{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T22:19:36Z","timestamp":1790288376329,"version":"4.1.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ Cardiovasc Genet"],"published-print":{"date-parts":[[2014,2]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>\n              Vascular Ehlers\u2013Danlos syndrome (VEDS) causes reduced life expectancy because of arterial dissections\/rupture and hollow organ rupture. Although the causative gene,\n              <jats:italic>COL3A1<\/jats:italic>\n              , was identified &gt;20 years ago, there has been limited progress in understanding the disease mechanisms or identifying treatments.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              We studied inflammatory and transforming growth factor-\u03b2 (TGF-\u03b2) signaling biomarkers in plasma and from dermal fibroblasts from patients with VEDS. Analyses were done in terms of clinical disease severity, genotype\u2013phenotype correlations, and body composition and fat deposition alterations. VEDS subjects had increased circulating TGF-\u03b21, TGF-\u03b22, monocyte chemotactic protein-1, C-reactive protein, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and leptin and decreased interleukin-8 versus controls. VEDS dermal fibroblasts secreted more TGF-\u03b22, whereas downstream canonical\/noncanonical TGF-\u03b2 signaling was not different. Patients with\n              <jats:italic>COL3A1<\/jats:italic>\n              exon skipping mutations had higher plasma intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and VEDS probands had abnormally high plasma C-reactive protein versus affected patients identified through family members before any disease manifestations. Patients with VEDS had higher mean platelet volumes, suggesting increased platelet turnover because of ongoing vascular damage, as well as increased regional truncal adiposity.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>These findings suggest that VEDS is a systemic disease with a major inflammatory component. C-reactive protein is linked to disease state and may be a disease activity marker. No changes in downstream TGF-\u03b2 signaling and increased platelet turnover suggest that chronic vascular damage may partially explain increased plasma TGF-\u03b21. Finally, we found a novel role for dysregulated TGF-\u03b22, as well as adipocyte dysfunction, as demonstrated through reduced interleukin-8 and elevated leptin in VEDS.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgenetics.113.000280","type":"journal-article","created":{"date-parts":[[2014,1,8]],"date-time":"2014-01-08T01:34:21Z","timestamp":1389144861000},"page":"80-88","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":45,"title":["Transforming Growth Factor-\u03b2 and Inflammation in Vascular (Type IV) Ehlers\u2013Danlos Syndrome"],"prefix":"10.1161","volume":"7","author":[{"given":"Rachel","family":"Morissette","sequence":"first","affiliation":[{"name":"From the Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD (R.M., Z.X., B.F.G., W.C., J.Y., L.S., J.L., N.C., N.B.M.); Department of Medicine, Johns Hopkins Bayview Proteomics Center, Johns Hopkins University, Baltimore, MD (F.S., J.Z., J.F.-B., J.E.V.E.); Department of Cardiovascular Surgery, University Hospital Berne, Berne, Switzerland (F.S.); and Stanford University School of Medicine, Stanford, CA (D.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Schoenhoff","sequence":"additional","affiliation":[{"name":"From the Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD (R.M., Z.X., B.F.G., W.C., J.Y., L.S., J.L., N.C., N.B.M.); Department of Medicine, Johns Hopkins Bayview Proteomics Center, Johns Hopkins University, Baltimore, MD (F.S., J.Z., J.F.-B., J.E.V.E.); Department of Cardiovascular Surgery, University Hospital Berne, Berne, Switzerland (F.S.); and Stanford University School of Medicine, Stanford, CA (D.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Xu","sequence":"additional","affiliation":[{"name":"From the Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD (R.M., Z.X., B.F.G., W.C., J.Y., L.S., J.L., N.C., N.B.M.); Department of Medicine, Johns Hopkins Bayview Proteomics Center, Johns Hopkins University, Baltimore, MD (F.S., J.Z., J.F.-B., J.E.V.E.); Department of Cardiovascular Surgery, University Hospital Berne, Berne, Switzerland (F.S.); and Stanford University School of Medicine, Stanford, CA (D.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Shilane","sequence":"additional","affiliation":[{"name":"From the Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD (R.M., Z.X., B.F.G., W.C., J.Y., L.S., J.L., N.C., N.B.M.); Department of Medicine, Johns Hopkins Bayview Proteomics Center, Johns Hopkins University, Baltimore, MD (F.S., J.Z., J.F.-B., J.E.V.E.); Department of Cardiovascular Surgery, University Hospital Berne, Berne, Switzerland (F.S.); and Stanford University School of Medicine, Stanford, CA (D.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin F.","family":"Griswold","sequence":"additional","affiliation":[{"name":"From the Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD (R.M., Z.X., B.F.G., W.C., J.Y., L.S., J.L., N.C., N.B.M.); Department of Medicine, Johns Hopkins Bayview Proteomics Center, Johns Hopkins University, Baltimore, MD (F.S., J.Z., J.F.-B., J.E.V.E.); Department of Cardiovascular Surgery, University Hospital Berne, Berne, Switzerland (F.S.); and Stanford University School of Medicine, Stanford, CA (D.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wuyan","family":"Chen","sequence":"additional","affiliation":[{"name":"From the Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD (R.M., Z.X., B.F.G., W.C., J.Y., L.S., J.L., N.C., N.B.M.); Department of Medicine, Johns Hopkins Bayview Proteomics Center, Johns Hopkins University, Baltimore, MD (F.S., J.Z., J.F.-B., J.E.V.E.); Department of Cardiovascular Surgery, University Hospital Berne, Berne, Switzerland (F.S.); and Stanford University School of Medicine, Stanford, CA (D.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiandong","family":"Yang","sequence":"additional","affiliation":[{"name":"From the Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD (R.M., Z.X., B.F.G., W.C., J.Y., L.S., J.L., N.C., N.B.M.); Department of Medicine, Johns Hopkins Bayview Proteomics Center, Johns Hopkins University, Baltimore, MD (F.S., J.Z., J.F.-B., J.E.V.E.); Department of Cardiovascular Surgery, University Hospital Berne, Berne, Switzerland (F.S.); and Stanford University School of Medicine, Stanford, CA (D.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhu","sequence":"additional","affiliation":[{"name":"From the Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD (R.M., Z.X., B.F.G., W.C., J.Y., L.S., J.L., N.C., N.B.M.); Department of Medicine, Johns Hopkins Bayview Proteomics Center, Johns Hopkins University, Baltimore, MD (F.S., J.Z., J.F.-B., J.E.V.E.); Department of Cardiovascular Surgery, University Hospital Berne, Berne, Switzerland (F.S.); and Stanford University School of Medicine, Stanford, CA (D.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justyna","family":"Fert-Bober","sequence":"additional","affiliation":[{"name":"From the Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD (R.M., Z.X., B.F.G., W.C., J.Y., L.S., J.L., N.C., N.B.M.); Department of Medicine, Johns Hopkins Bayview Proteomics Center, Johns Hopkins University, Baltimore, MD (F.S., J.Z., J.F.-B., J.E.V.E.); Department of Cardiovascular Surgery, University Hospital Berne, Berne, Switzerland (F.S.); and Stanford University School of Medicine, Stanford, CA (D.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie","family":"Sloper","sequence":"additional","affiliation":[{"name":"From the Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD (R.M., Z.X., B.F.G., W.C., J.Y., L.S., J.L., N.C., N.B.M.); Department of Medicine, Johns Hopkins Bayview Proteomics Center, Johns Hopkins University, Baltimore, MD (F.S., J.Z., J.F.-B., J.E.V.E.); Department of Cardiovascular Surgery, University Hospital Berne, Berne, Switzerland (F.S.); and Stanford University School of Medicine, Stanford, CA (D.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Lehman","sequence":"additional","affiliation":[{"name":"From the Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD (R.M., Z.X., B.F.G., W.C., J.Y., L.S., J.L., N.C., N.B.M.); Department of Medicine, Johns Hopkins Bayview Proteomics Center, Johns Hopkins University, Baltimore, MD (F.S., J.Z., J.F.-B., J.E.V.E.); Department of Cardiovascular Surgery, University Hospital Berne, Berne, Switzerland (F.S.); and Stanford University School of Medicine, Stanford, CA (D.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Commins","sequence":"additional","affiliation":[{"name":"From the Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD (R.M., Z.X., B.F.G., W.C., J.Y., L.S., J.L., N.C., N.B.M.); Department of Medicine, Johns Hopkins Bayview Proteomics Center, Johns Hopkins University, Baltimore, MD (F.S., J.Z., J.F.-B., J.E.V.E.); Department of Cardiovascular Surgery, University Hospital Berne, Berne, Switzerland (F.S.); and Stanford University School of Medicine, Stanford, CA (D.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer E.","family":"Van Eyk","sequence":"additional","affiliation":[{"name":"From the Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD (R.M., Z.X., B.F.G., W.C., J.Y., L.S., J.L., N.C., N.B.M.); Department of Medicine, Johns Hopkins Bayview Proteomics Center, Johns Hopkins University, Baltimore, MD (F.S., J.Z., J.F.-B., J.E.V.E.); Department of Cardiovascular Surgery, University Hospital Berne, Berne, Switzerland (F.S.); and Stanford University School of Medicine, Stanford, CA (D.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazli B.","family":"McDonnell","sequence":"additional","affiliation":[{"name":"From the Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD (R.M., Z.X., B.F.G., W.C., J.Y., L.S., J.L., N.C., N.B.M.); Department of Medicine, Johns Hopkins Bayview Proteomics Center, Johns Hopkins University, Baltimore, MD (F.S., J.Z., J.F.-B., J.E.V.E.); Department of Cardiovascular Surgery, University Hospital Berne, Berne, Switzerland (F.S.); and Stanford University School of Medicine, Stanford, CA (D.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200003093421001"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.72.4.1314"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00278783"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)89682-X"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)60960-9"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.112.197020"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1086\/301641"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/1523-1747.ep12286441"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e3182180c89"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1086\/324123"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1253\/circj.CJ-12-0874"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1124287"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1116"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2007.00942.x"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2349"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.744"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.3346\/jkms.2004.19.6.853"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.34332"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0912923"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2421"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320580216"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-182162"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI114863"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.1380060408"},{"key":"e_1_3_4_26_2","first-page":"112","article-title":"Inheritance of an RNA splicing mutation (G+ 1 IVS20) in the type III procollagen gene (COL3A1) in a family having aortic aneurysms and easy bruisability: phenotypic overlap between familial arterial aneurysms and Ehlers-Danlos syndrome type IV.","volume":"47","author":"Kontusaari S","year":"1990","unstructured":"Kontusaari S, Tromp G, Kuivaniemi H, Ladda RL, Prockop DJ. Inheritance of an RNA splicing mutation (G+ 1 IVS20) in the type III procollagen gene (COL3A1) in a family having aortic aneurysms and easy bruisability: phenotypic overlap between familial arterial aneurysms and Ehlers-Danlos syndrome type IV. Am J Hum Genet. 1990;47:112\u2013120.","journal-title":"Am J Hum Genet"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20091"},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","first-page":"12067","DOI":"10.1016\/S0021-9258(19)38508-4","article-title":"Identical G+1 to A mutations in three different introns of the type III procollagen gene (COL3A1) produce different patterns of RNA splicing in three variants of Ehlers-Danlos syndrome: IV: an explanation for exon skipping some mutations and not others.","volume":"265","author":"Kuivaniemi H","year":"1990","unstructured":"Kuivaniemi H, Kontusaari S, Tromp G, Zhao MJ, Sabol C, Prockop DJ. 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