Elastin is an essential determinant of arterial morphogenesis

Li, Dean Y.; Brooke, Benjamin S.; Davis, Elaine C.; Mecham, Robert P.; Sorensen, Lise K.; Boak, Beth B.; Eichwald, E. J.; Keating, Mark T.

doi:10.1038/30522

Cited by 709 publications

(592 citation statements)

References 18 publications

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“…Mice lacking the elastin gene (eln2/2) die within a few days of birth of vascular obstruction due to smooth muscle cell (SMC) overproliferation (Li et al, 1998a). The vessel wall is thickened at the time of death in these animals and the SMCs are misarranged.…”

Section: Tropoelastin/elastinmentioning

confidence: 99%

New insights into elastic fiber assembly

Wagenseil

Mecham

2007

Birth Defects Research Pt C

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355

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: Tropoelastin/elastinmentioning

confidence: 99%

New insights into elastic fiber assembly

Wagenseil

Mecham

2007

Birth Defects Research Pt C

Self Cite

355

354

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“…33 Disruption of elastin synthesis by targeting the promoter and exon 1 of the elastin gene induces subendothelial proliferation of ASMCs followed by obstructive disease and eventual obliteration of the lumen. Thus, although chondroitin sulfate chains of proteoglycans may affect the formation of elastic fibers, elastin in turn may also have a regulatory function, controlling ASMC proliferation and stabilizing arterial structure.…”

Section: Discussionmentioning

confidence: 99%

Retrovirally Mediated Overexpression of Versican V3 by Arterial Smooth Muscle Cells Induces Tropoelastin Synthesis and Elastic Fiber Formation In Vitro and In Neointima After Vascular Injury

Merrilees

Lemire

Fischer

et al. 2002

Circulation Research

100

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Abstract-Versican is an extracellular matrix (ECM) proteoglycan that is synthesized as multiple splice variants. In a recent study, we demonstrated that retroviral-mediated overexpression of the variant V3, which lacks chondroitin sulfate (CS) chains, altered arterial smooth muscle cell (ASMC) phenotype in short-term cell culture. We now report that V3-overexpressing ASMCs exhibit significantly increased expression of tropoelastin and increased formation of elastic fibers in long-term cell cultures. In addition, V3-overexpressing ASMCs seeded into ballooned rat carotid arteries continued to overexpress V3 and, at 4 weeks after seeding, produced a highly structured neointima significantly enriched in elastic fiber lamellae. In contrast to the hydrated, myxoid neointima produced by rounded or stellate vector-alonetransduced cells, V3-expressing cells produced a compact and highly ordered neointima, which contained elongated ASMCs that were arranged in parallel arrays and separated by densely packed collagen bundles and elastic fibers. These results indicate that a variant of versican is involved in elastic fiber assembly and may represent a novel therapeutic approach to facilitate the formation of elastic fibers. T he extracellular matrix (ECM) proteoglycan versican, the major chondroitin sulfate proteoglycan of vessel wall, 1 is distinguished by a central extended region with attached glycosaminoglycan (GAG) chains by an amino-terminal globular domain (G1) that binds hyaluronan (HA) and by a carboxy-terminal selectin-like domain (G3) that binds to other matrix components including tenascin-R and fibulin-1. [2][3][4][5][6] The mRNA that codes the GAG attachment region, which in the full-length form has 2 domains, can undergo differential splicing to produce 4 variants: V0, with 2 (␣ and ␤) GAG binding regions; V1 (with the ␤ GAG exon); V2 (with the ␣ GAG exon); and V3 with neither GAG exon and formed from the G1 and G3 domains only. 7-9 V3 is thus predicted to be a glycoprotein and not a proteoglycan. V3 mRNA has been demonstrated in aortic tissue as well as cultures of ASMCs by Northern blot 10 and has been detected, by polymerase chain reaction (PCR), from cDNA libraries for various tissues including brain, stomach, and liver. 9 Recently, we reported that retroviral insertion and overexpression of the gene for V3 into cultured Fischer rat ASMCs induces a number of phenotypic changes. 11 Compared with vector-alone-transduced cells, V3 ASMCs are more flattened and spread, show a large increase in area of close contacts and in the size of peripheral focal contacts, increased resistance to trypsin detachment, reduced pericellular coats, and decreased rates of growth and migration. The mechanism by which V3 effects these changes is not clear, although the morphological features, the reduced growth and migration, and the reduced cell coat, raise the possibility that V3 may affect the accumulation of components of the extracellular matrix. For example, Evanko et al 12 showed recently that the V1 isoform of versican in ...

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“…Studies of elastin knockout mice reveal a crucial role for elastin in arterial morphogenesis through regulation of SMC proliferation and phenotype (Li, Brooke et al 1998). This model is supported by in vitro studies showing that elastin can inhibit SMC proliferation in a dose dependent manner (Ito, Ishimaru et al 1998).…”

Section: Biological Properties Of Elastinmentioning

confidence: 90%