title: Altered versican cleavage in ADAMTS5 deficient mice; a novel etiology of myxomatous valve disease.
abstract: 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 displayed 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 endocardial 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.
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, 29425, USA.
authors.forename: Loren E
authors.initials: LE
authors.lastname: Dupuis
authors.forename: Daniel R
authors.initials: DR
authors.lastname: McCulloch
authors.forename: Jessica D
authors.initials: JD
authors.lastname: McGarity
authors.forename: Alexandria
authors.initials: A
authors.lastname: Bahan
authors.forename: Andy
authors.initials: A
authors.lastname: Wessels
authors.forename: Deidra
authors.initials: D
authors.lastname: Weber
authors.forename: A Megan
authors.initials: AM
authors.lastname: Diminich
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Nelson
authors.forename: Suneel S
authors.initials: SS
authors.lastname: Apte
authors.forename: Christine B
authors.initials: CB
authors.lastname: Kern
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000071116:ADAMTS5 Protein; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D004699:Endocardium / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology; D006349:Heart Valve Diseases / Q000209:etiology / Q000235:genetics; D006351:Heart Valves / Q000196:embryology* / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D053675:Versicans / Q000378:metabolism*
chemical_list: D055396:Bone Morphogenetic Protein 2; D053675:Versicans; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C498489:Adamts5 protein, mouse