title: 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-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.
authors.affiliation: Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gortan Cappellari
authors.affiliation: Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
authors.forename: Rocco
authors.initials: R
authors.lastname: Barazzoni
authors.affiliation: Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Cattin
authors.affiliation: Mouse Molecular Genetics Laboratory, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
authors.forename: Andrés F
authors.initials: AF
authors.lastname: Muro
authors.affiliation: Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Zanetti
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003925:Diabetic Angiopathies / Q000209:etiology* / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D005353:Fibronectins / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress
chemical_list: D005353:Fibronectins; C572454:extra domain A fibronectin, mouse; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse