Lack of fibronectin extra domain a alternative splicing exacerbates endothelial dysfunction in diabetes

Abstract

Glucose-induced changes of artery anatomy and function account for diabetic vascular complications, which heavily impact disease morbidity and mortality. Since fibronectin containing extra domain A (EDA+FN) is increased in diabetic vessels and participates to vascular remodeling, we wanted to elucidate whether and how EDA+FN is implicated in diabetes-induced endothelial dysfunction using isometric-tension recording in a murine model of diabetes. In thoracic aortas of EDA-/-, EDA+/+ (constitutively lacking and expressing EDA+FN respectively), and of wild-type mice (EDA wt/wt), streptozotocin (STZ)-induced diabetes impaired endothelial vasodilation to acetylcholine, irrespective of genotype. However STZ+EDA-/- mice exhibited increased endothelial dysfunction compared with STZ+EDA+/+ and with STZ+EDA wt/wt. Analysis of the underlying mechanisms revealed that STZ+EDA-/- mice show increased oxidative stress as demonstrated by enhanced aortic superoxide anion, nitrotyrosine levels and expression of NADPH oxidase NOX4 and TGF-β1, the last two being reverted by treatment with the antioxidant n-acetylcysteine. In contrast, NOX1 expression and antioxidant potential were similar in aortas from the three genotypes. Interestingly, reduced eNOS expression in STZ+EDA+/+ vessels is counteracted by increased eNOS coupling and function. Although EDA+FN participates to vascular remodelling, these findings show that it plays a crucial role in limiting diabetic endothelial dysfunction by preventing vascular oxidative stress.