Age-induced endothelial dysfunction: is it time to redefine the “reactivity” of reactive oxygen species?

Invited EditorialAge-induced endothelial dysfunction: is it time to redefine the “reactivity” of reactive oxygen species?Judy M. Muller-DelpJudy M. Muller-DelpDepartment of Physiology and Functional Genomics, University of Florida, Gainesville, FloridaPublished Online:01 May 2011https://doi.org/10.1152/japplphysiol.00272.2011This is the final version - click for previous versionMoreSectionsPDF (98 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations endothelium-dependent signaling through nitric oxide (NO) is a critical contributor to exercise hyperemia in skeletal muscle. The results of numerous studies indicate that age impairs NO-dependent vasodilation in skeletal muscle (5, 8, 9, 13, 14). The bioavailability of NO and subsequent vasodilation is regulated by a balance between NO synthesis and degradation. In the skeletal muscle vasculature, synthesis of NO has been reported to decline with age because of reduced expression and function of endothelial nitric oxide synthase (eNOS) (7, 13). Age-induced increases in reactive oxygen species (ROS) may also contribute to reduced availability of NO in the skeletal muscle resistance vasculature (10, 13). Although availability of NO is dependent on degradation or scavenging by ROS, direct interactions between these highly reactive species is difficult to assess using in vivo or in situ preparations. Questions remain regarding the role played by ROS in endothelial signaling, and recent reports have indicated that ROS may act as endothelial signaling molecules, promoting vasodilation under physiological conditions in several vascular beds (1–4, 7).In previous studies, Woodman and colleagues (10, 13, 14) have reported that reduced ability to scavenge superoxide may contribute to impaired endothelium-dependent vasodilation in feed arteries of soleus muscle. In this issue of the Journal of Applied Physiology, Trott et al. (11) report that NAD(P)H oxidase-derived ROS contribute to impairment of endothelium-dependent vasodilation in soleus muscle feed arteries; however, the current findings also suggest that a balance in regulation of the levels of ROS is critical to maintenance of endothelial function in skeletal muscle resistance arteries. Indeed, these authors report that both inhibition of NAD(P)H oxidase by apocynin and augmentation of scavenging of superoxide (O2−) by addition of exogenous superoxide dismutase (SOD) improve endothelial function in skeletal muscle feed arteries of aged rats; however, similar treatments decreased endothelium-dependent vasodilation to acetylcholine in arteries from young rats. These results imply that overproduction of O2−, or an inability to remove O2−, contributes to endothelial dysfunction with age. In contrast, a disruption of the regulation of endogenous O2− levels by addition of exogenous superoxide dismutase reduced endothelium-dependent vasodilation in arteries from young rats.Hydrogen peroxide (H2O2), the product of dismutation of O2−, has been reported to function as an endothelium-derived hyperpolarizing factor. In their study, Trott et al. (11) report that scavenging of H2O2 by catalase and PEG-catalase blunted endothelium-dependent vasodilation to acetylcholine in soleus muscle feed arteries from young rats. This finding is in line with reports describing a vasodilatory role for H2O2 in arterioles from several vascular beds, including skeletal muscle (1–3, 8). In contrast, Trott et al. (11) report that treatment of arteries from old rats with PEG-catalase increases acetylcholine-induced vasodilation. These results suggest that H2O2 functions as a critical signaling molecule in the endothelium of arteries from young rats, but that when H2O2 is produced in excess in the endothelium of arteries from old rats, this reactive species contributes to dysfunction of the endothelium. H2O2 has been reported to contribute to activation of NF-κB and development of a proinflammatory state in aged arteries (12); however, the mechanisms by which H2O2 regulates endothelium-dependent NO availability remain to be elucidated. The results of the current study (11) emphasize the need to better understand the balance between the potentially beneficial vasodilatory effects of H2O2 and the deleterious effects that occur with overproduction of H2O2, including potential generation of damaging hydroxyl radical (8).These results of the current study by Trott et al. (11) highlight the need for studies that investigate the effects of age on regulation of the balance of ROS in the endothelium. Hypotheses based on the assumption that ROS have only deleterious effects on endothelium-dependent vasodilation may lead to incomplete interpretation of experimental results. Because these molecules are highly reactive, studies of interactions between them need to consider the complexity of effects that can be generated by age-related alterations of the mechanisms that control their production and degradation. Reactivity and activation of signaling in the vascular smooth muscle by these reactive compounds must also be considered. Trott et al. also report that the responsiveness of soleus muscle feed arteries to H2O2 is decreased with age. In addition, protein content of the gp91phox subunit of NAD(P)H oxidase and MnSOD increased with age. These results suggest that the levels of NAD(P)H-derived H2O2 increase with age, but that this increase in H2O2 production does not translate into an increase in H2O2-mediated vasodilation. Future experiments are needed to determine the effects created by this apparent excess production of H2O2. In the presence of sufficient free iron, the highly damaging hydroxyl radical could be generated, contributing to impairment of endothelium-dependent vasodilation (7).The results of this study by Trott and colleagues (11) also indicate that the effects of age on NO- and H2O2-induced signaling were different for flow- and acetylcholine-induced vasodilation. These pathway-specific adaptations highlight the need to consider the nature of the stimuli imposed on the endothelium and the function of the vessels being studied when investigating the effects of age on ROS signaling. It is also important to note that age-related changes in endothelial ROS signaling in soleus muscle feed arteries differed from those reported by Sindler et al. (7) in soleus muscle 1A arterioles. Thus the difference in the milieu surrounding vessels within the muscle versus that which surrounds the feed artery, located just outside the muscle, is sufficient to result in specific adaptations in ROS signaling with advancing age.Trott et al. (11) demonstrate that age-related changes in NO- and ROS-mediated signaling in skeletal muscle resistance arteries cannot be studied in a manner that focuses exclusively on a single species of oxygen radical. Potential interactions between the reactive species involved in these signaling pathways are illustrated in Fig. 1. As shown by Trott et al. (11), endogenous NO and/or H2O2 may cause relaxation of vascular smooth muscle and subsequent vasodilation of skeletal muscle feed arteries; however, it is also possible that if age results in excess production of H2O2, this could 1) increase formation of cytotoxic OH−, or 2) produce negative effects on the activity of NAD(P)H and/or eNOS. Simlarly, ONOO− produced from the reaction of O2− and NO can act as a vasodilator of smooth muscle (6) but can also cause nitrosylation of proteins with damaging effects. Real-time approaches will be needed to accurately assess interactions between these highly reactive species; however, careful application of specific pharmacological inhibitors with critical control experiments, as employed in this study by Trott et al. (11), provide valuable insight into the nature of the adaptations in ROS signaling that occur with advancing age. Because of the complexity of interactions between these species, this presents a considerable challenge to investigators, in particular in the resistance vasculature, where tissue sample sizes are small. In future investigations, the effects of age on the balance and interaction between these reactive species must be investigated with a comprehensive approach that does not exclude the possibility that ROS function in normal signaling as well as in pathological conditions created by aging or disease.Fig. 1.Potential interactions between reactive oxygen species and their impact on NO- and H2O2-mediated signaling in skeletal muscle resistance arteries. VSM, vascular smooth muscle; eNOS, endothelial nitric oxide synthase.Download figureDownload PowerPointDISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the author(s).REFERENCES1. Drouin A , Thorin E. 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Exercise training attenuates aging-associated reductions in endothelium-dependent vasodilation of rat skeletal muscle arterioles. FASEB J 16: A766, 2002.ISI | Google Scholar10. Trott DW , Gunduz F , Laughlin MH , Woodman CR. Exercise training reverses age-related decrements in endothelium-dependent dilation in skeletal muscle feed arteries. J Appl Physiol 106: 1925–1934, 2009.Link | ISI | Google Scholar11. Trott DW , Seawright JW , Luttrell MJ , Woodman CR. NAD(P)H oxidase-derived reactive oxygen species contribute to age-related impairments of endothelium-dependent dilation in rat soleus feed arteries. J Appl Physiol (January 13, 2011). doi:10.1152/japplphysiol.01037.2010.Link | ISI | Google Scholar12. Ungvari Z , Orosz Z , Labinskyy N , Rivera A , Xiangmin Z , Smith K , Csiszar A. Increased mitochondrial H2O2 production promotes endothelial NF-κB activation in aged rat arteries. Am J Physiol Heart Circ Physiol 293: H37–H47, 2007.Link | ISI | Google Scholar13. Woodman CR , Price EM , Laughlin MH. Aging induces muscle-specific impairment of endothelium-dependent dilation in skeletal muscle feed arteries. J Appl Physiol 93: 1685–1690, 2002.Link | ISI | Google Scholar14. Woodman CR , Price EM , Laughlin MH. Selected contribution: aging impairs nitric oxide and prostacyclin mediation of endothelium-dependent dilation in soleus feed arteries. J Appl Physiol 95: 2164–2170, 2003.Link | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: J. M. Muller-Delp, Dept. of Physiology and Functional Genomics, Univ. of Florida, 1600 SW Archer Rd., PO Box 100274, Gainesville, FL 32610 (e-mail: [email protected]edu). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByChapitre 12. Stress et exerciceAltered potassium ATP channel signaling in mesenteric arteries of old high salt-fed rats30 June 2016 | Journal of Exercise Nutrition & Biochemistry, Vol. 20, No. 2The effects of aging on the functional and structural properties of the rat basilar artery11 June 2014 | Physiological Reports, Vol. 2, No. 6 More from this issue > Volume 110Issue 5May 2011Pages 1152-1153 Copyright & PermissionsCopyright © 2011 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00272.2011PubMed21393473History Published online 1 May 2011 Published in print 1 May 2011 Metrics