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Development, Aging and Repair of Elastic Fibers

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Macromolecules".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 34334

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Prof. Dr. Gilles Faury

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Université Grenoble Alpes, INSERM U1300, CHU Grenoble Alpes, Laboratoire HP2, 38042 Grenoble, France
Interests: cardiovascular physiology; elastic fibers in vascular development, genetic diseases and aging; intermittent hypoxia-induced cardiovascular dysfunction; biomechanics; elastin receptors; calcium signalling; pharmacotherapy
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Dear Colleagues,

Elastic fibers, made from elastin (90%) and microfibrillar components (10%), are the extracellular matrix structures endowing extensible tissues with elasticity in vertebrates. They are therefore essential for the physiology of organs whose proper function is closely related to their mechanical properties, such as skin, lungs and blood vessels. Besides, elastic fibers or their degradation products exert an important signalling role -through several membrane receptors- for many cell types, not only from extensible tissues, regulating multiple functions including proliferation, secretion, adhesion, contraction, …. Elastin is expressed, with possible alternative splicing, and elastic fibers are assembled during the end of gestation and childhood only. The adults then live with an elastic fiber stock that is progressively degraded or modified with age or disease, due to mechanical stretch and/or enzymatic/non-enzymatic chemical modifications. Because elastic fibers are essential for the function of several vital organs, developmental genetic disorders (Williams syndrome, Marfan syndrome, Cutis laxa, ...), later diseases (aneurysms, …) and aging processes involving elastic fibers abnormality or degradation lead to severe disease/dysfunction and ultimately death. There is therefore a strong need for: (i) a better understanding of the -normal or abnormal- synthesis and degradation processes of elastic fibers, and (ii) innovative treatments allowing for either improvement of natural elastic fiber component synthesis/assembly, or abnormal/dysfunctional elastic fiber repair or replacement. All the researchers working in these fields are warmly invited to submit their latest results or analyses. Experimental papers and review articles about molecular research in the basic science, clinical or translational fields are welcome.

Dr. Gilles Faury
Guest Editor

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Keywords

elastic fibers
elastin
microfibrils
tissue mechanics
cell signaling regulation
development
genetic disease
aging
regenerative medicine
biomaterials

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Published Papers (10 papers)

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Research

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29 pages, 5007 KiB

Open AccessArticle

Physiological Impact of a Synthetic Elastic Protein in Arterial Diseases Related to Alterations of Elastic Fibers: Effect on the Aorta of Elastin-Haploinsufficient Male and Female Mice

by Quentin Boëté, Ming Lo, Kiao-Ling Liu, Guillaume Vial, Emeline Lemarié, Maxime Rougelot, Iris Steuckardt, Olfa Harki, Axel Couturier, Jonathan Gaucher, Sophie Bouyon, Alexandra Demory, Antoine Boutin-Paradis, Naima El Kholti, Aurore Berthier, Jean-Louis Pépin, Anne Briançon-Marjollet, Elise Lambert, Romain Debret and Gilles Faury

Int. J. Mol. Sci. 2022, 23(21), 13464; https://doi.org/10.3390/ijms232113464 - 3 Nov 2022

Viewed by 2595

Abstract

Elastic fibers, made of elastin (90%) and fibrillin-rich microfibrils (10%), are the key extracellular components, which endow the arteries with elasticity. The alteration of elastic fibers leads to cardiovascular dysfunctions, as observed in elastin haploinsufficiency in mice (Eln^+/-) or humans (supravalvular aortic stenosis or Williams–Beuren syndrome). In Eln^+/+ and Eln^+/- mice, we evaluated (arteriography, histology, qPCR, Western blots and cell cultures) the beneficial impact of treatment with a synthetic elastic protein (SEP), mimicking several domains of tropoelastin, the precursor of elastin, including hydrophobic elasticity-related domains and binding sites for elastin receptors. In the aorta or cultured aortic smooth muscle cells from these animals, SEP treatment induced a synthesis of elastin and fibrillin-1, a thickening of the aortic elastic lamellae, a decrease in wall stiffness and/or a strong trend toward a reduction in the elastic lamella disruptions in Eln^+/- mice. SEP also modified collagen conformation and transcript expressions, enhanced the aorta constrictive response to phenylephrine in several animal groups, and, in female Eln^+/- mice, it restored the normal vasodilatory response to acetylcholine. SEP should now be considered as a biomimetic molecule with an interesting potential for future treatments of elastin-deficient patients with altered arterial structure/function. Full article

(This article belongs to the Special Issue Development, Aging and Repair of Elastic Fibers)

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16 pages, 2591 KiB

Open AccessArticle

Inhibition of Vascular Endothelial Cadherin Cleavage Prevents Elastic Fiber Alterations and Atherosclerosis Induced by Intermittent Hypoxia in the Mouse Aorta

by Olfa Harki, Sophie Bouyon, Marine Sallé, Alejandro Arco-Hierves, Emeline Lemarié, Alexandra Demory, Carole Chirica, Isabelle Vilgrain, Jean-Louis Pépin, Gilles Faury and Anne Briançon-Marjollet

Int. J. Mol. Sci. 2022, 23(13), 7012; https://doi.org/10.3390/ijms23137012 - 24 Jun 2022

Cited by 5 | Viewed by 2545

Abstract

Intermittent hypoxia (IH), the major feature of obstructive sleep apnea syndrome (OSAS), induces atherosclerosis and elastic fiber alterations. VE-cadherin cleavage is increased in OSAS patients and in an IH-cellular model. It is mediated by HIF-1 and Src-tyr-kinases pathways and results in endothelial hyperpermeability. Our aim was to determine whether blocking VE-cadherin cleavage in vivo could be an efficient strategy to inhibit deleterious IH-induced vascular remodeling, elastic fiber defects and atherogenesis. VE-cadherin regulation, aortic remodeling and atherosclerosis were studied in IH-exposed C57Bl/6J or ApoE-/-mice treated or not with Src-tyr-kinases inhibitors (Saracatinib/Pazopanib) or a HIF-1 inhibitor (Acriflavine). Human aortic endothelial cells were exposed to IH and treated with the same inhibitors. LDL and the monocytes transendothelium passage were measured. In vitro, IH increased transendothelium LDL and monocytes passage, and the tested inhibitors prevented these effects. In mice, IH decreased VE-cadherin expression and increased plasmatic sVE level, intima-media thickness, elastic fiber alterations and atherosclerosis, while the inhibitors prevented these in vivo effects. In vivo inhibition of HIF-1 and Src tyr kinase pathways were associated with the prevention of IH-induced elastic fiber/lamella degradation and atherogenesis, which suggests that VE-cadherin could be an important target to limit atherogenesis and progression of arterial stiffness in OSAS. Full article

(This article belongs to the Special Issue Development, Aging and Repair of Elastic Fibers)

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22 pages, 5066 KiB

Open AccessArticle

Copper-Binding Domain Variation in a Novel Murine Lysyl Oxidase Model Produces Structurally Inferior Aortic Elastic Fibers Whose Failure Is Modified by Age, Sex, and Blood Pressure

by Kit Man Tsang, Russell H. Knutsen, Charles J. Billington, Jr., Eric Lindberg, Heiko Steenbock, Yi-Ping Fu, Amanda Wardlaw-Pickett, Delong Liu, Daniela Malide, Zu-Xi Yu, Christopher K. E. Bleck, Jürgen Brinckmann and Beth A. Kozel

Int. J. Mol. Sci. 2022, 23(12), 6749; https://doi.org/10.3390/ijms23126749 - 17 Jun 2022

Cited by 5 | Viewed by 2630

Abstract

Lysyl oxidase (LOX) is a copper-binding enzyme that cross-links elastin and collagen. The dominant LOX variation contributes to familial thoracic aortic aneurysm. Previously reported murine Lox mutants had a mild phenotype and did not dilate without drug-induced provocation. Here, we present a new, more severe mutant, Lox^b^2b370.2Clo (c.G854T; p.Cys285Phe), whose mutation falls just N-terminal to the copper-binding domain. Unlike the other mutants, the C285F Lox protein was stably produced/secreted, and male C57Bl/6J Lox^+/^C285F mice exhibit increased systolic blood pressure (BP; p < 0.05) and reduced caliber aortas (p < 0.01 at 100mmHg) at 3 months that independently dilate by 6 months (p < 0.0001). Multimodal imaging reveals markedly irregular elastic sheets in the mutant (p = 2.8 × 10⁻⁸ for breaks by histology) that become increasingly disrupted with age (p < 0.05) and breeding into a high BP background (p = 6.8 × 10⁻⁴). Aortic dilation was amplified in males vs. females (p < 0.0001 at 100mmHg) and ameliorated by castration. The transcriptome of young Lox mutants showed alteration in dexamethasone (p = 9.83 × 10⁻³⁰) and TGFβ-responsive genes (p = 7.42 × 10⁻²⁹), and aortas from older C57Bl/6J Lox^+/^C285F mice showed both enhanced susceptibility to elastase (p < 0.01 by ANOVA) and increased deposition of aggrecan (p < 0.05). These findings suggest that the secreted Lox^+/^C285F mutants produce dysfunctional elastic fibers that show increased susceptibility to proteolytic damage. Over time, the progressive weakening of the connective tissue, modified by sex and blood pressure, leads to worsening aortic disease. Full article

(This article belongs to the Special Issue Development, Aging and Repair of Elastic Fibers)

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11 pages, 2469 KiB

Open AccessArticle

Early Alterations of Intra-Mural Elastic Lamellae Revealed by Synchrotron X-ray Micro-CT Exploration of Diabetic Aortas

by Aïcha Ben Zemzem, Xiaowen Liang, Laetitia Vanalderwiert, Camille Bour, Béatrice Romier-Crouzet, Sébastien Blaise, Michael J. Sherratt, Timm Weitkamp, Manuel Dauchez, Stéphanie Baud, Nicolas Passat, Laurent Debelle and Sébastien Almagro

Int. J. Mol. Sci. 2022, 23(6), 3250; https://doi.org/10.3390/ijms23063250 - 17 Mar 2022

Cited by 4 | Viewed by 2587

Abstract

Diabetes is a major concern of our society as it affects one person out of 11 around the world. Elastic fiber alterations due to diabetes increase the stiffness of large arteries, but the structural effects of these alterations are poorly known. To address this issue, we used synchrotron X-ray microcomputed tomography with in-line phase contrast to image in three dimensions C57Bl6J (control) and db/db (diabetic) mice with a resolution of 650 nm/voxel and a field size of 1.3 mm³. Having previously shown in younger WT and db/db mouse cohorts that elastic lamellae contain an internal supporting lattice, here we show that in older db/db mice the elastic lamellae lose this scaffold. We coupled this label-free method with automated image analysis to demonstrate that the elastic lamellae from the arterial wall are structurally altered and become 11% smoother (286,665 measurements). This alteration suggests a link between the loss of the 3D lattice-like network and the waviness of the elastic lamellae. Therefore, waviness measurement appears to be a measurable elasticity indicator and the 3D lattice-like network appears to be at the origin of the existence of this waviness. Both could be suitable indicators of the overall elasticity of the aorta. Full article

(This article belongs to the Special Issue Development, Aging and Repair of Elastic Fibers)

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14 pages, 3411 KiB

Open AccessArticle

FBN2 Silencing Recapitulates Hypoxic Conditions and Induces Elastic Fiber Impairment in Human Dermal Fibroblasts

by Jérémy Boizot, Mélaine Minville-Walz, Dieter Peter Reinhardt, Marielle Bouschbacher, Pascal Sommer, Dominique Sigaudo-Roussel and Romain Debret

Int. J. Mol. Sci. 2022, 23(3), 1824; https://doi.org/10.3390/ijms23031824 - 5 Feb 2022

Cited by 7 | Viewed by 2409

Abstract

Most chronic wounds are characterized by varying degrees of hypoxia and low partial pressures of O₂ that may favor the development of the wound and/or delay healing. However, most studies regarding extracellular matrix remodeling in wound healing are conducted under normoxic conditions. Here, we investigated the consequences of hypoxia on elastic network formation, both in a mouse model of pressure-induced hypoxic ulcer and in human primary fibroblasts cultured under hypoxic conditions. In vitro, hypoxia inhibited elastic fiber synthesis with a reduction in fibrillin-2 expression at the mRNA and protein levels. Lysyl oxidase maturation was reduced, concomitant with lower enzymatic activity. Fibrillin-2 and lysyl oxidase could interact directly, whereas the downregulation of fibrillin-2 was associated with deficient lysyl oxidase maturation. Elastic fibers were not synthesized in the hypoxic inflammatory tissues resulting from in vivo pressure-induced ulcer. Tropoelastin and fibrillin-2 were expressed sparsely in hypoxic tissues stained with carbonic anhydrase IX. Different hypoxic conditions in culture resulted in the arrest of elastic fiber synthesis. The present study demonstrated the involvement of FBN2 in regulating elastin deposition in adult skin models and described the specific impact of hypoxia on the elastin network without consequences on collagen and fibronectin networks. Full article

(This article belongs to the Special Issue Development, Aging and Repair of Elastic Fibers)

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17 pages, 2637 KiB

Open AccessArticle

Multi-Omics Profiling in Marfan Syndrome: Further Insights into the Molecular Mechanisms Involved in Aortic Disease

by Judith M. A. Verhagen, Joyce Burger, Jos A. Bekkers, Alexander T. den Dekker, Jan H. von der Thüsen, Marina Zajec, Hennie T. Brüggenwirth, Marianne L. T. van der Sterre, Myrthe van den Born, Theo M. Luider, Wilfred F. J. van IJcken, Marja W. Wessels, Jeroen Essers, Jolien W. Roos-Hesselink, Ingrid van der Pluijm, Ingrid M. B. H. van de Laar and Erwin Brosens

Int. J. Mol. Sci. 2022, 23(1), 438; https://doi.org/10.3390/ijms23010438 - 31 Dec 2021

Cited by 12 | Viewed by 3611

Abstract

Thoracic aortic aneurysm is a potentially life-threatening disease with a strong genetic contribution. Despite identification of multiple genes involved in aneurysm formation, little is known about the specific underlying mechanisms that drive the pathological changes in the aortic wall. The aim of our study was to unravel the molecular mechanisms underlying aneurysm formation in Marfan syndrome (MFS). We collected aortic wall samples from FBN1 variant-positive MFS patients (n = 6) and healthy donor hearts (n = 5). Messenger RNA (mRNA) expression levels were measured by RNA sequencing and compared between MFS patients and controls, and between haploinsufficient (HI) and dominant negative (DN) FBN1 variants. Immunohistochemical staining, proteomics and cellular respiration experiments were used to confirm our findings. FBN1 mRNA expression levels were highly variable in MFS patients and did not significantly differ from controls. Moreover, we did not identify a distinctive TGF-β gene expression signature in MFS patients. On the contrary, differential gene and protein expression analysis, as well as vascular smooth muscle cell respiration measurements, pointed toward inflammation and mitochondrial dysfunction. Our findings confirm that inflammatory and mitochondrial pathways play important roles in the pathophysiological processes underlying MFS-related aortic disease, providing new therapeutic options. Full article

(This article belongs to the Special Issue Development, Aging and Repair of Elastic Fibers)

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Review

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14 pages, 2029 KiB

Open AccessReview

Elastic Fibre Proteins in Elastogenesis and Wound Healing

by Xinyang Zhang, Yasmene F. Alanazi, Thomas A. Jowitt, Alan M. Roseman and Clair Baldock

Int. J. Mol. Sci. 2022, 23(8), 4087; https://doi.org/10.3390/ijms23084087 - 7 Apr 2022

Cited by 17 | Viewed by 3754

Abstract

As essential components of our connective tissues, elastic fibres give tissues such as major blood vessels, skin and the lungs their elasticity. Their formation is complex and co-ordinately regulated by multiple factors. In this review, we describe key players in elastogenesis: fibrillin-1, tropoelastin, latent TGFβ binding protein-4, and fibulin-4 and -5. We summarise their roles in elastogenesis, discuss the effect of their mutations on relevant diseases, and describe their interactions involved in forming the elastic fibre network. Moreover, we look into their roles in wound repair for a better understanding of their potential application in tissue regeneration. Full article

(This article belongs to the Special Issue Development, Aging and Repair of Elastic Fibers)

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22 pages, 2098 KiB

Open AccessReview

Zebrafish as a Model to Study Vascular Elastic Fibers and Associated Pathologies

by Marie Hoareau, Naïma El Kholti, Romain Debret and Elise Lambert

Int. J. Mol. Sci. 2022, 23(4), 2102; https://doi.org/10.3390/ijms23042102 - 14 Feb 2022

Cited by 14 | Viewed by 4311

Abstract

Many extensible tissues such as skin, lungs, and blood vessels require elasticity to function properly. The recoil of elastic energy stored during a stretching phase is provided by elastic fibers, which are mostly composed of elastin and fibrillin-rich microfibrils. In arteries, the lack of elastic fibers leads to a weakening of the vessel wall with an increased risk to develop cardiovascular defects such as stenosis, aneurysms, and dissections. The development of new therapeutic molecules involves preliminary tests in animal models that recapitulate the disease and whose response to drugs should be as close as possible to that of humans. Due to its superior in vivo imaging possibilities and the broad tool kit for forward and reverse genetics, the zebrafish has become an important model organism to study human pathologies. Moreover, it is particularly adapted to large scale studies, making it an attractive model in particular for the first steps of investigations. In this review, we discuss the relevance of the zebrafish model for the study of elastic fiber-related vascular pathologies. We evidence zebrafish as a compelling alternative to conventional mouse models. Full article

(This article belongs to the Special Issue Development, Aging and Repair of Elastic Fibers)

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7 pages, 548 KiB

Open AccessReview

The Multiple Functions of Fibrillin-1 Microfibrils in Organismal Physiology

by Keiichi Asano, Anna Cantalupo, Lauriane Sedes and Francesco Ramirez

Int. J. Mol. Sci. 2022, 23(3), 1892; https://doi.org/10.3390/ijms23031892 - 8 Feb 2022

Cited by 8 | Viewed by 5261

Abstract

Fibrillin-1 is the major structural component of the 10 nm-diameter microfibrils that confer key physical and mechanical properties to virtually every tissue, alone and together with elastin in the elastic fibers. Mutations in fibrillin-1 cause pleiotropic manifestations in Marfan syndrome (MFS), including dissecting thoracic aortic aneurysms, myocardial dysfunction, progressive bone loss, disproportionate skeletal growth, and the dislocation of the crystalline lens. The characterization of these MFS manifestations in mice, that replicate the human phenotype, have revealed that the underlying mechanisms are distinct and organ-specific. This brief review summarizes relevant findings supporting this conclusion. Full article

(This article belongs to the Special Issue Development, Aging and Repair of Elastic Fibers)

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24 pages, 1792 KiB

Open AccessReview

The “Elastic Perspective” of SARS-CoV-2 Infection and the Role of Intrinsic and Extrinsic Factors

by Federica Boraldi, Francesco Demetrio Lofaro, Andrea Cossarizza and Daniela Quaglino

Int. J. Mol. Sci. 2022, 23(3), 1559; https://doi.org/10.3390/ijms23031559 - 29 Jan 2022

Cited by 7 | Viewed by 3105

Abstract

Elastin represents the structural component of the extracellular matrix providing elastic recoil to tissues such as skin, blood vessels and lungs. Elastogenic cells secrete soluble tropoelastin monomers into the extracellular space where these monomers associate with other matrix proteins (e.g., microfibrils and glycoproteins) and are crosslinked by lysyl oxidase to form insoluble fibres. Once elastic fibres are formed, they are very stable, highly resistant to degradation and have an almost negligible turnover. However, there are circumstances, mainly related to inflammatory conditions, where increased proteolytic degradation of elastic fibres may lead to consequences of major clinical relevance. In severely affected COVID-19 patients, for instance, the massive recruitment and activation of neutrophils is responsible for the profuse release of elastases and other proteolytic enzymes which cause the irreversible degradation of elastic fibres. Within the lungs, destruction of the elastic network may lead to the permanent impairment of pulmonary function, thus suggesting that elastases can be a promising target to preserve the elastic component in COVID-19 patients. Moreover, intrinsic and extrinsic factors additionally contributing to damaging the elastic component and to increasing the spread and severity of SARS-CoV-2 infection are reviewed. Full article

(This article belongs to the Special Issue Development, Aging and Repair of Elastic Fibers)

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