suffer from aortic aneurysm formation combined with aortic tortuosity, in contrast to Ltbp4S−/− or Fibulin-4R/R mice. Together, in accordance with our previous biochemical findings of a physical interaction between Ltbp-4L and fibulin-4, these novel in vivo data clearly establish a functional link between Ltbp-4L and fibulin-4 as a crucial molecular requirement for survival and elastogenesis in mice.

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Captopril treatment during development alleviates mechanically induced aortic remodeling in newborn elastin knockout mice

Kim

Cocciolone

Staiculescu

et al. 2019

Biomech Model Mechanobiol

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Deposition of elastin and collagen in the aorta correlate with increases in blood pressure and flow during development, suggesting that the aorta adjusts its mechanical properties in response to hemodynamic stresses. Elastin knockout (Eln −/− ) mice have high blood pressure, pathological remodeling of the aorta, and die soon after birth. We hypothesized that decreasing blood pressure in Eln −/− mice during development may reduce hemodynamic stresses and alleviate pathological remodeling of the aorta. We treated Eln +/+ and Eln −/− mice with the anti-hypertensive medication captopril throughout embryonic development and then evaluated left ventricular (LV) pressure and aortic remodeling at birth. We found that captopril treatment decreased Eln −/− LV pressure to values near Eln +/+ mice and alleviated the wall thickening and changes in mechanical behavior observed in untreated Eln −/− aorta. The changes in thickness and mechanical behavior in captopriltreated Eln −/− aorta were not due to alterations in measured elastin or collagen amounts, but may have been caused by alterations in smooth muscle cell (SMC) properties. We used a constitutive model to understand how changes in stress contributions of each wall component could explain the observed changes in composite mechanical behavior. Our modeling results show that alterations in the collagen natural configuration and SMC properties in the absence of elastin may explain untreated Eln −/− aortic behavior and that partial rescue of the SMC properties may account for captopril-treated Eln −/− aortic behavior.

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Differences in genetic signaling, and not mechanical properties of the wall, are linked to ascending aortic aneurysms in fibulin-4 knockout mice

Abstract: Kim J, Procknow JD, Yanagisawa H, Wagenseil JE. Differences in genetic signaling, and not mechanical properties of the wall, are linked to ascending aortic aneurysms in fibulin-4 knockout mice. Am

Cited by 13 publications

References 88 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

Function of Ltbp‑4L and fibulin‑4 in survival and elastogenesis

Captopril treatment during development alleviates mechanically induced aortic remodeling in newborn elastin knockout mice

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