title: Endothelial cell-specific reactive oxygen species production increases susceptibility to aortic dissection.
abstract: BACKGROUND
  Increased production of reactive oxygen species (ROS) throughout the vascular wall is a feature of cardiovascular disease states, but therapeutic strategies remain limited by our incomplete understanding of the role and contribution of specific vascular cell ROS to disease pathogenesis. To investigate the specific role of endothelial cell (EC) ROS in the development of structural vascular disease, we generated a mouse model of endothelium-specific Nox2 overexpression and tested the susceptibility to aortic dissection after angiotensin II (Ang II) infusion.
  
  
  RESULTS
  A specific increase in endothelial ROS production in Nox2 transgenic mice was sufficient to cause Ang II-mediated aortic dissection, which was never observed in wild-type mice. Nox2 transgenic aortas had increased endothelial ROS production, endothelial vascular cell adhesion molecule-1 expression, matrix metalloproteinase activity, and CD45(+) inflammatory cell infiltration. Conditioned media from Nox2 transgenic ECs induced greater Erk1/2 phosphorylation in vascular smooth muscle cells compared with wild-type controls through secreted cyclophilin A (CypA). Nox2 transgenic ECs (but not vascular smooth muscle cells) and aortas had greater secretion of CypA both at baseline and in response to Ang II stimulation. Knockdown of CypA in ECs abolished the increase in vascular smooth muscle cell Erk1/2 phosphorylation conferred by EC conditioned media, and preincubation with CypA augmented Ang II-induced vascular smooth muscle cell ROS production.
  
  
  CONCLUSIONS
  These findings demonstrate a pivotal role for EC-derived ROS in the determination of the susceptibility of the aortic wall to Ang II-mediated aortic dissection. ROS-dependent CypA secretion by ECs is an important signaling mechanism through which EC ROS regulate susceptibility of structural components of the aortic wall to aortic dissection.
authors.affiliation: From the BHF Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK (L.M.F., G.D., J.K.B., E.M., M.J.C., A.B.H., M.A.M., J.E.S., R.P.L., K.M.C.); and Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK (A.M., J.-M.L.).
authors.forename: Lampson M
authors.initials: LM
authors.lastname: Fan
authors.affiliation: From the BHF Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK (L.M.F., G.D., J.K.B., E.M., M.J.C., A.B.H., M.A.M., J.E.S., R.P.L., K.M.C.); and Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK (A.M., J.-M.L.).
authors.forename: Gillian
authors.initials: G
authors.lastname: Douglas
authors.affiliation: From the BHF Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK (L.M.F., G.D., J.K.B., E.M., M.J.C., A.B.H., M.A.M., J.E.S., R.P.L., K.M.C.); and Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK (A.M., J.-M.L.).
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Bendall
authors.affiliation: From the BHF Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK (L.M.F., G.D., J.K.B., E.M., M.J.C., A.B.H., M.A.M., J.E.S., R.P.L., K.M.C.); and Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK (A.M., J.-M.L.).
authors.forename: Eileen
authors.initials: E
authors.lastname: McNeill
authors.affiliation: From the BHF Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK (L.M.F., G.D., J.K.B., E.M., M.J.C., A.B.H., M.A.M., J.E.S., R.P.L., K.M.C.); and Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK (A.M., J.-M.L.).
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Crabtree
authors.affiliation: From the BHF Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK (L.M.F., G.D., J.K.B., E.M., M.J.C., A.B.H., M.A.M., J.E.S., R.P.L., K.M.C.); and Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK (A.M., J.-M.L.).
authors.forename: Ashley B
authors.initials: AB
authors.lastname: Hale
authors.affiliation: From the BHF Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK (L.M.F., G.D., J.K.B., E.M., M.J.C., A.B.H., M.A.M., J.E.S., R.P.L., K.M.C.); and Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK (A.M., J.-M.L.).
authors.forename: Anna
authors.initials: A
authors.lastname: Mai
authors.affiliation: From the BHF Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK (L.M.F., G.D., J.K.B., E.M., M.J.C., A.B.H., M.A.M., J.E.S., R.P.L., K.M.C.); and Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK (A.M., J.-M.L.).
authors.forename: Jian-Mei
authors.initials: JM
authors.lastname: Li
authors.affiliation: From the BHF Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK (L.M.F., G.D., J.K.B., E.M., M.J.C., A.B.H., M.A.M., J.E.S., R.P.L., K.M.C.); and Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK (A.M., J.-M.L.).
authors.forename: Martina A
authors.initials: MA
authors.lastname: McAteer
authors.affiliation: From the BHF Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK (L.M.F., G.D., J.K.B., E.M., M.J.C., A.B.H., M.A.M., J.E.S., R.P.L., K.M.C.); and Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK (A.M., J.-M.L.).
authors.forename: Jurgen E
authors.initials: JE
authors.lastname: Schneider
authors.affiliation: From the BHF Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK (L.M.F., G.D., J.K.B., E.M., M.J.C., A.B.H., M.A.M., J.E.S., R.P.L., K.M.C.); and Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK (A.M., J.-M.L.).
authors.forename: Robin P
authors.initials: RP
authors.lastname: Choudhury
authors.affiliation: From the BHF Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK (L.M.F., G.D., J.K.B., E.M., M.J.C., A.B.H., M.A.M., J.E.S., R.P.L., K.M.C.); and Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK (A.M., J.-M.L.). keith.channon@cardiov.ox.ac.uk.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
mesh_terms: D000784:Aortic Dissection / Q000453:epidemiology* / Q000209:etiology / Q000378:metabolism; D000804:Angiotensin II / Q000009:adverse effects; D000818:Animals; D001014:Aortic Aneurysm / Q000453:epidemiology* / Q000209:etiology / Q000378:metabolism; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000453:epidemiology* / Q000209:etiology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; D000804:Angiotensin II; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D020782:Matrix Metalloproteinases; D021983:Cyclophilins
keywords: NADPH oxidase; angiotensin II; aorta; cyclophilin A; dissection; reactive oxygen species