Human MAGI1 expression in endothelial cells protects from the development of localized and systemic scleroderma in mice.

BACKGROUND

Systemic sclerosis and localized scleroderma are rheumatoid fibrotic diseases characterized by altered blood vessel permeability and dysregulated angiogenesis. MAGI1 is an intracellular protein expressed at the epithelial and endothelial cell junction, regulating cell adhesion and epithelial/endothelial integrity. Endothelial cell MAGI1 regulates angiogenic function and blood flow. In the present study, we investigated the role of transgenic human MAGI1 in endothelial cells in animal models of localized scleroderma and systemic sclerosis.

METHODS

Wild-type and human MAGI1-overexpressing endothelial cells in mice were challenged with sodium hypochlorite or bleomycin injections to induce sclerosis/scleroderma, mimicking the human disease. Conventional methods and automated software were employed to investigate the integrity of lung and skin tissue and quantify fibrosis. In vivo permeability and in vitro angiogenic models were employed to investigate the regulation of endothelial cell function.

RESULTS

Dermal thickening, lung tissue density, fibrotic foci development, and collagen accumulation induced by Bleomycin or sodium hypochlorite were significantly reduced in mice overexpressing human MAGI1 in endothelial cells relative to wild-type mice. Skin permeability and in vitro endothelial cell permeability were also reduced under MAGI1 overexpression. Furthermore, MAGI1 overexpression reduced the in vitro proangiogenic effects of VEGF-A, providing a putative mechanism of action.

CONCLUSIONS

The results indicate that endothelial cells expressing transgenic human MAGI1 attenuate tissue permeability and fibrotic responses in models of bleomycin- and sodium hypochlorite-induced scleroderma/sclerosis. MAGI1 overexpression blocks VEGF-A-induced permeability and angiogenesis in endothelial cells. Therefore, restoring endothelial cells could potentially alleviate VEGF-A-driven diseases such as localized scleroderma and systemic sclerosis.