title: NADPH oxidase 4 attenuates cerebral artery changes during the progression of Marfan syndrome.
abstract: Marfan syndrome (MFS) is a connective tissue disorder that is often associated with the fibrillin-1 (Fbn1) gene mutation and characterized by cardiovascular alterations, predominantly ascending aortic aneurysms. Although neurovascular complications are uncommon in MFS, the improvement in Marfan patients' life expectancy is revealing other secondary alterations, potentially including neurovascular disorders. However, little is known about small-vessel pathophysiology in MFS. MFS is associated with hyperactivated transforming growth factor (TGF)-β signaling, which among numerous other downstream effectors, induces the NADPH oxidase 4 (Nox4) isoform of NADPH oxidase, a strong enzymatic source of H2O2 We hypothesized that MFS induces middle cerebral artery (MCA) alterations and that Nox4 contributes to them. MCA properties from 3-, 6-, or 9-mo-old Marfan (Fbn1(C1039G/+)) mice were compared with those from age/sex-matched wild-type littermates. At 6 mo, Marfan compared with wild-type mice developed higher MCA wall/lumen (wild-type: 0.081 ± 0.004; Marfan: 0.093 ± 0.002; 60 mmHg; P < 0.05), coupled with increased reactive oxygen species production, TGF-β, and Nox4 expression. However, wall stiffness and myogenic autoregulation did not change. To investigate the influence of Nox4 on cerebrovascular properties, we generated Marfan mice with Nox4 deficiency (Nox4(-/-)). Strikingly, Nox4 deletion in Marfan mice aggravated MCA wall thickening (cross-sectional area; Marfan: 6,660 ± 363 μm(2); Marfan Nox4(-/-): 8,795 ± 824 μm(2); 60 mmHg; P < 0.05), accompanied by decreased TGF-β expression and increased collagen deposition and Nox1 expression. These findings provide the first evidence that Nox4 mitigates cerebral artery structural changes in a murine model of MFS.
authors.affiliation: Departament de Farmacologia, de Terapèutica i de Toxicologia, Institut de Neurociències, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain;
authors.forename: Yara
authors.initials: Y
authors.lastname: Onetti
authors.affiliation: Departament de Biologia Cellular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain;
authors.forename: Thayna
authors.initials: T
authors.lastname: Meirelles
authors.affiliation: Institut Clínic del Tòrax, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; and.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Dantas
authors.affiliation: Institute for Cardiovascular Physiology, Goethe-University Frankfurt, Frankfurt, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schröder
authors.affiliation: Departament de Farmacologia, de Terapèutica i de Toxicologia, Institut de Neurociències, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain;
authors.forename: Elisabet
authors.initials: E
authors.lastname: Vila
authors.affiliation: Departament de Biologia Cellular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain; Institut Clínic del Tòrax, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; and.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Egea
authors.affiliation: Departament de Farmacologia, de Terapèutica i de Toxicologia, Institut de Neurociències, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain; francesc.jimenez@uab.cat.
authors.forename: Francesc
authors.identifier: 0000-0002-9034-2041
authors.initials: F
authors.lastname: Jiménez-Altayó
mesh_terms: D000818:Animals; D062186:Arterial Pressure; D002561:Cerebrovascular Disorders / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D000071838:Fibrillin-1 / Q000235:genetics; D020022:Genetic Predisposition to Disease; D008297:Male; D008382:Marfan Syndrome / Q000150:complications* / Q000201:enzymology / Q000235:genetics; D040542:Mechanotransduction, Cellular; D018345:Mice, Knockout; D020768:Middle Cerebral Artery / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D013314:Stress, Mechanical; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D066253:Vascular Remodeling; D059289:Vascular Stiffness; D054392:Adipokines
chemical_list: D003094:Collagen; D000071838:Fibrillin-1; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; C000605724:Fbn1 protein, mouse; D054392:Adipokines; C000614711:NOX1 protein, mouse; C422943:Nox4 protein, mouse
keywords: Nox4; fibrillin-1; neurovascular disorders; transforming growth factor-β