Age-related changes in endothelial function and blood flow regulation

Toda, Noboru

doi:10.1016/j.pharmthera.2011.10.004

Cited by 174 publications

(154 citation statements)

References 226 publications

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“…The phenotypes observed in the aorta of young Rln Ϫ/Ϫ mice were not apparent in the old mice, but this was driven by changes in old Rln ϩ/ϩ mice. It has been well established that aged vessels have increased oxidative stress associated with altered NOS activity (8,21). In the present study, superoxide production, NADPH oxidase 2, and nitrotyrosine were not measured in aortae of older mice due to difficulty in obtaining Rln Ϫ/Ϫ mice and therefore limited tissue availability in the aged group.…”

Section: Discussionmentioning

confidence: 80%

“…Rln treatment also attenuates the stimulated production of ROS, nitrotyrosine, and arginase II in rat aortic rings incubated with TNF-␣ (5). Endothelial dysfunction is a hallmark of aging and vascular disease and is characterized by impaired vascular reactivity resulting from reduced NO availability, increased circulating vasoconstrictors, and elevated vascular oxidative stress (8,21). Given that Rln and its receptor are both expressed in a number of blood vessels, including the aorta and renal, uterine, and mesenteric arteries (9,17,24), and Rln appears to have several vasoprotective functions, we hypothesized that a lack of endogenous Rln may exacerbate or lead to the early onset of endothelial dysfunction associated with aging.…”

Section: Unlike Resistance Arteries Endogenous Relaxin Has Very Littmentioning

confidence: 99%

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Increased superoxide production and altered nitric oxide-mediated relaxation in the aorta of young but not old male relaxin-deficient mice

Jelinic

Parry

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Ng HH, Jelinic M, Parry LJ, Leo C. Increased superoxide production and altered nitric oxide-mediated relaxation in the aorta of young but not old male relaxin-deficient mice. Am J Physiol Heart Circ Physiol 309: H285-H296, 2015. First published May 8, 2015 doi:10.1152/ajpheart.00786.2014.-The vascular effects of exogenous relaxin (Rln) treatment are well established and include decreased myogenic reactivity and enhanced relaxation responses to vasodilators in small resistance arteries. These vascular responses are reduced in older animals, suggesting that Rln is less effective in mediating arterial function with aging. The present study investigated the role of endogenous Rln in the aorta and the possibility that vascular dysfunction occurs more rapidly with aging in Rln-deficient (Rln Ϫ/Ϫ ) mice. We compared vascular function and underlying vasodilatory pathways in the aorta of male wild-type (Rln ϩ/ϩ ) and Rlnmice at 4 and 16 mo of age using wire myography. Superoxide production, but not nitrotyrosine or NADPH oxidase expression, was significantly increased in the aorta of young Rln Ϫ/Ϫ mice, whereas endothelial nitric oxide (NO) synthase and basal NO availability were both significantly decreased compared with Rln ϩ/ϩ mice. In the presence of the cyclooxygenase inhibitor indomethacin, sensitivity to ACh was significantly decreased in young Rln Ϫ/Ϫ mice, demonstrating altered NO-mediated relaxation that was normalized in the presence of a membrane-permeable SOD or ROS scavenger. These vascular phenotypes were not exacerbated in old Rln Ϫ/Ϫ mice and, in most cases, did not differ significantly from old Rln ϩ/ϩ mice. Despite the vascular phenotypes in Rln Ϫ/Ϫ mice, endothelium-dependent and -independent vasodilation were not adversely affected. Our data show a role for endogenous Rln in reducing superoxide production and maintaining NO availability in the aorta but also demonstrate that Rln deficiency does not compromise vascular function in this artery or exacerbate endothelial dysfunction associated with aging.

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Section: Discussionmentioning

confidence: 80%

Section: Unlike Resistance Arteries Endogenous Relaxin Has Very Littmentioning

confidence: 99%

Increased superoxide production and altered nitric oxide-mediated relaxation in the aorta of young but not old male relaxin-deficient mice

Jelinic

Parry

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…4 Of note, superoxide anion (O 2 − ) inactivates endothelium-derived NO. [5][6][7] From the interaction of O 2 − with NO, the highly reactive peroxynitrite (ONOO − ) is formed. 5 As a consequence, vasodilation and the antithrombotic and antiinflammatory effects mediated by the endothelium are impaired, resulting in vascular damage.…”

mentioning

confidence: 99%

Deletion of the Activated Protein-1 Transcription Factor JunD Induces Oxidative Stress and Accelerates Age-Related Endothelial Dysfunction

et al. 2013

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Background-Reactive oxygen species are major determinants of vascular aging. JunD, a member of the activated protein-1 family of transcription factors, is emerging as a major gatekeeper against oxidative stress. However, its contribution to reactive oxygen species homeostasis in the vasculature remains unknown. Methods and Results-Endothelium-dependent vasorelaxation was impaired in young and old JunD(-/-) mice (6 and 22 months old) compared with age-matched wild-type mice. JunD(-/-) mice displayed an age-independent decline in endothelial nitric oxide release and endothelial nitric oxide synthase activity and increased mitochondrial superoxide formation and peroxynitrite levels. Furthermore, vascular expression and activity of the free radical scavengers manganese and extracellular superoxide dismutase and aldehyde dehydrogenase 2 were reduced, whereas the NADPH oxidase subunits p47phox, Nox2, and Nox4 were upregulated. These redox changes were associated with premature vascular aging, as shown by reduced telomerase activity, increased beta-galactosidase-positive cells, upregulation of the senescence markers p16(INK4a) and p53, and mitochondrial disruption. Interestingly, old wild-type mice showed a reduction in JunD expression and transcriptional activity resulting from promoter hypermethylation and binding with tumor suppressor menin, respectively. In contrast, JunD overexpression blunted age-induced endothelial dysfunction. In human endothelial cells, JunD knockdown exerted a similar impairment of the O-2 (-)/nitric oxide balance that was prevented by concomitant NADPH inhibition. In parallel, JunD expression was reduced in monocytes from old versus young healthy subjects and correlated with mRNA levels of scavenging and oxidant enzymes. Conclusions-JunD provides protection in aging-induced endothelial dysfunction and may represent a novel target to prevent reactive oxygen species-driven vascular aging. (Circulation. 2013;127:1229-1240.

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“…NO is an endogenous vasodilator that promotes the increase of blood flow, decreases vascular resistance, inhibits platelet aggregation, and also acts protecting endothelial cells from senescence and apoptosis (Ferroni et al 2006;Toda 2012). A strong relationship has been found between telomere attrition and cell senescence in HUVECs, suggesting that DNA damage manifested as telomere shortening is likely to play a central role in the development of endothelial dysfunction in the pathogenesis of vascular disease (Hastings et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Influence of endothelial dysfunction on telomere length in subjects with metabolic syndrome: LIPGENE study

González-Guardia

Yubero‐Serrano

Rangel‐Zúñiga

et al. 2014

AGE

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Previous evidences support that increased oxidative stress (OxS) may play an important role in metabolic syndrome (MetS) and both are closely linked to vascular dysfunction. This study determined whether there is a relationship between endothelial function and relative telomere length (RTL) in MetS subjects. In this crosssectional study from the LIPGENE cohort, a total of 88 subjects (36 men and 52 women) were divided into four groups by quartiles of telomere length. We measured ischemic reactive hyperemia (IRH), total nitrite (NO) and protein carbonyl (PC) plasma levels, F2-isoprostanes urinary levels, and superoxide dismutase (SOD) and glutathione peroxidase (GPx) plasma activities. IRH and NO plasma levels were higher in subjects with longer RTL (quartiles 3 and 4), while PC plasma levels, F2-isoprostanes urinary levels, and GPx and SOD plasma activities were lower in quartile 4 subjects (longest RTL). Additionally, MetS subjects with longer RTL had greater homeostatic model assessment-β level and lower triglycerides plasma levels. Our results suggest that endothelial dysfunction, associated with high levels of OxS, could be entailed in an increment of telomere attrition. Thus, further support of the molecular and cellular mechanisms involved in vascular dysfunction may contribute to the development AGE (2014) 36:9681 DOI 10.1007/s11357-014-9681-9Lorena González-Guardia and Elena María Yubero-Serrano contributed equally to this work. Electronic supplementary material

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Age-related changes in endothelial function and blood flow regulation

Cited by 174 publications

References 226 publications

Increased superoxide production and altered nitric oxide-mediated relaxation in the aorta of young but not old male relaxin-deficient mice

Increased superoxide production and altered nitric oxide-mediated relaxation in the aorta of young but not old male relaxin-deficient mice

Deletion of the Activated Protein-1 Transcription Factor JunD Induces Oxidative Stress and Accelerates Age-Related Endothelial Dysfunction

Influence of endothelial dysfunction on telomere length in subjects with metabolic syndrome: LIPGENE study

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