title: Prostanoid-mediated contractions of the carotid artery become Nox2-independent with aging.
abstract: 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.
authors.affiliation: Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA, matthias.meyer@ksa.ch.
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Meyer
authors.forename: Natalie C
authors.initials: NC
authors.lastname: Fredette
authors.forename: Matthias
authors.initials: M
authors.lastname: Barton
authors.forename: Eric R
authors.initials: ER
authors.lastname: Prossnitz
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000375:Aging / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002339:Carotid Arteries / Q000187:drug effects* / Q000502:physiology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D045462:Endothelium-Dependent Relaxing Factors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000502:physiology*; D009569:Nitric Oxide / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D013113:Spin Labels; D046509:Tissue Culture Techniques; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D045462:Endothelium-Dependent Relaxing Factors; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D017482:Receptors, Thromboxane; D013113:Spin Labels; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D010656:Phenylephrine; D009569:Nitric Oxide; C045749:SQ 29548; D052250:Nitric Oxide Synthase Type III; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D000109:Acetylcholine; C001803:tempol