title: Up-regulation of thromboxane A₂ impairs cerebrovascular eNOS function in aging atherosclerotic mice.
abstract: We previously reported that in healthy mouse cerebral arteries, endothelial nitric oxide synthase (eNOS) produces H₂O₂, leading to endothelium-dependent dilation. In contrast, thromboxane A₂ (TXA₂), a potent pro-oxidant and pro-inflammatory endogenous vasoconstrictor, is associated with eNOS dysfunction. Our objectives were to elucidate whether (1) the cerebrovascular eNOS-H₂O₂ pathway was sensitive to oxidative stress associated with aging and dyslipidemia and (2) TXA₂ contributed to cerebral eNOS dysfunction. Atherosclerotic (ATX = LDLR(-/-); hApoB(+/+)) and wild-type (WT) control mice were used at 3 and 12 months old (m/o). Three-m/o ATX mice were treated with the cardio-protective polyphenol catechin for 9 months. Dilations to ACh and the simultaneous eNOS-derived H₂O₂ production were recorded in isolated pressurized cerebral arteries. The age-associated decrease in cerebral eNOS-H₂O₂ pathway observed in WT was premature in ATX mice, decreasing at 3 m/o and abolished at 12 m/o. Thromboxane synthase inhibition by furegrelate increased dilations at 12 months in WT and at 3 and 12 months in ATX mice, suggesting an anti-dilatory role of TXA₂ with age hastened by dyslipidemia. In addition, the non-selective NADP(H) oxidase inhibitor apocynin improved the eNOS-H₂O₂ pathway only in 12-m/o ATX mice. Catechin normalized the function of this pathway, which became sensitive to L-NNA and insensitive to furegrelate or apocynin; catechin also prevented the rise in TXA₂ synthase expression. In conclusion, the age-dependent cerebral endothelial dysfunction is precocious in dyslipidemia and involves TXA₂ production that limits eNOS activity. Preventive catechin treatment reduced the impact of endogenous TXA₂ on the control of cerebral tone and maintained eNOS function.
authors: Faculty of Medicine, Department of Physiology, Université de Montréal, Montreal, QC, Canada.
authors: Annick
authors: A
authors: Drouin
authors: Nada
authors: N
authors: Farhat
authors: Virginie
authors: V
authors: Bolduc
authors: Nathalie
authors: N
authors: Thorin-Trescases
authors: Marc-Antoine
authors: MA
authors: Gillis
authors: Louis
authors: L
authors: Villeneuve
authors: Albert
authors: A
authors: Nguyen
authors: Eric
authors: E
authors: Thorin
references: Stroke. 1979 May-Jun;10(3):306-9
references: 462519
references: Int J Stroke. 2009 Dec;4(6):461-70
references: 19930058
references: Thromb Res. 2005;115(5):367-73
references: 15733969
references: Arterioscler Thromb Vasc Biol. 2005 Feb;25(2):442-6
references: 15499038
references: Cardiovasc Res. 2009 Oct 1;84(1):24-32
references: 19586943
references: Exp Gerontol. 2004 Jul;39(7):1027-34
references: 15236762
references: Stroke. 1987 Jan-Feb;18(1):195-9
references: 2949399
references: Arterioscler Thromb Vasc Biol. 2010 Apr;30(4):749-57
references: 20093625
references: FASEB J. 2005 Feb;19(2):258-60
references: 15569775
references: Clin Sci (Lond). 2010 Apr 07;119(1):1-17
references: 20370718
references: Hypertension. 2008 Feb;51(2):211-7
references: 18086956
references: Stroke. 1993 Feb;24(2):219-23
references: 8421822
references: Stroke. 2001 Mar;32(3):761-6
references: 11239199
references: Am J Physiol Heart Circ Physiol. 2007 Oct;293(4):H2508-15
references: 17644574
references: Am J Physiol Heart Circ Physiol. 2010 Jun;298(6):H2062-70
references: 20382853
references: Arterioscler Thromb Vasc Biol. 2011 Jan;31(1):125-32
references: 20947827
references: Stroke. 1993 Dec;24(12):2059-64; discussion 2064-5
references: 8248988
references: Fed Proc. 1987 Jan;46(1):133-8
references: 2948837
references: Circ Res. 2011 Mar 4;108(5):566-73
references: 21233456
references: Pflugers Arch. 2010 May;459(6):853-62
references: 20224869
references: Cardiovasc Res. 2007 Jan 1;73(1):73-81
references: 17113574
references: Biochem Pharmacol. 1988 Mar 1;37(5):837-41
references: 2830882
references: Am J Physiol Heart Circ Physiol. 2004 Aug;287(2):H588-94
references: 15277199
references: J Mol Neurosci. 2007 Sep;33(1):94-9
references: 17901552
references: Stroke. 2007 Jul;38(7):2136-41
references: 17525390
references: Arterioscler Thromb. 1991 Sep-Oct;11(5):1147-55
references: 1911701
references: Cardiovasc Res. 2008 Nov 1;80(2):271-9
references: 18596059
references: Stroke. 1999 Aug;30(8):1542-7
references: 10436098
references: Stroke. 1977 Jul-Aug;8(4):480-3
references: 898244
references: BMB Rep. 2009 Apr 30;42(4):200-5
references: 19403042
references: Stroke. 2009 Jul;40(7):2480-5
references: 19478218
references: J Biol Chem. 2009 Mar 6;284(10):6348-60
references: 19095646
references: J Cereb Blood Flow Metab. 2006 Jun;26(6):836-45
references: 16222243
references: Mediators Inflamm. 2009;2009:494928
references: 19636434
references: Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4544-9
references: 9539774
references: Circulation. 2008 Jan 22;117(3):421-8
references: 18158360
references: Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):2744-52
references: 9409251
references: Stroke. 2010 Apr;41(4):784-9
references: 20167907
references: Arterioscler Thromb Vasc Biol. 1998 Sep;18(9):1506-13
references: 9743241
references: Circ Res. 2003 Feb 7;92(2):e31-40
references: 12574154
references: Am J Physiol Heart Circ Physiol. 2007 Jan;292(1):H451-8
references: 16980343
references: J Med Food. 2009 Apr;12(2):334-9
references: 19459734
references: Stroke. 1989 Feb;20(2):242-7
references: 2919413
references: J Thromb Thrombolysis. 2009 May;27(4):438-46
references: 18521540
references: Circulation. 2006 Apr 4;113(13):1708-14
references: 16585403
references: Circ Res. 2009 Mar 27;104(6):e42-54
references: 19265038
references: Am J Physiol Heart Circ Physiol. 2011 Mar;300(3):H1032-43
references: 21186270
references: Brain Res Bull. 2000 Dec;53(6):743-9
references: 11179838
references: Circ J. 2010 Mar;74(3):578-88
references: 20134098
references: Br J Nutr. 2009 Dec;102(12):1790-802
references: 19751534
references: Am J Physiol. 1990 Apr;258(4 Pt 2):H1138-43
references: 2109940
references: Stroke. 2009 May;40(5):1827-33
references: 19286591
references: J Nutr Biochem. 2006 May;17(5):291-306
references: 16443357
references: Blood Vessels. 1987;24(3):117-9
references: 3109527
references: J Pharmacol Sci. 2003 May;92(1):1-6
references: 12832848
references: Brain Res. 2010 Feb 26;1316:163-72
references: 20026315
references: Am J Clin Nutr. 2004 Jan;79(1):54-61
references: 14684397
references: J Nutr. 2001 Jan;131(1):27-32
references: 11208934