Transforming Growth Factor-β (TGF-β) and Inflammation in Vascular (Type IV) Ehlers Danlos Syndrome
Background—Vascular Ehlers Danlos syndrome (VEDS) causes reduced life expectancy due to arterial dissections/rupture and hollow organ rupture. Although the causative gene, COL3A1, was identified over 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, MCP-1, CRP, ICAM-1, VCAM-1, and leptin and decreased IL-8 versus controls. VEDS dermal fibroblasts secreted more TGF-β2, while downstream canonical/non-canonical TGF-β signaling was not different. Patients with COL3A1 exon skipping mutations had higher plasma ICAM-1 and VCAM-1, and VEDS probands had abnormally high plasma CRP versus affected patients identified through family members prior to any disease manifestations. VEDS patients had higher mean platelet volumes, suggesting increased platelet turnover due to 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. CRP 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 IL-8 and elevated leptin in VEDS.
- Received May 28, 2013.
- Revision received December 16, 2013.
- Accepted December 19, 2013.