{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T03:14:09Z","timestamp":1790997249311,"version":"4.1.0"},"reference-count":59,"publisher":"The Company of Biologists","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,8,1]]},"abstract":"<jats:p>Aortic valve disease (AVD) is characterized by elastic fiber fragmentation (EFF), fibrosis and aberrant angiogenesis. Emilin1 is an elastin-binding glycoprotein that regulates elastogenesis and inhibits TGF-\u03b2 signaling, but the role of Emilin1 in valve tissue is unknown. We tested the hypothesis that Emilin1 deficiency results in AVD, mediated by non-canonical (MAPK\/phosphorylated Erk1 and Erk2) TGF-\u03b2 dysregulation. Using histology, immunohistochemistry, electron microscopy, quantitative gene expression analysis, immunoblotting and echocardiography, we examined the effects of Emilin1 deficiency (Emilin1\u2212\/\u2212) in mouse aortic valve tissue. Emilin1 deficiency results in early postnatal cell-matrix defects in aortic valve tissue, including EFF, that progress to latent AVD and premature death. The Emilin1\u2212\/\u2212 aortic valve displays early aberrant provisional angiogenesis and late neovascularization. In addition, Emilin1\u2212\/\u2212 aortic valves are characterized by early valve interstitial cell activation and proliferation and late myofibroblast-like cell activation and fibrosis. Interestingly, canonical TGF-\u03b2 signaling (phosphorylated Smad2 and Smad3) is upregulated constitutively from birth to senescence, whereas non-canonical TGF-\u03b2 signaling (phosphorylated Erk1 and Erk2) progressively increases over time. Emilin1 deficiency recapitulates human fibrotic AVD, and advanced disease is mediated by non-canonical (MAPK\/phosphorylated Erk1 and Erk2) TGF-\u03b2 activation. The early manifestation of EFF and aberrant angiogenesis suggests that these processes are crucial intermediate factors involved in disease progression and therefore might provide new therapeutic targets for human AVD.<\/jats:p>","DOI":"10.1242\/dmm.015255","type":"journal-article","created":{"date-parts":[[2014,7,23]],"date-time":"2014-07-23T07:48:33Z","timestamp":1406101713000},"page":"987-996","source":"Crossref","is-referenced-by-count":58,"title":["TGF-\u03b2 mediates early angiogenesis and latent fibrosis in an Emilin1-deficient mouse model of aortic valve disease"],"prefix":"10.1242","volume":"7","author":[{"given":"Charu","family":"Munjal","sequence":"first","affiliation":[{"name":"Division of Cardiology, The Heart Institute, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy M.","family":"Opoka","sequence":"additional","affiliation":[{"name":"Division of Cardiology, The Heart Institute, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Osinska","sequence":"additional","affiliation":[{"name":"Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne F.","family":"James","sequence":"additional","affiliation":[{"name":"Division of Cardiology, The Heart Institute, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio M.","family":"Bressan","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, University of Padua, 35121 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert B.","family":"Hinton","sequence":"additional","affiliation":[{"name":"Division of Cardiology, The Heart Institute, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042422440461600_b1-0070987","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1021\/pr1009806","article-title":"Networked-based characterization of extracellular matrix proteins from adult mouse pulmonary and aortic valves","volume":"10","author":"Angel","year":"2011","journal-title":"J. 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