Collagen III is critically important for the proper function of extracellular matrix. This is clearly demonstrated by the pathology of vascular Ehlers Danlos Syndrome. Reduced life expectancy due to catastrophic aortic rupture and the multitude of other severe medical conditions observed in vEDS patients underscore the involvement of Collagen III in physiology. The pathogenic mutations in COL3A1 have a dominant-negative effect (one mutant protein strand may form a triple helix with two normal strands and cause improper folding and function). The mutated protein interacts with normal Collagen III and other ECM components, thereby disrupting tissue formation and cellular function. Much of the mutated Collagen III seems to be retained inside the cells, however, dysfunctional ECM still forms. Skin fibroblasts derived from vEDS patients lack an organized ECM and accumulate cytoplasmic Fibronectin [8]. Indeed, Fibronectin binds fibral collagens and plays an important role in ECM structure and function. Overall, we observed a fibrosis-like profile in the ECM composition of vEDS fibroblasts. This includes upregulation of other collagens, and changes to other ECM components, growth factors, and pro-inflammatory cytokines. Intracellular accumulation of Collagen III has been shown previously [9]. Overly modified Collagen III was measured using polyacrylamide gel electrophoresis [10,11,12]. Previous studies have explored the abnormal structure of connective tissue and arteries in vEDS patients [13,14,15]. Some have described aortic tissue from vEDS patients as being moth-eaten, malformed, fragile, rigid, and having characteristics of fibrotic tissue [2, 10, 16]. Therefore, vEDS could be considered as a type of fibrotic disease and thus inform the development of therapeutic interventions.

The hallmark of fibrotic tissue is increased collagen cross-linking. We observed significant increases in cross linked C-telopeptide of Collagen III (CTXIII) in vEDS fibroblasts and concomitant increase in LOXL2 protein and LOX enzyme activity. Collagen cross links increase the rigidity of connective tissues. LOX enzymes play an important role in Collagen cross-linking and should be considered a therapeutic target for vEDS. LOX inhibitors (BAPN) and other more potent and specific LOXL2/LOXL3 inhibitors increase flexibility of soft tissues. However, studies of Marfan Syndrome (a connective tissue disorder due to mutations in Fibrillin-1/FBN) indicated that neonatal administration of BAPN caused accelerated dilation of the ascending aorta and even premature death in Marfan Syndrome mice. Therefore, understanding the timing, dose, and specificity of LOX inhibitors is important.

Dysregulation of TGFβ and Wnt pathways in vEDS indicate that these pathways could be targets for therapeutic intervention. TGFβ is elevated in plasma obtained from vEDS subjects [17]. This upregulation of TGFβ suggests a role in the pathogenesis of vEDS. TGFβ is known to upregulate LOX enzymes, collagens, and fibronectin. Fibronectin is very important for proper formation of collagen fibrils and ECM deposition. Together, the upregulation of these proteins supports the notion that there is dysregulation of ECM formation in vEDS and compensatory mechanisms at play.

Blood pressure medications are used off-label to treat vEDS. By reducing heart rate and pulsate pressure, celiprolol, a β1 antagonist/β2 agonist, may reduce the mechanical stress on collagen fibers within the arterial wall and be of benefit in patients with vEDS [2]. Beta adrenergic stimulation leads to TGFβ expression and may contribute to the mechanism of action of celiprolol. Other β1 antagonist such as metoprolol are used off label in the US to treat vEDS to reduce pulsate pressure, but do not have β2 agonist activity. In a study using transgenic vEDS mice, celiprolol accelerated rather than reduced death from aortic rupture in both the severe Col3a1G938D/+ and mild Col3a1G209S/+ vEDS mouse models, despite having the predicted effect on pulse rate. Losartan, propranolol, atenolol, amlodipine did not rescue death from aortic rupture in these mice [18].

We also found that WNT5A is increased in vEDS, as evidenced in the proteomics data set. Wnt signaling is an important regulator of LOXL2 expression and collagen cross-linking activity [19]. Wnt5a signaling is profibrotic and therefore, reducing Wnt5a may improve proper ECM formation in vEDS patients.

Another possible treatment for vEDS is the use of stem cells. Stem cells play an important role in vascular formation and regeneration of damaged tissues. Allogeneic stem cells, or stem cells from a matched donor, may repair the damaged tissue and ECM in vEDS patients. Stem cells delivered to the site of damage following dissection, aneurysm, or tissue tare may facilitate repair and replacement of ECM [20, 21]. This strategy has been explored as a treatment for Osteogenesis Imperfecta (OI), or brittle bone disease, caused by dominant negative mutation in Collagen I that causes frequent fractures. The investigators show that mesenchymal stem cells have the ability to migrate, engraft, and differentiate into bone cells in OI patients [22].