Prostanoid-mediated contractions of the carotid artery become Nox2-independent with aging
- 150 Downloads
Aging is a major risk factor for carotid artery disease that may lead to stroke and dementia. Vascular effects associated with aging include increased vasomotor tone, as well as enhanced contractility to endothelial vasoconstrictor prostanoids and reduced nitric oxide (NO) bioactivity partly due to increased oxidative stress. We hypothesized that vascular NADPH oxidase (Nox)-derived superoxide may be involved in prostanoid- and NO-related functional aging. NO-mediated relaxations and prostanoid-mediated contractions to acetylcholine as well as phenylephrine-dependent contractions were investigated in the carotid artery from young (4 months) and aged mice (24 months). Gene expression of Nox subunits and endothelial NO synthase (eNOS) was determined in the carotid artery and aorta. In young mice, the thromboxane-prostanoid receptor antagonist SQ 29,548 fully blocked acetylcholine-induced contractions while reducing responses to phenylephrine by 75 %. The Nox2-targeted inhibitor Nox2ds-tat and the superoxide scavenger tempol reduced acetylcholine-stimulated, prostanoid-mediated contractions by 85 and 75 %, respectively, and phenylephrine-dependent contractions by 45 %. Unexpectedly, in aged mice, the substantial Nox2-dependent component of acetylcholine- and phenylephrine-induced, prostanoid-mediated contractions was abolished. In addition, endothelium-dependent, NO-mediated relaxations were impaired with aging. The expression of Nox subunits was greater in the aorta compared with the carotid artery, in which Nox1 was undetectable. eNOS gene expression was reduced in the aorta of aged compared to young mice. In conclusion, aging decreases prostanoid-mediated contractility in the carotid artery involving a loss of Nox2 activity and is associated with impaired endothelium-dependent, NO-mediated relaxation. These findings may contribute to a better understanding of the pathophysiology of carotid artery disease and the aging process.
KeywordsAging Carotid artery NADPH oxidase Nox2 Prostanoid Superoxide
We thank Dr. Chelin Hu and Daniel F. Cimino for expert technical assistance. This study was supported by the National Institutes of Health (R01 CA127731 and CA163890 to E.R.P.), Dedicated Health Research Funds from the University of New Mexico School of Medicine allocated to the Signature Program in Cardiovascular and Metabolic Diseases (to E.R.P.), and the Swiss National Science Foundation (grants 135874 and 141501 to M.R.M. and grants 108258 and 122504 to M.B.). N.C.F. was supported by NIH training grant HL07736.
- Durrant JR, Seals DR, Connell ML, Russell MJ, Lawson BR, Folian BJ, Donato AJ, Lesniewski LA (2009) Voluntary wheel running restores endothelial function in conduit arteries of old mice: direct evidence for reduced oxidative stress, increased superoxide dismutase activity and down-regulation of NADPH oxidase. J Physiol 587:3271–3285PubMedCentralCrossRefPubMedGoogle Scholar
- Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, Launer LJ, Laurent S, Lopez OL, Nyenhuis D, Petersen RC, Schneider JA, Tzourio C, Arnett DK, Bennett DA, Chui HC, Higashida RT, Lindquist R, Nilsson PM, Roman GC, Sellke FW, Seshadri S (2011) Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association/american stroke association. Stroke 42:2672–2713PubMedCentralCrossRefPubMedGoogle Scholar
- Judkins CP, Diep H, Broughton BR, Mast AE, Hooker EU, Miller AA, Selemidis S, Dusting GJ, Sobey CG, Drummond GR (2010) Direct evidence of a role for Nox2 in superoxide production, reduced nitric oxide bioavailability, and early atherosclerotic plaque formation in ApoE-/- mice. Am J Physiol Heart Circ Physiol 298:H24–H32CrossRefPubMedGoogle Scholar
- Ling X, Cota-Gomez A, Flores NC, Hernandez-Saavedra D, McCord JM, Marecki JC, Haskins K, McDuffie M, Powers K, Kench J, Oka M, McMurtry I, Flores SC (2005) Alterations in redox homeostasis and prostaglandins impair endothelial-dependent vasodilation in euglycemic autoimmune nonobese diabetic mice. Free Radic Biol Med 39:1089–1098CrossRefPubMedGoogle Scholar
- Wang G, Sarkar P, Peterson JR, Anrather J, Pierce JP, Moore JM, Feng J, Zhou P, Milner TA, Pickel VM, Iadecola C, Davisson RL (2013) COX-1-derived PGE2 and PGE2 type 1 receptors are vital for angiotensin II-induced formation of reactive oxygen species and Ca(2+) influx in the subfornical organ. Am J Physiol Heart Circ Physiol 305:H1451–H1461PubMedCentralCrossRefPubMedGoogle Scholar
- Wong SL, Leung FP, Lau CW, Au CL, Yung LM, Yao X, Chen ZY, Vanhoutte PM, Gollasch M, Huang Y (2009) Cyclooxygenase-2-derived prostaglandin F2alpha mediates endothelium-dependent contractions in the aortae of hamsters with increased impact during aging. Circ Res 104:228–235CrossRefPubMedGoogle Scholar