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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 (EDAwt/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?+?EDAwt/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-?1, 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.

SUBMITTER: Gortan Cappellari G 

PROVIDER: S-EPMC5126581 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Lack of Fibronectin Extra Domain A Alternative Splicing Exacerbates Endothelial Dysfunction in Diabetes.

Gortan Cappellari Gianluca G   Barazzoni Rocco R   Cattin Luigi L   Muro Andrés F AF   Zanetti Michela M  

Scientific reports 20161129


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<sup>-/-</sup>, EDA<s  ...[more]

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