scholarly journals Targeted Disruption of Fibulin-4 Abolishes Elastogenesis and Causes Perinatal Lethality in Mice

2006 ◽  
Vol 26 (5) ◽  
pp. 1700-1709 ◽  
Author(s):  
Precious J. McLaughlin ◽  
Qiuyun Chen ◽  
Masahito Horiguchi ◽  
Barry C. Starcher ◽  
J. Brett Stanton ◽  
...  
Keyword(s):  
Lysyl Oxidase ◽  
Elastic Fiber ◽  
Aneurysm Rupture ◽  
Elastic Fibers ◽  
Targeted Disruption ◽  
Descending Aorta ◽  
Extracellular Matrix Molecule ◽  
Cross Links ◽  
Perinatal Lethality ◽  
Severe Lung

ABSTRACT Elastic fibers provide tissues with elasticity which is critical to the function of arteries, lungs, skin, and other dynamic organs. Loss of elasticity is a major contributing factor in aging and diseases. However, the mechanism of elastic fiber development and assembly is poorly understood. Here, we show that lack of fibulin-4, an extracellular matrix molecule, abolishes elastogenesis. fibulin-4 −/− mice generated by gene targeting exhibited severe lung and vascular defects including emphysema, artery tortuosity, irregularity, aneurysm, rupture, and resulting hemorrhages. All the homozygous mice died perinatally. The earliest abnormality noted was a uniformly narrowing of the descending aorta in fibulin-4 −/− embryos at embryonic day 12.5 (E12.5). Aorta tortuosity and irregularity became noticeable at E15.5. Histological analysis demonstrated that fibulin-4 −/− mice do not develop intact elastic fibers but contain irregular elastin aggregates. Electron microscopy revealed that the elastin aggregates are highly unusual in that they contain evenly distributed rod-like filaments, in contrast to the amorphous appearance of normal elastic fibers. Desmosine analysis indicated that elastin cross-links in fibulin-4 −/− tissues were largely diminished. However, expression of tropoelastin or lysyl oxidase mRNA was unaffected in fibulin-4 −/− mice. In addition, fibulin-4 strongly interacts with tropoelastin and colocalizes with elastic fibers in culture. These results demonstrate that fibulin-4 plays an irreplaceable role in elastogenesis.

scholarly journals Dill Extract Induces Elastic Fiber Neosynthesis and Functional Improvement in the Ascending Aorta of Aged Mice with Reversal of Age-Dependent Cardiac Hypertrophy and Involvement of Lysyl Oxidase-Like-1

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 173 ◽  
Author(s):  
Wassim Fhayli ◽  
Quentin Boëté ◽  
Nadjib Kihal ◽  
Valérie Cenizo ◽  
Pascal Sommer ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Lysyl Oxidase ◽  
Elastic Fiber ◽  
Ascending Aorta ◽  
Functional Improvement ◽  
Elastic Fibers ◽  
Aged Mice ◽  
Age Related ◽  
And Function

Elastic fibers (90% elastin, 10% fibrillin-rich microfibrils) are synthesized only in early life and adolescence mainly by the vascular smooth muscle cells through the cross-linking of its soluble precursor, tropoelastin. Elastic fibers endow the large elastic arteries with resilience and elasticity. Normal vascular aging is associated with arterial remodeling and stiffening, especially due to the end of production and degradation of elastic fibers, leading to altered cardiovascular function. Several pharmacological treatments stimulate the production of elastin and elastic fibers. In particular, dill extract (DE) has been demonstrated to stimulate elastin production in vitro in dermal equivalent models and in skin fibroblasts to increase lysyl oxidase–like-1 (LOXL-1) gene expression, an enzyme contributing to tropoelastin crosslinking and elastin formation. Here, we have investigated the effects of a chronic treatment (three months) of aged male mice with DE (5% or 10% v/v, in drinking water) on the structure and function of the ascending aorta. DE treatment, especially at 10%, of aged mice protected pre-existing elastic lamellae, reactivated tropoelastin and LOXL-1 expressions, induced elastic fiber neo-synthesis, and decreased the stiffness of the aging aortic wall, probably explaining the reversal of the age-related cardiac hypertrophy also observed following the treatment. DE could thus be considered as an anti-aging product for the cardiovascular system.

THE ELASTIC FIBER A REVIEW

1973 ◽  
Vol 21 (3) ◽  
pp. 199-208 ◽  
Author(s):  
RUSSELL ROSS
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Elastic Properties ◽  
Lysyl Oxidase ◽  
Elastic Fiber ◽  
Net Charge ◽  
Amorphous Component ◽  
Cross Links

A number of important questions remain to be answered concerning our understanding of elastic tissues. The size and molecular weight of the elastin precursor remains to be clearly established. The number of proteins involved in the microfibrillar component of the elastic fiber are as yet undetermined, although it would appear that they are glycoproteins that may represent a species of reasonably high molecular weight. Clearly the elastic fiber contains two morphologic components. During morphogenesis, the elastic fiber begins to appear in the form of aggregates of microfibrils that take the shape and direction of the presumptive elastic fiber. With increasing maturity elastin begins to form within the interstices of each bundle of microfibrils. By the time the elastic fiber is fully formed it consists largely of the amorphous component, elastin, surrounded by an envelope of microfibrils with microfibrils embedded within its interstices. It has been suggested that the microfibrils form and take their shape extracellularly under the influence of the cells that have secreted their precursors. After the aggregates of microfibrils have taken their shape Ross and Bornstein (22) have suggested that the elastin may interact ionically with the surface of the microfibrils, since each of these two components has an opposite net charge, and may be held in position while desmosine cross-links are established through the action of the enzyme, lysyl oxidase. Thus the microfibrils would serve as a scaffolding to determine morphogenetically the shape and direction to be later taken by the mature elastic fiber. The reason for the elastic properties of the elastin is still yet poorly understood, and the means by which the cells synthesize and secrete both of these components remain to be investigated.

scholarly journals Elastic Laminar Reorganization Occurs with Outward Diameter Expansion during Collateral Artery Growth and Requires Lysyl Oxidase for Stabilization

2021 ◽  
Author(s):  
Ryan M McEnaney ◽  
Dylan D McCreary ◽  
Nolan Skirtich ◽  
Elizabeth Andraska ◽  
Ulka Sachdev ◽  
...  
Keyword(s):  
Structural Changes ◽  
Lysyl Oxidase ◽  
Elastic Fiber ◽  
Multiphoton Microscopy ◽  
Fiber Formation ◽  
Elastic Fibers ◽  
Large Artery ◽  
Luminal Diameter ◽  
Collateral Arteries ◽  
Collateral Artery

When a large artery becomes occluded, hemodynamic changes stimulate remodeling of arterial networks to form collateral arteries in a process termed arteriogenesis. However, the structural changes necessary for collateral remodeling have not been defined. We hypothesize that decon-struction of the extracellular matrix is essential to the remodeling of smaller arteries into effective collaterals. Using multiphoton microscopy, we analyzed collagen and elastin structure in maturing collateral arteries isolated from ischemic rat hindlimbs. Collateral arteries harvested at different timepoints showed progressive diameter expansion associated with striking rearrangement of in-ternal elastic lamina (IEL) into a loose fibrous mesh, a pattern persisting at 8 weeks. Despite a 2.5-fold increase in luminal diameter, total elastin content remained unchanged in collaterals compared with control arteries. Among the collateral midzones, baseline elastic fiber content is low. Outward remodeling of these vessels with a 10-20 fold diameter increase was associated with fractures of the elastic fibers and evidence of increased wall tension as demonstrated by straight-ening of the adventitial collagen. Inhibition of lysyl oxidase (LOX) function with β-aminopropionitrile resulted in severe fragmentation or complete loss of continuity of the IEL in developing collaterals. Collateral artery development is associated with permanent redistribution of existing elastic fibers to accommodate diameter growth. We found no evidence of new elastic fiber formation. Stabilization of the arterial wall during outward remodeling is necessary and dependent on LOX activity.

scholarly journals Fibulin-5/DANCE has an elastogenic organizer activity that is abrogated by proteolytic cleavage in vivo

2007 ◽  
Vol 176 (7) ◽  
pp. 1061-1071 ◽  
Author(s):  
Maretoshi Hirai ◽  
Tetsuya Ohbayashi ◽  
Masahito Horiguchi ◽  
Katsuya Okawa ◽  
Akari Hagiwara ◽  
...  
Keyword(s):  
Lysyl Oxidase ◽  
Elastic Fiber ◽  
Elastic Fibers ◽  
Cross Linking ◽  
Fiber Assembly ◽  
Organizer Activity ◽  
Serum Dependent ◽  
Serum Free Conditions ◽  
Deficient Mice

Elastic fibers are required for the elasticity and integrity of various organs. We and others previously showed that fibulin-5 (also called developing arteries and neural crest EGF-like [DANCE] or embryonic vascular EGF-like repeat–containing protein [EVEC]) is indispensable for elastogenesis by studying fibulin-5–deficient mice, which recapitulate human aging phenotypes caused by disorganized elastic fibers (Nakamura, T., P.R. Lozano, Y. Ikeda, Y. Iwanaga, A. Hinek, S. Minamisawa, C.F. Cheng, K. Kobuke, N. Dalton, Y. Takada, et al. 2002. Nature. 415:171–175; Yanagisawa, H., E.C. Davis, B.C. Starcher, T. Ouchi, M. Yanagisawa, J.A. Richardson, and E.N. Olson. 2002. Nature. 415:168–171). However, the molecular mechanism by which fiblin-5 contributes to elastogenesis remains unknown. We report that fibulin-5 protein potently induces elastic fiber assembly and maturation by organizing tropoelastin and cross-linking enzymes onto microfibrils. Deposition of fibulin-5 on microfibrils promotes coacervation and alignment of tropoelastins on microfibrils, and also facilitates cross-linking of tropoelastin by tethering lysyl oxidase-like 1, 2, and 4 enzymes. Notably, recombinant fibulin-5 protein induced elastogenesis even in serum-free conditions, although elastogenesis in cell culture has been believed to be serum-dependent. Moreover, the amount of full-length fibulin-5 diminishes with age, while truncated fibulin-5, which cannot promote elastogenesis, increases. These data suggest that fibulin-5 could be a novel therapeutic target for elastic fiber regeneration.

scholarly journals Comparative gene array analyses of severe elastic fiber defects in late embryonic and newborn mouse aorta

2018 ◽  
Vol 50 (11) ◽  
pp. 988-1001 ◽  
Author(s):  
Marius Catalin Staiculescu ◽  
Austin J. Cocciolone ◽  
Jesse D. Procknow ◽  
Jungsil Kim ◽  
Jessica E. Wagenseil
Keyword(s):  
Developmental Stage ◽  
Lysyl Oxidase ◽  
Elastic Fiber ◽  
Gene Array ◽  
Aortic Aneurysms ◽  
Elastic Fibers ◽  
Newborn Mouse ◽  
Newborn Mice ◽  
Mouse Aorta ◽  
Array Analyses

Elastic fibers provide reversible elasticity to the large arteries and are assembled during development when hemodynamic forces are increasing. Mutations in elastic fiber genes are associated with cardiovascular disease. Mice lacking expression of the elastic fiber genes elastin ( Eln−/−), fibulin-4 ( Efemp2−/−), or lysyl oxidase ( Lox−/−) die at birth with severe cardiovascular malformations. All three genetic knockout models have elastic fiber defects, aortic wall thickening, and arterial tortuosity. However, Eln−/− mice develop arterial stenoses, while Efemp2−/− and Lox−/− mice develop ascending aortic aneurysms. We performed comparative gene array analyses of these three genetic models for two vascular locations and developmental stages to determine differentially expressed genes and pathways that may explain the common and divergent phenotypes. We first examined arterial morphology and wall structure in newborn mice to confirm that the lack of elastin, fibulin-4, or lysyl oxidase expression provided the expected phenotypes. We then compared gene expression levels for each genetic model by three-way ANOVA for genotype, vascular location, and developmental stage. We found three genes upregulated by genotype in all three models, Col8a1, Igfbp2, and Thbs1, indicative of a common response to severe elastic fiber defects in developing mouse aorta. Genes that are differentially regulated by vascular location or developmental stage in all three models suggest mechanisms for location or stage-specific disease pathology. Comparison of signaling pathways enriched in all three models shows upregulation of integrins and matrix proteins involved in early wound healing, but not of mature matrix molecules such as elastic fiber proteins or fibrillar collagens.

scholarly journals Enhancement of elastin expression by transdermal administration of sialidase isozyme Neu2

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Akira Minami ◽  
Yuka Fujita ◽  
Jun Goto ◽  
Ayano Iuchi ◽  
Kosei Fujita ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Skin Diseases ◽  
Lower Layer ◽  
Elastic Fiber ◽  
Sialic Acid Residue ◽  
Elastic Fibers ◽  
Transdermal Administration ◽  
Sialidase Activity ◽  
Fiber Assembly ◽  
Senescence Accelerated Mice

AbstractReduction of elastin in the skin causes various skin diseases as well as wrinkles and sagging with aging. Sialidase is a hydrolase that cleaves a sialic acid residue from sialoglycoconjugate. Cleavage of sialic acid from microfibrils by the sialidase isozyme Neu1 facilitates elastic fiber assembly. In the present study, we showed that a lower layer of the dermis and muscle showed relatively intense sialidase activity. The sialidase activity in the skin decreased with aging. Choline and geranate (CAGE), one of the ionic liquids, can deliver the sialidase subcutaneously while maintaining the enzymatic activity. The elastin level in the dermis was increased by applying sialidase from Arthrobacter ureafaciens (AUSA) with CAGE on the skin for 5 days in rats and senescence-accelerated mice prone 1 and 8. Sialidase activity in the dermis was considered to be mainly due to Neu2 based on the expression level of sialidase isozyme mRNA. Transdermal administration of Neu2 with CAGE also increased the level of elastin in the dermis. Therefore, not only Neu1 but also Neu2 would be involved in elastic fiber assembly. Transdermal administration of sialidase is expected to be useful for improvement of wrinkles and skin disorders due to the loss of elastic fibers.

scholarly journals Clinical Relevance of Elastin in the Structure and Function of Skin

2021 ◽  
Author(s):  
Leslie Baumann ◽  
Eric F Bernstein ◽  
Anthony S Weiss ◽  
Damien Bates ◽  
Shannon Humphrey ◽  
...  
Keyword(s):  
Wound Healing ◽  
Clinical Relevance ◽  
Structural Integrity ◽  
Elastic Fiber ◽  
Subcutaneous Fat ◽  
Structure And Function ◽  
Fiber Formation ◽  
Elastic Fibers ◽  
Superficial Dermis ◽  
And Function

Abstract Elastin is the main component of elastic fibers, which provide stretch, recoil, and elasticity to the skin. Normal levels of elastic fiber production, organization, and integration with other cutaneous extracellular matrix proteins, proteoglycans, and glycosaminoglycans are integral to maintaining healthy skin structure, function, and youthful appearance. Although elastin has very low turnover, its production decreases after individuals reach maturity and it is susceptible to damage from many factors. With advancing age and exposure to environmental insults, elastic fibers degrade. This degradation contributes to the loss of the skin’s structural integrity; combined with subcutaneous fat loss, this results in looser, sagging skin, causing undesirable changes in appearance. The most dramatic changes occur in chronically sun-exposed skin, which displays sharply altered amounts and arrangements of cutaneous elastic fibers, decreased fine elastic fibers in the superficial dermis connecting to the epidermis, and replacement of the normal collagen-rich superficial dermis with abnormal clumps of solar elastosis material. Disruption of elastic fiber networks also leads to undesirable characteristics in wound healing, and the worsening structure and appearance of scars and stretch marks. Identifying ways to replenish elastin and elastic fibers should improve the skin’s appearance, texture, resiliency, and wound-healing capabilities. However, few therapies are capable of repairing elastic fibers or substantially reorganizing the elastin/microfibril network. This review describes the clinical relevance of elastin in the context of the structure and function of healthy and aging skin, wound healing, and scars and introduces new approaches being developed to target elastin production and elastic fiber formation.

scholarly journals Lysyl oxidase activity and elastin/glycosaminoglycan interactions in growing chick and rat aortas.

1987 ◽  
Vol 105 (3) ◽  
pp. 1463-1469 ◽  
Author(s):  
C Fornieri ◽  
M Baccarani-Contri ◽  
D Quaglino ◽  
I Pasquali-Ronchetti
Keyword(s):  
Hydrophobic Interactions ◽  
Isonicotinic Acid ◽  
Lysyl Oxidase ◽  
Acid Hydrazide ◽  
Elastic Fibers ◽  
Amino Groups ◽  
Lysine Residues ◽  
Oxidase Inhibition

Hydrophobic tropoelastin molecules aggregate in vitro in physiological conditions and form fibers very similar to natural ones (Bressan, G. M., I. Pasquali Ronchetti, C. Fornieri, F. Mattioli, I. Castellani, and D. Volpin, 1986, J. Ultrastruct. Molec. Struct. Res., 94:209-216). Similar hydrophobic interactions might be operative in in vivo fibrogenesis. Data are presented suggesting that matrix glycosaminoglycans (GAGs) prevent spontaneous tropoelastin aggregation in vivo, at least up to the deamination of lysine residues on tropoelastin by matrix lysyl oxidase. Lysyl oxidase inhibitors beta-aminopropionitrile, aminoacetonitrile, semicarbazide, and isonicotinic acid hydrazide were given to newborn chicks, to chick embryos, and to newborn rats, and the ultrastructural alterations of the aortic elastic fibers were analyzed and compared with the extent of the enzyme inhibition. When inhibition was greater than 65% all chemicals induced alterations of elastic fibers in the form of lateral aggregates of elastin, which were always permeated by cytochemically and immunologically recognizable GAGs. The number and size of the abnormal elastin/GAGs aggregates were proportional to the extent of lysyl oxidase inhibition. The phenomenon was independent of the animal species. All data suggest that, upon inhibition of lysyl oxidase, matrix GAGs remain among elastin molecules during fibrogenesis by binding to positively charged amino groups on elastin. Newly synthesized and secreted tropoelastin has the highest number of free epsilon amino groups, and, therefore, the highest capability of binding to GAGs. These polyanions, by virtue of their great hydration and dispersing power, could prevent random spontaneous aggregation of hydrophobic tropoelastin in the extracellular space.

scholarly journals Collagen and Elastic Fiber Content Correlation Analysis between Horizontal and Vertical Orientations of Skin Samples of Human Body

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Naveen Kumar ◽  
Pramod Kumar ◽  
Satheesha Nayak Badagabettu ◽  
Ranjini Kudva ◽  
Sudarshan Surendran ◽  
...  
Keyword(s):  
Abdominal Wall ◽  
Negative Correlation ◽  
Anterior Abdominal Wall ◽  
Elastic Fiber ◽  
Elastic Fibers ◽  
Correlation Pattern ◽  
Unequal Distribution ◽  
Dermal Collagen ◽  
Lateral Chest ◽  
Skin Samples

Background. Unequal distribution of dermal collagen and elastic fibers in different orientations of skin is reported to be one of the multifocal causes of scar related complications. Present study is to understand the correlation pattern between collagen in horizontal (CH) and in vertical (CV) directions as well as that of elastic in horizontal (EH) and vertical (EV) directions.Materials and Method. A total of 320 skin samples were collected in two orientations from suprascapular, anterior chest, lateral chest, anterior abdominal wall, and inguinal regions of 32 human cadavers. Spearman correlation coefficient (r) was calculated between the variables (CH,CV,EH, andEV).Results. Significant positive correlation betweenCHandCV, and betweenEHandEVobserved in all 5 areas tested. A negative correlation betweenCVandEVat suprascapular, lateral chest, and inguinal regions and negative correlation betweenCHandEHat anterior chest and anterior abdominal wall have been identified.Conclusion. Knowledge of asymmetric content of dermal collagen and elastic fibers together with the varied strength and degree of association in the given area provides guidelines to the dermatologists and aesthetic surgeons in placing elective incisions in the direction maximally utilizing the anatomical facts for aesthetically pleasing result.

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