| First Author | Onetti Y | Year | 2016 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 310 |
| Issue | 9 | Pages | H1081-90 |
| PubMed ID | 26945079 | Mgi Jnum | J:233008 |
| Mgi Id | MGI:5780606 | Doi | 10.1152/ajpheart.00770.2015 |
| Citation | Onetti Y, et al. (2016) NADPH oxidase 4 attenuates cerebral artery changes during the progression of Marfan syndrome. Am J Physiol Heart Circ Physiol 310(9):H1081-90 |
| abstractText | 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)-beta 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-beta, 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 mum(2); Marfan Nox4(-/-): 8,795 +/- 824 mum(2); 60 mmHg; P < 0.05), accompanied by decreased TGF-beta 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. |
