Type III collagen is important for type I collagen fibrillogenesis and for dermal and cardiovascular development

Type III collagen, a major fibrillar collagen consisting of three α1(III)-chains, is expressed in early embryos, throughout embryogenesis and in a wide variety of adult tissues. Mutations in COL3A1 cause vascular Ehlers-Danlos Syndrome (vEDS), a severe, life-threatening disorder, characterized by thin skin and propensity to rupture of arteries and hollow organs. Most mutations are glycine substitutions in the triple helical domain of procollagen. However, the mechanisms by which mutant type III collagen cause dermal and vascular fragility are not well understood. To study the role of type III collagen in development and disease, we generated two transgenic mouse models using a BAC transgenic approach. The col3a1-MUT highly expresses a col3a1 transgene that harbours a typical glycine substitution (p.(Gly183Ser); c.547G>A) within the α1(III)-procollagen helical domain, whereas the col3a1-WT-OE overexpresses WT col3a1. Col3a1-MUT male mice display a thin, fragile skin and develop severe transdermal skin wounds by 3-4 months of age. Biomechanical testing reveals significantly reduced tensile strength of skin and aortic wall. These features are not observed in col3a1-WT-OE. Ultrastructural analysis of skin from col3a1-MUT mice reveals reduced thickness of the epidermis and disturbed cornification. The collagen fibril diameter in the dermis is highly variable and cytoplasmic accumulation of large aggregates is observed. Smooth muscle cells of the aorta produce normal collagen fibrils, but make less connection with the lamina elastica. These ultrastructural abnormalities are not observed in col3a1WT-OE, indicating that the observed phenotype in col3a1-MUT is due to the Gly substitution, and not caused by overexpression of normal type III collagen. Interestingly, collagen fibrils embedded within the cytoplasm and completely enclosed by intracellular membranes, reminiscent of the fibripositor structures described in embryonic mouse tail tendon, are seen in skin fibroblasts from col3a1-WT-OE. Together, our findings underscore a key role for type III collagen in collagen fibrillogenesis in skin and arterial tissue. These two novel animal models provide opportunities for the study of secretion and co-trafficking of fibrillar collagens and in-depth analyses of the role of abnormal type III collagen in vEDS