Developmental expression of fibrillin genes suggests heterogeneity of extracellular microfibrils.

Extracellular microfibrils, alone or in association with elastin, confer critical biomechanical properties on a variety of connective tissues. Little is known about the composition of the microfibrils or the factors responsible for their spatial organization into tissue-specific macroaggregates. Recent work has revealed the existence of two structurally related microfibrillar components, termed fibrillin-1 and fibrillin-2. The functional relationships between these glycoproteins and between them and other components of the microfibrils and elastic fibers are obscure. As a first step toward elucidating these important points, we compared the expression pattern of the fibrillin genes during mammalian embryogenesis. The results revealed that the two genes are differentially expressed, in terms of both developmental stages and tissue distribution. In the majority of cases, fibrillin-2 transcripts appear earlier and accumulate for a shorter period of time than fibrillin-1 transcripts. Synthesis of fibrillin-1 correlates with late morphogenesis and the appearance of well-defined organ structures; fibrillin-2 synthesis, on the other hand, coincides with early morphogenesis and, in particular, with the beginning of elastogenesis. The findings lend indirect support to our original hypothesis stating that fibrillins contribute to the compositional and functional heterogeneity of the microfibrils. The available evidence is also consistent with the notion that the fibrillins might have distinct, but related roles in microfibril physiology. Accordingly, we propose that fibrillin-1 provides mostly force-bearing structural support, whereas fibrillin-2 predominantly regulates the early process of elastic fiber assembly.

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Molecular Analysis of Fibulin-5 Function during De Novo Synthesis of Elastic Fibers

Molecular and Cellular Biology ◽

10.1128/mcb.01330-06 ◽

2007 ◽

Vol 27 (3) ◽

pp. 1083-1095 ◽

Cited By ~ 41

Author(s):

Qian Zheng ◽

Elaine C. Davis ◽

James A. Richardson ◽

Barry C. Starcher ◽

Tiansen Li ◽

...

Keyword(s):

Calcium Binding ◽

De Novo ◽

Elastic Fiber ◽

Elastic Fibers ◽

Cellular Behavior ◽

Fiber Assembly ◽

Structural Support ◽

The Matrix ◽

Epidermal Growth

ABSTRACT Elastic fibers contribute to the structural support of tissues and to the regulation of cellular behavior. Mice deficient for the fibulin-5 gene (fbln5 − / −) were used to further elucidate the molecular mechanism of elastic fiber assembly. Major elastic fiber components were present in the skin of fbln5 − / − mice despite a dramatic reduction of mature elastic fibers. We found that fibulin-5 preferentially bound the monomeric form of elastin through N-terminal and C-terminal elastin-binding regions and to a preexisting matrix scaffold through calcium-binding epidermal growth factor (EGF)-like (CB-EGF) domains. We further showed that adenovirus-mediated gene transfer of fbln5 was sufficient to regenerate elastic fibers and increase elastic fiber-cell connections in vivo. A mutant fibulin-5 lacking the first 28 amino acids of the first CB-EGF domain, however, was unable to rescue elastic fiber defects. Fibulin-5 thus serves as an adaptor molecule between monomeric elastin and the matrix scaffold to aid in elastic fiber assembly. These results also support the potential use of fibulin-5 as a therapeutic agent for the treatment of elastinopathies.

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Enhancement of elastin expression by transdermal administration of sialidase isozyme Neu2

Scientific Reports ◽

10.1038/s41598-021-82820-1 ◽

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.

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Recent updates on the molecular network of elastic fiber formation

Essays in Biochemistry ◽

10.1042/ebc20180052 ◽

2019 ◽

Vol 63 (3) ◽

pp. 365-376 ◽

Cited By ~ 4

Author(s):

Seung Jae Shin ◽

Hiromi Yanagisawa

Keyword(s):

Elastic Fiber ◽

Building Blocks ◽

Fiber Formation ◽

Elastic Fibers ◽

Fiber Network ◽

Associated Proteins ◽

Fibrillin 1 ◽

A Cell ◽

Self Aggregation

Abstract Elastic fibers confer elasticity and recoiling to tissues and organs and play an essential role in induction of biochemical responses in a cell against mechanical forces derived from the microenvironment. The core component of elastic fibers is elastin (ELN), which is secreted as the monomer tropoelastin from elastogenic cells, and undergoes self-aggregation, cross-linking and deposition on to microfibrils, and assemble into insoluble ELN polymers. For elastic fibers to form, a microfibril scaffold (primarily formed by fibrillin-1 (FBN1)) is required. Numerous elastic fiber-associated proteins are involved in each step of elastogenesis and they instruct and/or facilitate the elastogenesis processes. In this review, we designated five proteins as key molecules in elastic fiber formation, including ELN, FBN1, fibulin-4 (FBLN4), fibulin-5 (FBLN5), and latent TGFβ-binding protein-4 (LTBP4). ELN and FBN1 serve as building blocks for elastic fibers. FBLN5, FBLN4 and LTBP4 have been demonstrated to play crucial roles in elastogenesis through knockout studies in mice. Using these molecules as a platform and expanding the elastic fiber network through the generation of an interactome map, we provide a concise review of elastogenesis with a recent update as well as discuss various biological functions of elastic fiber-associated proteins beyond elastogenesis in vivo.

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Effect of vaginal distention on elastic fiber synthesis and matrix degradation in the vaginal wall: potential role in the pathogenesis of pelvic organ prolapse

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90447.2008 ◽

2008 ◽

Vol 295 (4) ◽

pp. R1351-R1358 ◽

Cited By ~ 28

Author(s):

D. D. Rahn ◽

J. F. Acevedo ◽

R. A. Word

Keyword(s):

Pelvic Organ Prolapse ◽

Protease Activity ◽

Potential Role ◽

Elastic Fiber ◽

Pelvic Organ ◽

Vaginal Wall ◽

Elastic Fibers ◽

Wild Type ◽

Fiber Assembly ◽

Pregnant Mice

Matrix metalloprotease (MMP) activity is increased in the postpartum vagina of wild-type (WT) animals. This degradative activity is also accompanied by a burst in elastic fiber synthesis and assembly. The mechanisms that precipitate these changes are unclear. The goals of this study were to determine how vaginal distention (such as in parturition) affects elastic fiber homeostasis in the vaginal wall and the potential significance of these changes in the pathogenesis of pelvic organ prolapse. Vaginal distention with a balloon simulating parturition resulted in increased MMP-2 and MMP-9 activity in the vaginal wall of nonpregnant and pregnant animals. This was accompanied by visible fragmented and disrupted elastic fibers in the vaginal wall. In nonpregnant animals, the abundant amounts of tropoelastin and fibulin-5 in the vagina were not increased further by distention. In contrast, in pregnant animals, the suppressed levels of both proteins were increased 3-fold after vaginal distention. Distention performed in fibulin-5-deficient ( Fbln5−/−) mice with defective elastic fiber synthesis and assembly induced accelerated pelvic organ prolapse, which never recovered. We conclude that, in pregnant mice, vaginal distention results in increased protease activity in the vaginal wall but also increased synthesis of proteins important for elastic fiber assembly. Distention may thereby contribute to the burst of elastic fiber synthesis in the postpartum vagina. The finding that distention results in accelerated pelvic organ prolapse in Fbln5−/− animals, but not in WT, indicates that elastic fiber synthesis is crucial for recovery of the vaginal wall from distention-induced increases in vaginal protease activity.

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Interaction of Tropoelastin with the Amino-terminal Domains of Fibrillin-1 and Fibrillin-2 Suggests a Role for the Fibrillins in Elastic Fiber Assembly

Journal of Biological Chemistry ◽

10.1074/jbc.m003665200 ◽

2000 ◽

Vol 275 (32) ◽

pp. 24400-24406 ◽

Cited By ~ 95

Author(s):

Timothy M. Trask ◽

Barbara Crippes Trask ◽

Timothy M. Ritty ◽

William R. Abrams ◽

Joel Rosenbloom ◽

...

Keyword(s):

Elastic Fiber ◽

Fiber Assembly ◽

Amino Terminal ◽

Fibrillin 1 ◽

Terminal Domains

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Progressive Microstructural Deterioration Dictates Evolving Biomechanical Dysfunction in the Marfan Aorta

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.800730 ◽

2021 ◽

Vol 8 ◽

Author(s):

Cristina Cavinato ◽

Minghao Chen ◽

Dar Weiss ◽

Maria Jesús Ruiz-Rodríguez ◽

Martin A. Schwartz ◽

...

Keyword(s):

Structural Integrity ◽

Ex Vivo ◽

Elastic Fiber ◽

Three Dimensional ◽

Microstructural Characterization ◽

Aortic Aneurysms ◽

Elastic Fibers ◽

Cell Phenotype ◽

Medial Degeneration ◽

Fibrillin 1

Medial deterioration leading to thoracic aortic aneurysms arises from multiple causes, chief among them mutations to the gene that encodes fibrillin-1 and leads to Marfan syndrome. Fibrillin-1 microfibrils associate with elastin to form elastic fibers, which are essential structural, functional, and instructional components of the normal aortic wall. Compromised elastic fibers adversely impact overall structural integrity and alter smooth muscle cell phenotype. Despite significant progress in characterizing clinical, histopathological, and mechanical aspects of fibrillin-1 related aortopathies, a direct correlation between the progression of microstructural defects and the associated mechanical properties that dictate aortic functionality remains wanting. In this paper, age-matched wild-type, Fbn1C1041G/+, and Fbn1mgR/mgR mouse models were selected to represent three stages of increasing severity of the Marfan aortic phenotype. Ex vivo multiphoton imaging and biaxial mechanical testing of the ascending and descending thoracic aorta under physiological loading conditions demonstrated that elastic fiber defects, collagen fiber remodeling, and cell reorganization increase with increasing dilatation. Three-dimensional microstructural characterization further revealed radial patterns of medial degeneration that become more uniform with increasing dilatation while correlating strongly with increased circumferential material stiffness and decreased elastic energy storage, both of which comprise aortic functionality.

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Pigmentation Affects Elastic Fiber Patterning and Biomechanical Behavior of the Murine Aortic Valve

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.754560 ◽

2021 ◽

Vol 8 ◽

Author(s):

Sana Nasim ◽

Popular Pandey ◽

Rosemeire M. Kanashiro-Takeuchi ◽

Jin He ◽

Joshua D. Hutcheson ◽

...

Keyword(s):

Aortic Valve ◽

Elastic Fiber ◽

Biomechanical Properties ◽

Systemic Circulation ◽

Elastic Fibers ◽

Multiphoton Imaging ◽

Force Microscopy ◽

Biomechanical Behavior ◽

Atomic Force ◽

Fiber Organization

The aortic valve (AoV) maintains unidirectional blood distribution from the left ventricle of the heart to the aorta for systemic circulation. The AoV leaflets rely on a precise extracellular matrix microarchitecture of collagen, elastin, and proteoglycans for appropriate biomechanical performance. We have previously demonstrated a relationship between the presence of pigment in the mouse AoV with elastic fiber patterning using multiphoton imaging. Here, we extended those findings using wholemount confocal microscopy revealing that elastic fibers were diminished in the AoV of hypopigmented mice (KitWv and albino) and were disorganized in the AoV of K5-Edn3 transgenic hyperpigmented mice when compared to wild type C57BL/6J mice. We further used atomic force microscopy to measure stiffness differences in the wholemount AoV leaflets of mice with different levels of pigmentation. We show that AoV leaflets of K5-Edn3 had overall higher stiffness (4.42 ± 0.35 kPa) when compared to those from KitWv (2.22 ± 0.21 kPa), albino (2.45 ± 0.16 kPa), and C57BL/6J (3.0 ± 0.16 kPa) mice. Despite the striking elastic fiber phenotype and noted stiffness differences, adult mutant mice were found to have no overt cardiac differences as measured by echocardiography. Our results indicate that pigmentation, but not melanocytes, is required for proper elastic fiber organization in the mouse AoV and dictates its biomechanical properties.

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Elastin, arterial mechanics, and cardiovascular disease

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00087.2018 ◽

2018 ◽

Vol 315 (2) ◽

pp. H189-H205 ◽

Cited By ~ 32

Author(s):

Austin J. Cocciolone ◽

Jie Z. Hawes ◽

Marius C. Staiculescu ◽

Elizabeth O. Johnson ◽

Monzur Murshed ◽

...

Keyword(s):

Cardiovascular Disease ◽

Aortic Stenosis ◽

Autosomal Dominant ◽

Elastic Fiber ◽

Cutis Laxa ◽

Supravalvular Aortic Stenosis ◽

Elastic Fibers ◽

Arterial Mechanics ◽

Fiber Assembly

Large, elastic arteries are composed of cells and a specialized extracellular matrix that provides reversible elasticity and strength. Elastin is the matrix protein responsible for this reversible elasticity that reduces the workload on the heart and dampens pulsatile flow in distal arteries. Here, we summarize the elastin protein biochemistry, self-association behavior, cross-linking process, and multistep elastic fiber assembly that provide large arteries with their unique mechanical properties. We present measures of passive arterial mechanics that depend on elastic fiber amounts and integrity such as the Windkessel effect, structural and material stiffness, and energy storage. We discuss supravalvular aortic stenosis and autosomal dominant cutis laxa-1, which are genetic disorders caused by mutations in the elastin gene. We present mouse models of supravalvular aortic stenosis, autosomal dominant cutis laxa-1, and graded elastin amounts that have been invaluable for understanding the role of elastin in arterial mechanics and cardiovascular disease. We summarize acquired diseases associated with elastic fiber defects, including hypertension and arterial stiffness, diabetes, obesity, atherosclerosis, calcification, and aneurysms and dissections. We mention animal models that have helped delineate the role of elastic fiber defects in these acquired diseases. We briefly summarize challenges and recent advances in generating functional elastic fibers in tissue-engineered arteries. We conclude with suggestions for future research and opportunities for therapeutic intervention in genetic and acquired elastinopathies.

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