title: Transforming growth factor-β and inflammation in vascular (type IV) Ehlers-Danlos syndrome.
abstract: BACKGROUND
  Vascular Ehlers-Danlos syndrome (VEDS) causes reduced life expectancy because of arterial dissections/rupture and hollow organ rupture. Although the causative gene, COL3A1, was identified >20 years ago, there has been limited progress in understanding the disease mechanisms or identifying treatments.
  
  
  RESULTS
  We studied inflammatory and transforming growth factor-β (TGF-β) signaling biomarkers in plasma and from dermal fibroblasts from patients with VEDS. Analyses were done in terms of clinical disease severity, genotype-phenotype correlations, and body composition and fat deposition alterations. VEDS subjects had increased circulating TGF-β1, TGF-β2, 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-β2, whereas downstream canonical/noncanonical TGF-β signaling was not different. Patients with COL3A1 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.
  
  
  CONCLUSIONS
  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-β signaling and increased platelet turnover suggest that chronic vascular damage may partially explain increased plasma TGF-β1. Finally, we found a novel role for dysregulated TGF-β2, as well as adipocyte dysfunction, as demonstrated through reduced interleukin-8 and elevated leptin in VEDS.
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD.
authors.forename: Rachel
authors.initials: R
authors.lastname: Morissette
authors.forename: Florian
authors.initials: F
authors.lastname: Schoenhoff
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xu
authors.forename: David A
authors.initials: DA
authors.lastname: Shilane
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Griswold
authors.forename: Wuyan
authors.initials: W
authors.lastname: Chen
authors.forename: Jiandong
authors.initials: J
authors.lastname: Yang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.forename: Justyna
authors.initials: J
authors.lastname: Fert-Bober
authors.forename: Leslie
authors.initials: L
authors.lastname: Sloper
authors.forename: Jason
authors.initials: J
authors.lastname: Lehman
authors.forename: Natalie
authors.initials: N
authors.lastname: Commins
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Van Eyk
authors.forename: Nazli B
authors.initials: NB
authors.lastname: McDonnell
mesh_terms: D054392:Adipokines / Q000097:blood; D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D001823:Body Composition; D002097:C-Reactive Protein / Q000032:analysis; D002648:Child; D024061:Collagen Type III / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004535:Ehlers-Danlos Syndrome / Q000097:blood* / Q000209:etiology / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D056726:Genetic Association Studies; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000097:blood*; D053773:Transforming Growth Factor beta1 / Q000032:analysis / Q000097:blood; D053781:Transforming Growth Factor beta2 / Q000032:analysis / Q000097:blood; D055815:Young Adult
chemical_list: D054392:Adipokines; D015415:Biomarkers; C439971:COL3A1 protein, human; D024061:Collagen Type III; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D002097:C-Reactive Protein
keywords: Ehlers-Danlos syndrome; aneurysm; biomarkers; extracellular matrix; inflammation