EMILIN-1 Deficiency Induces Elastogenesis and Vascular Cell Defects

Zanetti, Miriam; Braghetta, Paola; Sabatelli, Patrizia; Mura, Isabella; Doliana, Roberto; Colombatti, Alfonso; Volpin, Dino; Bonaldo, Paolo; Bressan, Giorgio M.

doi:10.1128/mcb.24.2.638-650.2004

Cited by 168 publications

(167 citation statements)

References 31 publications

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“…EMILIN-12/2 embryonic fibroblasts form elastin fibers in vitro that are thinner and straighter than control fibroblasts and lack the complete colocalization of elastin and fibulin-5 observed in controls. Fibulin-2 and fibrillin-1 fibers appear normal (Zanetti et al, 2004). Similar to eln1/2 mice, emilin12/2 mice have significant high renin-induced hypertension and vessels with smaller diameters and thinner walls (Faury et al, 2003;Zacchigna et al, 2006).…”

Section: Elastin Microfibril Interface Located Protein (Emilin)-1mentioning

confidence: 90%

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New insights into elastic fiber assembly

Wagenseil

Mecham

2007

Birth Defects Research Pt C

345

354

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Elastic fibers provide recoil to tissues that undergo repeated stretch, such as the large arteries and lung. These large extracellular matrix (ECM) structures contain numerous components, and our understanding of elastic fiber assembly is changing as we learn more about the various molecules associated with the assembly process. The main components of elastic fibers are elastin and microfibrils. Elastin makes up the bulk of the mature fiber and is encoded by a single gene. Microfibrils consist mainly of fibrillin, but also contain or associate with proteins such as microfibril associated glycoproteins (MAGPs), fibulins, and EMILIN-1. Microfibrils were thought to facilitate alignment of elastin monomers prior to cross-linking by lysyl oxidase (LOX). We now know that their role, as well as the overall assembly process, is more complex. Elastic fiber formation involves elaborate spatial and temporal regulation of all of the involved proteins and is difficult to recapitulate in adult tissues. This report summarizes the known interactions between elastin and the microfibrillar proteins and their role in elastic fiber assembly based on in vitro studies and evidence from knockout mice. We also propose a model of elastic fiber assembly based on the current data that incorporates interactions between elastin, LOXs, fibulins and the microfibril, as well as the pivotal role played by cells in structuring the final functional fiber. Birth Defects Research (Part C) 81:229-240,

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Section: Elastin Microfibril Interface Located Protein (Emilin)-1mentioning

confidence: 90%

“…Anti-EMILIN-1 antibodies promote the formation of elastin aggregates rather than fibers in SMC cultures (Bressan et al, 1993). EMILIN-1 binds elastin in solid-phase binding assays and both elastin and fibulin-5 in immunoprecipitation assays (Zanetti et al, 2004).…”

Section: Elastin Microfibril Interface Located Protein (Emilin)-1mentioning

confidence: 99%

New insights into elastic fiber assembly

Wagenseil

Mecham

2007

Birth Defects Research Pt C

345

354

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“…To test whether expressed transgenes were functional, we searched for reversal of blood vessels morphological alterations induced by Emilin1 deficiency. Although no ultrastructural defects were detected in resistance arteries (data not shown), aorta showed irregular outline and fragmentation of elastic lamellae, frequent blebbing, and detachment of ECs from the subendothelial extracellular matrix and atrophic, sometimes necrotic, VSMCs surrounded by enlarged extracellular space and disrupted adhesions of VSMCs to the elastic lamellae 5 ( Figure …”

Section: Transgenes Expression Patternsmentioning

confidence: 99%

“…The increase in TGF-β signaling induced by Emilin-1 deficiency results in systemic hypertension, accompanied by narrowing of arterial tree and structural alterations of the wall of elastic arteries. 4,5 In spite of this important information on alterations induced by Emilin-1 deficiency, it is still unknown which cell types mediate protein effects. In particular, it has not been investigated whether hypertension is causally related to abnormal behavior of vascular SMCs (VSMCs) or ECs.…”

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confidence: 99%

Vascular Smooth Muscle Emilin-1 Is a Regulator of Arteriolar Myogenic Response and Blood Pressure

Litteri

Carnevale

D’Urso

et al. 2012

ATVB

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Objective-Emilin-1 is a protein of elastic extracellular matrix involved in blood pressure (BP) control by negatively affecting transforming growth factor (TGF)-β processing. Emilin1 null mice are hypertensive. This study investigates how Emilin-1 deals with vascular mechanisms regulating BP. Methods and Results-This study uses a phenotype rescue approach in which Emilin-1 is expressed in either endothelial cells or vascular smooth muscle cells of transgenic animals with the Emilin1 −/− background. We found that normalization of BP required Emilin-1 expression in smooth muscle cells, whereas expression of the protein in endothelial cells did not modify the hypertensive phenotype of Emilin1 −/− mice. We also explored the effect of treatment with anti-TGF-β antibodies on the hypertensive phenotype of Emilin1 −/− mice, finding that neutralization of TGF-β in Emilin1 null mice normalized BP quite rapidly (2 weeks). Finally, we evaluated the vasoconstriction response of resistance arteries to perfusion pressure and neurohumoral agents in different transgenic mouse lines. Interestingly, we found that the hypertensive phenotype was coupled with an increased arteriolar myogenic response to perfusion pressure, while the vasoconstriction induced by neurohumoral agents remained unaffected. We further elucidate that, as for the hypertensive phenotype, the increased myogenic response was attributable to increased TGF-β activity. Key Words: Emilin1 ◼ myogenic response ◼ systemic hypertension ◼ transforming growth factor ◼ vascular smooth muscle Conclusion-Our

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“…The latter, a cysteine-rich sequence of about 75 amino acids, is shared by a number of genes (seven in mammals) that have been grouped into the Emilin gene family (www.gene.ucl.ac.uk/nomenclature/genefamily/emilin.html#HGNC_table2). Gene targeting experiments suggest that the protein has a role in the assembly of elastic fibers, particularly in blood vessels; in its absence, elastic lamellae of aorta are interrupted and their outline is irregular (12). A function of Emilin1 in elastogenesis is also indicated by the finding that the protein binds to other components of elastic fibers such as Elastin and Fibulin-5 (12).…”

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confidence: 88%

Analysis of Regulatory Regions of Emilin1 Gene and Their Combinatorial Contribution to Tissue-specific Transcription

Fabbro

Gemmis

Braghetta

et al. 2005

Journal of Biological Chemistry

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The location of regions that regulate transcription of the murine Emilin1 gene was investigated in a DNA fragment of 16.8 kb, including the entire gene and about 8.7 and 0.6 kb of 5-and 3-flanking sequences, respectively. The 8.7-kb segment contains the 5-end of the putative 2310015E02Rik gene and the sequence that separates it from Emilin1, whereas the 0.6-kb fragment covers the region between Emilin1 and Ketohexokinase genes. Sequence comparison between species identified several conserved regions in the 5-flanking sequence. Most of them contained chromatin DNase I-hypersensitive sites, which were located at about ؊950 (HS1), ؊3100 (HS2), ؊4750 (HS3), and ؊5150 (HS4) in cells expressing Emilin1 mRNA. Emilin1 transcription initiates at multiple sites, the major of which correspond to two Initiator sequences. Promoter assays suggest that core promoter activity was mainly dependent on Initiator1 and on Sp1-binding sites close to the Initiators. Moreover, one important regulatory region was contained between ؊1 and ؊169 bp and a second one between ؊630 bp and ؊1.1 kb. The latter harbors a putative binding site for transcription factor AP1 matching the location of HS1. The function of different regions was studied by expressing lacZ constructs in transgenic mice. The results show that the 16.8-kb segment contains regulatory sequences driving high level transcription in all the tissues where Emilin1 is expressed. Moreover, the data suggest that transcription in different tissues is achieved through combinatorial cooperation between various regions, rather than being dependent on a single cis-activating region specific for each tissue.

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EMILIN-1 Deficiency Induces Elastogenesis and Vascular Cell Defects

Cited by 168 publications

References 31 publications

New insights into elastic fiber assembly

New insights into elastic fiber assembly

Vascular Smooth Muscle Emilin-1 Is a Regulator of Arteriolar Myogenic Response and Blood Pressure

Analysis of Regulatory Regions of Emilin1 Gene and Their Combinatorial Contribution to Tissue-specific Transcription

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