- [Show abstract] [Hide abstract] ABSTRACT: Objective: Aortic pulse-wave velocity (aPWV) increases with age and is a strong independent predictor of incident cardiovascular diseases (CVDs) in healthy middle-aged and older adults. aPWV is lower in middle-aged and older adults who perform regular aerobic exercise than in their sedentary peers. As exercise is associated with reduced systemic inflammation, we hypothesized that suppression of the pro-inflammatory transcription factor nuclear factor κ B (NFκB) may mediate this process. Methods: aPWV was measured in young sedentary [n = 10, blood pressure (BP) 108 ± 3/59 ± 2 mmHg; mean ± SEM], middle-aged and older sedentary (n = 9, 124 ± 7/73 ± 5 mmHg) and middle-aged and older aerobic exercise-trained (n = 12, 110 ± 4/67 ± 2 mmHg) healthy, nonhypertensive men and women. Results: Baseline aPWV increased with age [626 ± 14 (young sedentary) vs. 859 ± 49 (middle-aged and older sedentary) cm/s, P < 0.001] but was 20% lower in middle-aged and older trained (686 ± 30 cm/s) than in middle-aged and older sedentary (P < 0.005). Short-term (4 days x 2500-4500 mg) treatment with the NFκB inhibitor salsalate (randomized, placebo-controlled cross-over design) reduced aPWV (to 783 ± 44 cm/s, P < 0.05) without changing BP (P = 0.40) or heart rate (P = 0.90) in middle-aged and older sedentary, but had no effect in young sedentary (623 ± 19) or middle-aged and older trained (699 ± 30). Following salsalate treatment, aPWV no longer was significantly different in middle-aged and older sedentary vs. middle-aged and older trained (P = 0.29). The reduction in aPWV with salsalate administration was inversely related to baseline (placebo) aPWV (r = -0.60, P < 0.001). Conclusion: These results support the hypothesis that suppressed NFκB signalling may partially mediate the lower aortic stiffness in middle-aged and older adults who regularly perform aerobic exercise. Because aPWV predicts incident cardiovascular events in this population, this suggests that tonic suppression of NFκB signalling in middle-aged and older exercising adults may potentially lower cardiovascular risk.
- [Show abstract] [Hide abstract] ABSTRACT: We tested the hypothesis that aortic perivascular adipose (PVAT) from young low-density lipoprotein receptor deficient (LDLr-/-) mice promotes aortic stiffness and remodeling, which would be mediated by greater PVAT-derived interleukin (IL-6) secretion. Arterial stiffness was assessed by aortic pulse wave velocity (aPWV) and with ex vivo intrinsic mechanical properties testing in young (4-6 months) wild-type (WT) and LDLr-/- chow fed mice. Compared with WT, LDLr-/- mice had increased aPWV (407 ± 18 vs. 353 ± 13 cm/s) and intrinsic mechanical stiffness (5308 ± 623 vs. 3355 ± 330 kPa) that was associated with greater aortic protein expression of collagen I and advanced glycation end products (AGEs) (all, P < 0.05 vs. WT). Aortic segments from LDLr-/- compared with WT mice cultured in the presence of PVAT had greater intrinsic mechanical stiffness (6092 ± 480 vs. 3710 ± 316 kPa), and was reversed in LDLr-/- mouse arteries cultured without PVAT (3473 ± 577 kPa)(both, P < 0.05). Collagen I and AGEs were increased in LDLr-/- mouse arteries cultured with PVAT (P < 0.05 vs. WT), which was attenuated when arteries were cultured in the absence PVAT (P < 0.05). PVAT from LDLr-/- mice secreted larger amounts of IL-6 (3.4 ± 0.1 vs. 2.3 ± 0.7 ng/ml)(P < 0.05), and an IL-6 neutralizing antibody decreased intrinsic mechanical stiffness in LDLr-/- aortic segments cultured with PVAT (P < 0.05). Collectively, these data provide evidence for a role of PVAT-derived IL-6 in the pathogenesis of aortic stiffness and remodeling in chow fed LDLr-/- mice. Copyright © 2014, American Journal of Physiology - Heart and Circulatory Physiology.
Chapter: Overview of Arterial Stiffness[Show abstract] [Hide abstract] ABSTRACT: Arterial stiffness is a novel risk factor for cardiovascular disease resulting from functional and structural changes within arteries. Greater arterial stiffening places negative consequences on the heart, because greater effort is required for the myocardium to overcome the resultant increase in afterload. While the etiology of arterial stiffness is not entirely clear, aging appears to be the principal accelerator of the functional and structural remodeling that occurs in the arteries after the third decade of life. Importantly, arterial stiffness can be easily assessed with potential for routine clinical measurement.
Chapter: Mechanisms of Arterial Stiffness[Show abstract] [Hide abstract] ABSTRACT: Current understanding for the mechanisms contributing to arterial stiffness is limited. The field is rapidly growing, however, and the complex process of functional, structural and signaling pathways working together to stiffen arteries is becoming increasingly clear. As such, arterial dilation and constriction, extracellular matrix accumulation and stiffening of individual cells via specific signal transduction pathways inter-connect providing numerous targets for potential therapeutic intervention. Herein we highlight the mechanisms that are largely implicated in arterial stiffness, and those that may be emerging as important targets.
Chapter: Implications of Arterial Stiffness[Show abstract] [Hide abstract] ABSTRACT: The implications for increased arterial stiffness are just now beginning to be understood. However, there is still much unknown in this emerging field of study. In this chapter we overview several areas of clinical importance that influence arterial stiffness, which include aging, sex, race, body composition, and cardiorespiratory fitness, and the implications of these on cardiovascular health and target organ damage. These discussions merely highlight the complex interactions that occur with aging alone, which become increasingly convoluted with multiple pathologies. Thus, our discussion only begins to elucidate the very complex processes contributing to aortic stiffness and the overall health implications.
Chapter: Interventions to Destiffen Arteries[Show abstract] [Hide abstract] ABSTRACT: Stiffening of arteries is a condition associated with aging and disease that results in a less compliant arterial system. Arterial stiffness is an important CVD risk factor that is associated with premature mortality and heightened morbidity. Intervening to reduce arterial stiffening is a challenge, yet there is mounting evidence supporting the effects of lifestyle and dietary modifications to reduce aortic pulse wave velocity (aPWV), the gold standard measure of aortic stiffness. Plant-based polyphenolic compounds, omega-3 fatty acids, antioxidant vitamins C and E, regular aerobic exercise, sodium reduction and weight loss have all shown to be successful strategies to destiffen arteries. First-line strategies to combat CVD risk factors such as arterial stiffening should include lifestyle modifications.
- [Show abstract] [Hide abstract] ABSTRACT: After feeding, Burmese pythons (Python molurus bivittatus) undergo physiological cardiac remodeling associated with increased cardiac output. Because the left ventricle (LV) of the heart and aorta are anatomically and mechanically coupled, we tested the hypothesis that chronic overfeeding causes aortic remodeling. Nine-month old snakes consumed 25% of their total body weight every 2 weeks (normal fed, NF, n=5) or once every 3 days (overfed, OF, n=7) for 12 weeks. Compared with NF, OF had a greater aortic lumen diameter (D, 2.42 ± 0.11 vs. 1.47 ± 0.04 mm, p<0.01) and total wall thickness (WT, 353 ± 12 vs. 227 ± 12 μm, p<0.001), with unchanged WT:D ratio (p=0.67). This remodeling was associated with increased intrinsic mechanical stiffening (elastic modulus: 6,457 ± 670 vs. 3,667 ± 501 kPa, p=0.01; stiffness: 18,811 ± 4,318 vs. 7,093 ± 1,187 kPa*m, p<0.05) and expression of collagen I (2.27 ± 0.34 vs. 1.00 ± 0.15 AU, p<0.05) and advanced glycation end-products (1.84 ± 0.33 vs. 1.00 ± 0.35 AU, p<0.05). However, no difference in the oxidative stress marker nitrotyrosine was observed between groups, and OF actually had greater expression of the antioxidant enzyme CuZnSOD (2.45 ± 0.06 vs. 1.00 ± 0.25 AU, p=0.05). Chronic overfeeding induces a physiological remodeling of the aorta in Burmese pythons that is not mediated by oxidative stress, but may be an adaptive response to increased blood flow and cardiac remodeling.
Dataset: Supplementary Material 1
Dataset: Supplementary Material 2[Show abstract] [Hide abstract] ABSTRACT: Table S1 Arterial morphology and blood pressure in young, old and old TEMPOL-treated mice. Table S2 Arterial morphology and blood pressure in young recipient mice after transplanted with PVAT from young, old or old TEMPOLtreated donors for 8 weeks. Fig. S1 Adventitial collagen I expression in young, old and old TEMPOL-treated mice. Fig. S2 Superoxide production in adipocytes isolated from PVAT of young and old mice. Fig. S3 Cytokine secretion profile of cultured PVAT from young and old mice. Fig. S4 Adventitial collagen I expression in young recipient mice transplanted with PVAT from young, old or old TEMPOL donors.
- [Show abstract] [Hide abstract] ABSTRACT: Aging is the major risk factor for cardiovascular diseases (CVD). This is attributable primarily to adverse changes in arteries, notably increases in large elastic artery stiffness and endothelial dysfunction mediated by inadequate concentrations of the vascular-protective molecule, nitric oxide (NO), and higher levels of oxidative stress and inflammation. Inorganic nitrite is a promising precursor molecule for augmenting circulating and tissue NO bioavailability because it requires only a one-step reduction to NO. Nitrite also acts as an independent signaling molecule, exerting many of the effects previously attributed to NO. Results of recent studies indicate that nitrite may be effective in the treatment of vascular aging. Short-term oral sodium nitrite supplementation reduces aortic pulse wave velocity, the gold-standard measure of large elastic artery stiffness, in old mice and ameliorates endothelial dysfunction, as indicated by normalization of NO-mediated endothelium-dependent dilation. These improvements in age-related vascular dysfunction with nitrite are mediated by reductions in oxidative stress and inflammation, and may be linked to increases in mitochondrial biogenesis and health. Increasing nitrite levels via dietary intake of nitrate appears to have similarly beneficial effects in many of the same physiological and clinical settings. Several clinical trials are being performed to determine the broad therapeutic potential of increasing nitrite bioavailability on human health and disease, including studies related to vascular aging. In summary, inorganic nitrite, as well as dietary nitrate, supplementation represents a promising therapy for treatment of arterial aging and prevention of age-associated CVD in humans.
- [Show abstract] [Hide abstract] ABSTRACT: We tested the hypothesis that superoxide signaling within aortic perivascular adipose tissue (PVAT) contributes to large elastic artery stiffening in old mice. Young (4-6 mo), old (26-28 mo), and old treated with TEMPOL, a superoxide scavenger (1mM in drinking water for 3 weeks), male C57BL6/N mice were studied. Compared with young, old had greater large artery stiffness assessed by aortic pulse wave velocity (aPWV, 436±9 vs. 344±5 cm/s) and intrinsic mechanical testing (3821±427 vs. 1925±271 kPa) (both P<0.05). TEMPOL treatment in old reversed both measures of arterial stiffness. Aortic PVAT superoxide production was greater in old (P<0.05 vs. Y), which was normalized with TEMPOL. Compared with young, old controls had greater pro-inflammatory proteins in PVAT conditioned media (P<0.05). Young recipient mice transplanted with PVAT from old compared with young donors for 8 weeks had greater aPWV (409±7 vs. 342±8 cm/s) and intrinsic mechanical properties (3197±647 vs. 1889±520 kPa) (both P<0.05), which was abolished with TEMPOL supplementation in old donors. Tissue-cultured aortic segments from old in the presence of PVAT had greater mechanical stiffening compared with old cultured in the absence of PVAT and old with PVAT and TEMPOL (both, P<0.05). In addition, PVAT-derived superoxide was associated with arterial wall hypertrophy and greater adventitial collagen I expression with aging that was attenuated by TEMPOL. Aging or TEMPOL treatment did not affect blood pressure. Our findings provide evidence for greater age-related superoxide production and pro-inflammatory proteins in PVAT, and directly link superoxide signaling in PVAT to large elastic artery stiffness. This article is protected by copyright. All rights reserved.
- [Show abstract] [Hide abstract] ABSTRACT: Systolic BP and large elastic artery stiffness both increase with age and are reduced by dietary sodium restriction. Production of the natriuretic hormone marinobufagenin, an endogenous α1 Na+,K+-ATPase inhibitor, is increased in salt-sensitive hypertension and contributes to the rise in systolic BP during sodium loading. The hypothesis was that dietary sodium restriction performed in middle-aged/older adults (eight men and three women; 60±2 years) with moderately elevated systolic BP (139±2/83±2 mmHg) would reduce urinary marinobufagenin excretion as well as systolic BP and aortic pulse-wave velocity (randomized, placebo-controlled, and crossover design). This study also explored the associations among marinobufagenin excretion with systolic BP and aortic pulse-wave velocity across conditions of 5 weeks of a low-sodium (77±9 mmol/d) and 5 weeks of a normal-sodium (144±7 mmol/d) diet. Urinary marinobufagenin excretion (weekly measurements; 25.4±1.8 versus 30.7±2.1 pmol/kg per day), systolic BP (127±3 versus 138±5 mmHg), and aortic pulse-wave velocity (700±40 versus 843±36 cm/s) were lower during the low- versus normal-sodium condition (all P<0.05). Across all weeks, marinobufagenin excretion was related with systolic BP (slope=0.61, P<0.001) and sodium excretion (slope=0.46, P<0.001). These associations persisted during the normal- but not the low-sodium condition (both P<0.005). Marinobufagenin excretion also was associated with aortic pulse-wave velocity (slope=0.70, P=0.02) and endothelial cell expression of NAD(P)H oxidase-p47phox (slope=0.64, P=0.006). These results show, for the first time in humans, that dietary sodium restriction reduces urinary marinobufagenin excretion and that urinary marinobufagenin excretion is positively associated with systolic BP, aortic stiffness (aortic pulse-wave velocity), and endothelial cell expression of the oxidant enzyme NAD(P)H oxidase. Importantly, marinobufagenin excretion is positively related to systolic BP over ranges of sodium intake typical of an American diet, extending previous observations in rodents and humans fed experimentally high-sodium diets.
- [Show abstract] [Hide abstract] ABSTRACT: Large elastic artery stiffness is an independent predictor of age-related cardiovascular events that is attributable to structural remodeling throughout the artery. The intima, media and adventitial layers of the artery uniquely remodel with advancing age and all contribute to arterial stiffening. The specific expression of the extracellular matrix proteins collagen and elastin, and post-translational modifications of these proteins by advanced glycation end-products are key mechanisms in arterial stiffening with age and will be reviewed in the context of region-specific expression. In addition, interventions for attenuating age-related arterial stiffness and novel imaging advances for translating basic findings to older clinical populations will be discussed.
- [Show abstract] [Hide abstract] ABSTRACT: Background: Fetal intrauterine growth restriction (IUGR) results in increased placental resistance to blood flow, fetal hypertension, and increased pulsatility stresses shown to lead to vascular remodeling. We tested our hypothesis that IUGR causes decreased compliance in the carotid and umbilical arteries due to altered extracellular matrix (ECM) composition and structure. Methods: A sheep model of placental insufficiency-induced IUGR (PI-IUGR) was created by exposure of the pregnant ewe to elevated ambient temperatures. Umbilical and carotid arteries from near-term fetuses were tested with pressure-diameter measurements to compare passive compliance in control and PI-IUGR tissues. ECM composition was measured via biochemical assay, and the organization was determined by using histology and second-harmonic generation imaging. Results: We found that PI-IUGR increased arterial stiffness with increased collagen engagement, or transition stretch. PI-IUGR carotid arteries exhibited increased collagen and elastin quantity, and PI-IUGR umbilical arteries exhibited increased sulfated glycosaminoglycans. Histomorphology showed altered collagen-to-elastin ratios with altered cellular proliferation. Increased stiffness indicates altered collagen-to-elastin ratios with less elastin contribution leading to increased collagen engagement. Conclusion: Because vessel stiffness is a significant predictor in the development of hypertension, disrupted ECM deposition in IUGR provides a potential link between IUGR and adult hypertension.
- [Show abstract] [Hide abstract] ABSTRACT: We tested the hypothesis that curcumin supplementation would reverse arterial dysfunction and vascular oxidative stress with aging. Young (Y, 4-6 mo) and old (O, 26-28 mo) male C57BL6/N mice were given normal or curcumin supplemented (0.2%) chow for 4weeks (n=5-10/group/measure). Large elastic artery stiffness, assessed by aortic pulse wave velocity (aPWV), was greater in O (448±15 vs. 349±15cm/s) and associated with greater collagen I and advanced glycation end-products and less elastin (all P<0.05). In O, curcumin restored aPWV (386±15cm/s), collagen I and AGEs to levels not different vs. Y. Ex vivo carotid artery acetylcholine (ACh)-induced endothelial-dependent dilation (EDD, 79±3 vs. 94±2%), nitric oxide (NO) bioavailability and protein expression of endothelial NO synthase (eNOS) were lower in O (all P<0.05). In O, curcumin restored NO-mediated EDD (92±2%) to levels of Y. Acute ex vivo administration of the superoxide dismutase (SOD) mimetic TEMPOL normalized EDD in O control mice (93±3%), but had no effect in Y control or O curcumin treated animals. O had greater arterial nitrotyrosine abundance, superoxide production and NADPH oxidase p67 subunit expression, and lower manganese SOD (all P<0.05), all of which were reversed with curcumin. Curcumin had no effects on Y. Curcumin supplementation ameliorates age-associated large elastic artery stiffening, NO-mediated vascular endothelial dysfunction, oxidative stress and increases in collagen and AGEs in mice. Curcumin may be a novel therapy for treating arterial aging in humans.
- [Show abstract] [Hide abstract] ABSTRACT: We tested the hypothesis that sodium nitrite treatment reverses large elastic artery stiffening in old mice via reductions in collagen I, increases in elastin and/or decreases in advanced glycation end products (AGEs) mediated by reduced oxidative stress. Aortic pulse wave velocity (aPWV), a measure of large elastic artery stiffness, was greater in old (26-28months) compared with young (4-6months) control animals (520±9 vs. 405±6cm/s, p<0.05), and this was reversed by 3weeks of sodium nitrite treatment (50mg/L) (435±17cm/s). Age-related increases (p<0.05) in aortic superoxide production were associated with greater total and adventitial nitrotyrosine staining, all of which were reversed by nitrite treatment. Total and adventitial transforming growth factor β and collagen I were increased, and total and medial elastin were reduced with aging (p<0.05), but were unaffected by sodium nitrite. Aorta from old mice had increased total, adventitial and medial AGEs (p<0.05 vs. young), which were normalized by sodium nitrite treatment. In aortic segments from young mice in vitro, pyrogallol (10μM), a superoxide generator, induced an "aging-like" increase in AGEs, and direct treatment with AGEs induced vascular stiffening; these effects were prevented by incubation with sodium nitrite. De-stiffening of aged large elastic arteries by short-term sodium nitrite therapy is mediated in part by normalization of AGEs secondary to amelioration of oxidative stress.
- [Show abstract] [Hide abstract] ABSTRACT: Thickening of the intimal layer of arteries characterized by expression of smooth muscle α-actin (SMαA), collagen deposition, and inflammation is an important pathophysiological change with aging assumed to be mediated by smooth muscle cells migrating from the medial layer. We tested the novel hypothesis that these characteristics could also reflect an endothelial-mesenchymal (smooth muscle-like) transition (EnMT). Late ('old') compared with early ('young') passage (45.0 ± 1.2 vs. 27.1 ± 0.5 population doublings) human aortic endothelial cells demonstrated greater smooth muscle (spindle) morphological changes, expression of SMαA and collagen I, nuclear factor-κB activation, and transforming growth factor-β (TGF-β) (all p < 0.05). Based on increases in SMαA, stimulation with the proinflammatory cytokine tumor necrosis factor-α, but not with TGF-β, induced EnMT in early passage cells similar to that observed in late passage cells. Here, we present the first evidence for EnMT induced in a model of endothelial cell aging and provide support for proinflammatory signaling in mediating this phenotypic change.
- [Show abstract] [Hide abstract] ABSTRACT: To test the hypothesis that the antioxidant enzyme superoxide dismutase (SOD) mimetic TEMPOL improves arterial aging, young (Y, 4-6 months) and old (O, 26-28 months) male C57BL6 mice received regular or TEMPOL-supplemented (1mM) drinking water for 3 weeks (n = 8 per group). Aortic superoxide was 65% greater in O (P < 0.05 vs. Y), which was normalized by TEMPOL. O had large elastic artery stiffening, as indicated by greater aortic pulse wave velocity (aPWV, 508 ± 22 vs. 418 ± 22 AU), which was associated with increased adventitial collagen I expression (P < 0.05 vs. Y). TEMPOL reversed the age-associated increases in aPWV (434 ± 21 AU) and collagen in vivo, and SOD reversed the increases in collagen I in adventitial fibroblasts from older rats in vitro. Isolated carotid arteries of O had impaired endothelial function as indicated by reduced acetylcholine-stimulated endothelium-dependent dilation (EDD) (75.6 ± 3.2 vs. 94.5 ± 2.0%) mediated by reduced nitric oxide (NO) bioavailability (L-NAME) associated with decreased endothelial NO synthase (eNOS) expression (P < 0.05 vs. Y). TEMPOL restored EDD (94.5 ± 1.4%), NO bioavailability and eNOS in O. Nitrotyrosine and expression of NADPH oxidase were ~100-200% greater, and MnSOD was ~75% lower in O (P < 0.05 vs. Y). TEMPOL normalized nitrotyrosine and NADPH oxidase in O, without affecting MnSOD. Aortic pro-inflammatory cytokines were greater in O (P < 0.05 vs. Y) and normalized by TEMPOL. Short-term treatment of excessive superoxide with TEMPOL ameliorates large elastic artery stiffening and endothelial dysfunction with aging, and this is associated with normalization of arterial collagen I, eNOS, oxidative stress, and inflammation.