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

Kim, Jungsil; Staiculescu, Marius C.; Cocciolone, Austin J.; Yanagisawa, Hiromi; Mecham, Robert P.; Wagenseil, Jessica E.

doi:10.1016/j.jbiomech.2017.07.011

Cited by 42 publications

(37 citation statements)

References 50 publications

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“…Neonatal EHBD lack collagen and elastin, suggesting that the mechanical properties of the neonatal duct differ from the adult duct. In arteries, elastin and collagen provide resistance to stretch at low and high pressures, respectively, and data from knockout mice suggest that elastin is also necessary for reducing energy loss during loading and unloading (31). Our data thus imply that neonatal ducts have a decreased ability to respond appropriately to mechanical stresses such as that resulting from obstruction.…”

Section: Intrahepatic and Extrahepatic Cholangiocytes Are Developmentmentioning

confidence: 66%

Coordinated development of the mouse extrahepatic bile duct: implications for neonatal susceptibility to biliary injury

Khandekar

Llewellyn

Kriegermeier

et al. 2019

Preprint

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Background & Aims: The extrahepatic bile duct is the primary tissue initially affected by the cholangiopathy biliary atresia. Biliary atresia affects neonates exclusively and current animal models suggest that the developing bile duct is uniquely susceptible to damage. In this study, we aimed to define the anatomical and functional differences between the neonatal and adult mouse extrahepatic bile ducts.Methods: We studied mouse passaged cholangiocytes, mouse BALB/c neonatal and adult primary cholangiocytes and isolated extrahepatic bile ducts, and a collagen reporter mouse. Methods included transmission electron microscopy, lectin staining, immunostaining, rhodamine uptake assays, bile acid toxicity assays, and in vitro modeling of the matrix.Results: The cholangiocyte monolayer of the neonatal extrahepatic bile duct was immature, lacking the uniform apical glycocalyx and mature cell-cell junctions typical of adult cholangiocytes. Functional studies showed that the glycocalyx protected against bile acid injury and that neonatal cholangiocyte monolayers were more permeable than adult monolayers. In adult ducts, the submucosal space was filled with collagen I, elastin, hyaluronic acid, and proteoglycans. In contrast, the neonatal submucosa had little collagen I and elastin, although both increased rapidly after birth.In vitro modeling suggested that the composition of the neonatal submucosa relative to the adult submucosa led to increased diffusion of bile. A Col-GFP reporter mouse showed that cells in the neonatal but not adult submucosa were actively producing collagen. Conclusion:We identified four key differences between the neonatal and adult extrahepatic bile duct. We showed that these features may have functional implications, suggesting the neonatal extrahepatic bile ducts are particularly susceptible to injury and fibrosis.Lay Summary Biliary atresia is a disease that affects newborns and is characterized by extrahepatic bile duct injury and obstruction with resulting liver injury. We identify four key differences between the epithelial and submucosal layers of the neonatal and adult extrahepatic bile duct and show that these may render the neonatal duct particularly susceptible to injury. Highlights 1) The apical glycocalyx is thin and patchy in neonatal compared to adult cholangiocytes 2) Neonatal cholangiocytes have immature cell-cell junctions and increased permeability 3) The neonatal submucosal space has minimal collagen I or elastin 4) The neonatal submucosal space contains many actively collagen-secreting cells Graphical abstract

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Section: Intrahepatic and Extrahepatic Cholangiocytes Are Developmentmentioning

confidence: 66%

Coordinated development of the mouse extrahepatic bile duct: implications for neonatal susceptibility to biliary injury

Khandekar

Llewellyn

Kriegermeier

et al. 2019

Preprint

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“…It was proposed earlier that their contribution is unlikely because of steric constraints caused by the Pro residues (21). Several studies have shown that Pro impedes the formation of ␣-helical conformations, which are thought to be required to bring the Lys side chains in close proximity (42,43). However, Baig et al (44) identified a peptide, belonging either to domain 4 or domain 8 (both KP) in bovine elastin, that was involved in the formation of DES/IDES.…”

Section: Native Cross-links In Elastinmentioning

confidence: 99%

Elastin is heterogeneously cross-linked

Schräder

Heinz

Majovsky

et al. 2018

Journal of Biological Chemistry

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Elastin is an essential vertebrate protein responsible for the elasticity of force-bearing tissues such as those of the lungs, blood vessels, and skin. One of the key features required for the exceptional properties of this durable biopolymer is the extensive covalent cross-linking between domains of its monomer molecule tropoelastin. To date, elastin's exact molecular assembly and mechanical properties are poorly understood. Here, using bovine elastin, we investigated the different types of cross-links in mature elastin to gain insight into its structure. We purified and proteolytically cleaved elastin from a single tissue sample into soluble cross-linked and noncross-linked peptides that we studied by high-resolution MS. This analysis enabled the elucidation of cross-links and other elastin modifications. We found that the lysine residues within the tropoelastin sequence were simultaneously unmodified and involved in various types of cross-links with different other domains. The Lys-Pro domains were almost exclusively linked via lysinonorleucine, whereas Lys-Ala domains were found to be cross-linked via lysinonorleucine, allysine aldol, and desmosine. Unexpectedly, we identified a high number of intramolecular cross-links between lysine residues in close proximity. In summary, we show on the molecular level that elastin formation involves random cross-linking of tropoelastin monomers resulting in an unordered network, an unexpected finding compared with previous assumptions of an overall beaded structure.

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“…Since the orientation and organization of elastic fibers can determine important functional properties of blood vessels, including resistance to strain and load bearing strength 26,27 , we decided to assess the degree of aortic elastic fiber disorganization using the FFT algorithm as previously described 10 . In our previous report we showed that at 3, 6, and 9 months of age, the orientation indices (indications of fiber disorganization) for elastin fibers, were significantly reduced as compared to healthy counterparts 10 .…”

Section: Discussionmentioning

confidence: 99%

Characterization of doxycycline-mediated inhibition of Marfan syndrome-associated aortic dilation by multiphoton microscopy

Tehrani

Cui

Jones

et al. 2020

Sci Rep

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Marfan syndrome (MfS) is a connective tissue disorder that results in aortic root widening and aneurysm if unmanaged. We have previously reported doxycycline, a nonselective matrix metalloproteinases (MMPs) inhibitor, to attenuate aortic root widening and improve aortic contractility and elasticity in MFS mice. We were also first to use multiphoton microscopy, a non-invasive and label-free imaging technique, to quantify and link the aortic ultrastructure to possible changes in the skin dermis. Here, we aimed to assess the effects of long-term doxycycline treatment on the aortic ultrastructure and skin dermis of MFS mice through immunohistochemical evaluation and quantification of elastic and collagen content and morphology using multiphoton microscopy. our results demonstrate a rescue of aortic elastic fiber fragmentation and disorganization accompanied by a decrease in MMP-2 and MMP-9 expression within the aortic wall in doxycycline-treated MFS mice. At 12 months of age, reduced skin dermal thickness was observed in both MFS and control mice, but only dermal thinning in MFS mice was rescued by doxycycline treatment. MMP-2 and MMP-9 expression was reduced in the skin of doxycycline-treated MfS mice. A decrease in dermal thickness was found to be positively associated with increased aortic root elastin disorganization and wall thickness. Our findings confirm the beneficial effects of doxycycline on ultrastructural properties of aortic root as well as on skin elasticity and structural integrity in MfS mice.Marfan Syndrome (MFS), an autosomal dominant genetic disorder affecting the connective tissues, is caused by mutations in the gene encoding the extracellular matrix (ECM) glycoprotein fibrillin-1 (FBN1) 1 . With an estimated incidence of 1 in 3,000-5,000 individuals, MFS patients exhibit prominent cardiovascular, skeletal, ocular and pulmonary abnormalities 2 . FBN1 protein monomers associate with one another to form microfibrils with structural and regulatory functions in the ECM and act as important scaffolds for elastin fiber and collagen deposition, and thus, provide structural integrity 3 . It is suggested that downstream detrimental effects of FBN1 protein abnormality in MFS is mainly due to disruption of its regulatory role of sequestering the latent form of transforming growth factor beta (TGF-β) in the extracellular space of connective tissue throughout the body 2 . In the cardiovascular system, degeneration of microfibrils leads to loss of elastin fiber integrity within the blood vessel wall, resulting in aortic elastin fiber fragmentation, disorganization, and reduced load bearing capacity, all of which contribute to aortic root aneurysm, dissections, and rupture as the leading cause of mortality in patients if left untreated 4 .Using a well-established mouse model of MFS that carries FBN-1 mutation similar to one found in human MFS patients with aortic aneurysm, our group has previously demonstrated that aortic aneurysm progression in MFS is associated with an upregulation of the matrix-degrading enzy...

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

Cited by 42 publications

References 50 publications

Coordinated development of the mouse extrahepatic bile duct: implications for neonatal susceptibility to biliary injury

Coordinated development of the mouse extrahepatic bile duct: implications for neonatal susceptibility to biliary injury

Elastin is heterogeneously cross-linked

Characterization of doxycycline-mediated inhibition of Marfan syndrome-associated aortic dilation by multiphoton microscopy

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