| Altered versican cleavage in ADAMTS5 deficient mice; A novel etiology of myxomatous valve disease. | |
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MedLine Citation:
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PMID: 21749862 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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In fetal valve maturation the mechanisms by which the relatively homogeneous proteoglycan-rich extracellular matrix (ECM) of endocardial cushions is replaced by a specialized and stratified ECM found in mature valves are not understood. Therefore, we reasoned that uncovering proteases critical for 'remodeling' the proteoglycan rich (extracellular matrix) ECM may elucidate novel mechanisms of valve development. We have determined that mice deficient in ADAMTS5, (A Disintegrin-like And Metalloprotease domain with ThromboSpondin-type 1 motifs) which we demonstrated is expressed predominantly by valvular endocardium during cardiac valve maturation, exhibited enlarged valves. ADAMTS5 deficient valves contained a reduction in cleavage of its substrate versican, a critical cardiac proteoglycan. In vivo reduction of versican, in Adamts5(-/-) mice, achieved through Vcan heterozygosity, substantially rescued the valve anomalies. An increase in BMP2 immunolocalization, Sox9 expression and mesenchymal cell proliferation were observed in Adamts5(-/-) valve mesenchyme and correlated with expansion of the spongiosa (proteoglycan-rich) region in Adamts5(-/-) valve cusps. Furthermore, these data suggest that ECM remodeling via ADAMTS5 is required for endocardium to mesenchymal signaling in late fetal valve development. Although adult Adamts5(-/-) mice are viable they do not recover from developmental valve anomalies and have myxomatous cardiac valves with 100% penetrance. Since the accumulation of proteoglycans is a hallmark of myxomatous valve disease, based on these data we hypothesize that a lack of versican cleavage during fetal valve development may be a potential etiology of adult myxomatous valve disease. |
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Authors:
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Loren E Dupuis; Daniel R McCulloch; Jessica D McGarity; Alexandria Bahan; Andy Wessels; Deidra Weber; A Megan Diminich; Courtney M Nelson; Suneel S Apte; Christine B Kern |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-7-1 |
Journal Detail:
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Title: Developmental biology Volume: - ISSN: 1095-564X ISO Abbreviation: - Publication Date: 2011 Jul |
Date Detail:
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Created Date: 2011-7-13 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0372762 Medline TA: Dev Biol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011. Published by Elsevier Inc. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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