Transforming growth factor-β and inflammation in vascular (type IV) Ehlers-Danlos syndrome

Morissette, Rachel; Schoenhoff, Florian; Xu, Zhi; Shilane, David A.; Griswold, Benjamin F.; Chen, Wuyan; Yang, Jiandong; Zhu, Jie; Fert-Bober, Justyna; Sloper, Leslie; Lehman, Jason; Commins, Natalie; Van Eyk, Jennifer E.; McDonnell, Nazli B.

doi:10.1161/circgenetics.113.000280

Cited by 53Connective tissue disorders researchTGF-β signaling in diseasesSystemic Sclerosis and Related Diseases

Transforming growth factor-β and inflammation in vascular (type IV) Ehlers-Danlos syndrome

Morissette, Rachel, Schoenhoff, Florian, Xu, Zhi, Shilane, David A., Griswold, Benjamin F., Chen, Wuyan, Yang, Jiandong, Zhu, Jie +6 more·2014·Circulation: Cardiovascular Genetics

DOI 10.1161/circgenetics.113.000280

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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. Methods and 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.

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A previous study on vEDS skin fibroblasts did not disclose aberrant canonical and noncanonical TGFβ pathways, despite increased levels of TGFβ2 ligand in the cells' media.
“Nevertheless, a previous study on vEDS skin fibroblasts did not disclose aberrant canonical and noncanonical TGFβ pathways, despite the increased levels of TGFβ2 ligand in the cells’ media [22].”
From Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome (2018) · cites this paper as [22]

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Additional file 1 of Dysregulation of extracellular matrix and Lysyl Oxidase in Ehlers-Danlos syndrome type IV skin fibroblasts
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Additional file 2 of Dysregulation of extracellular matrix and Lysyl Oxidase in Ehlers-Danlos syndrome type IV skin fibroblasts
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Abstract 5095: The Role of Circulating Transforming Growth Factor-β in Vascular Ehlers-Danlos Syndrome: Implications for Drug Therapy
Schoenhoff, F., Griswold, B. F., Matt, P., Sloper, L., Yamazaki, M., Carlson, O. D., Dietz, H. C., Eyk, J. E. V., & McDonnell, N. B. (2009) · Circulation · doi:10.1161/circ.120.suppl_18.s1048-b · Cited by 2 · see citing works
Self-citation
The role of circulating transforming growth factor-beta in vascular Ehlers-Danlos syndrome: implications for drug therapy
Schoenhoff, F., Griswold, B. F., Matt, P., Sloper, L., Yamazaki, M., Carlson, O., Dietz, H. C., Eyk, J. V., & McDonnell, N. (2009) · Bern Open Repository and Information System (University of Bern)
Self-citation
Targetable cellular signaling events mediate vascular pathology in vascular Ehlers-Danlos syndrome
Bowen, C. J., Calderón, J. F., Burger, Z., Rykiel, G., Davis, E. C., Helmers, M. R., Benke, K. S., MacFarlane, E. G., & Dietz, H. C. (2019) · Journal of Clinical Investigation · doi:10.1172/jci130730 · Cited by 78 · see citing works
Dysregulation of extracellular matrix and Lysyl Oxidase in Ehlers-Danlos syndrome type IV skin fibroblasts
Foehr, R. M., Anderson, K., Dombrowski, O., Foehr, A., & Foehr, E. D. (2024) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-023-03007-7 · Cited by 9 · see citing works
Serum Type III Procollagen Propeptide as a Potential Biomarker of Vascular Ehlers-Danlos Syndrome
Yagyu, T., Ida, K., & Noguchi, T. (2022) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2022.02.009

Authors: Morissette, R., Schoenhoff, F., Xu, Z., Shilane, D. A., Griswold, B. F., Chen, W., Yang, J., Zhu, J., Fert-Bober, J., Sloper, L., Lehman, J., Commins, N., Van Eyk, J. E., & McDonnell, N. B.
Affiliations: University of Bern (CH)
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.).
ORCID: Morissette, Rachel
Schoenhoff, Florian
Shilane, David A.
Yang, Jiandong
Zhu, Jie
Commins, Natalie
Venue: Circulation: Cardiovascular Genetics
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2014-02
Volume: 7
Issue: 1
Pages: 80-88
ISSN: 1942-325X (ISSN-L)
1942-3268
DOI: 10.1161/circgenetics.113.000280
OpenAlex: W2145300195
Cited by: 51
References: 50
Citations by year: 2026: 2 · 2025: 1 · 2024: 4 · 2023: 7 · 2022: 4 · 2021: 4 · 2020: 5 · 2019: 1 · 2018: 4 · 2017: 5 · 2016: 5 · 2015: 7 · 2014: 2
FWCI: 4.15
Type: journal article
Language: en
Update notices: correction (2014-06-01)
Open access: closed
Locations: Circulation Cardiovascular Genetics (publishedVersion)
PubMed (publishedVersion)
Bern Open Repository and Information System (University of Bern) (submittedVersion)
Funders: Johns Hopkins University
National Institutes of Health
National Institute on Aging
National Heart, Lung, and Blood Institute (RC1HL100021)
National Center for Research Resources (1U54RR023561-01A1)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
Keywords: vascular Ehlers-Danlos syndrome, COL3A1, TGF-beta, TGF-beta2, inflammation, C-reactive protein, dermal fibroblasts, arterial dissection, platelet turnover, truncal adiposity, adipocyte dysfunction, leptin, interleukin-8, MCP-1, VCAM-1, ICAM-1, genotype-phenotype correlation, disease activity markers
MeSH terms: Adolescent, Adult, Body Composition, C-Reactive Protein, Child, Ehlers-Danlos Syndrome, Female, Fibroblasts, Humans, Inflammation, Male, Middle Aged, Signal Transduction, Biomarkers, Transforming Growth Factor beta, Collagen Type III, RNA, Small Interfering, Transforming Growth Factor beta1, Transforming Growth Factor beta2, Adipokines, Young Adult, Genetic Association Studies

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Transforming growth factor-β and inflammation in vascular (type IV) Ehlers-Danlos syndrome

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