Large Elastic Artery Stiffness Research Articles

Gonadal status modulates large elastic artery stiffness in healthy middle-aged and older men.

Hypogonadism is a risk factor for cardiovascular disease (CVD) in men related, in part, to increased oxidative stress. Elevated large artery stiffness and central pulsatile hemodynamics (e.g., pulse pressure and wave reflection magnitude) are independent risk factors for CVD. However, whether large artery stiffness and central pulsatile hemodynamics are (1) elevated in hypogonadal men independent of traditional CVD risk factors and (2) related to increased oxidative stress is unknown. Young men (N = 23; 30 ± 4years) and middle-aged/older (MA/O) men with normal (> 400-1000ng/dL; n = 57; 59 ± 7years) or low testosterone (< 300ng/dL; n = 21; 59 ± 7years) underwent assessments of large artery stiffness (carotid ß-stiffness via ultrasonography) and central pulsatile hemodynamics (pulse wave analysis; SphygmoCor XCEL) following an infusion of saline or vitamin C to test the tonic suppression of vascular function by oxidative stress. Carotid stiffness differed by age (p < 0.001) and gonadal status within MA/O men (low testosterone vs. normal testosterone: 9.3 ± 0.7 vs. 8.0 ± 0.3U, p = 0.036). Central pulsatile hemodynamics did not differ by age or gonadal status (p > 0.119). Vitamin C did not alter carotid stiffness in any group (p > 0.171). There was a significant group × infusion interaction on aortic reflection magnitude (p = 0.015). Vitamin C treatment reduced aortic reflection magnitude in young and MA/O men with normal testosterone (both p < 0.001) but not MA/O men with low testosterone (p = 0.891). Collectively, hypogonadism may accelerate age-related large artery stiffening in MA/O men with low testosterone, independent of CVD risk factors; however, this is not related to increased reactive oxygen species sensitive to an acute vitamin C infusion.

Socioeconomic status as a potential mediator of arterial aging in marginalized ethnic and racial groups: current understandings and future directions.

Cardiovascular diseases (CVDs) are the leading cause of death in the United States. However, disparities in CVD-related morbidity and mortality exist as marginalized racial and ethnic groups are generally at higher risk for CVDs (Black Americans, Indigenous People, South and Southeast Asians, Native Hawaiians, and Pacific Islanders) and/or development of traditional CVD risk factors (groups above plus Hispanics/Latinos) relative to non-Hispanic Whites (NHW). In this comprehensive review, we outline emerging evidence suggesting these groups experience accelerated arterial dysfunction, including vascular endothelial dysfunction and large elastic artery stiffening, a nontraditional CVD risk factor that may predict risk of CVDs in these groups with advancing age. Adverse exposures to social determinants of health (SDOH), specifically lower socioeconomic status (SES), are exacerbated in most of these groups (except South Asians-higher SES) and may be a potential mediator of accelerated arterial aging. SES negatively influences the ability of marginalized racial and ethnic groups to meet aerobic exercise guidelines, the first-line strategy to improve arterial function, due to increased barriers, such as time and financial constraints, lack of motivation, facility access, and health education, to performing conventional aerobic exercise. Thus, identifying alternative interventions to conventional aerobic exercise that 1) overcome these common barriers and 2) target the biological mechanisms of aging to improve arterial function may be an effective, alternative method to aerobic exercise to ameliorate accelerated arterial aging and reduce CVD risk. Importantly, dedicated efforts are needed to assess these strategies in randomized-controlled clinical trials in these marginalized racial and ethnic groups.

Arterial stiffness and wave reflection responses to acute and chronic high intensity interval training in healthy older adults

Aging leads to large elastic artery stiffness which is associated with early return of wave reflection. These age-related alterations increase left ventricular afterload, predisposing older adults to cardiovascular disease. Endurance training is an effective strategy to reduce cardiovascular disease risk. We have developed a supervised home-based exercise intervention using high intensity interval training on an all-extremity non-weight-bearing ergometer (HIIT-ANE). This study aimed to test the following hypotheses in healthy older adults: 1) arterial stiffness and wave reflection would decrease in response to chronic HIIT-ANE, 2) arterial stiffness and wave reflection responses to acute HIIT-ANE would differ in the untrained compared to the trained states, and 3) arterial stiffness and aortic wave reflection responses to acute and chronic HIIT-ANE would be related. Twenty older adults (66±1 years, mean ± SE; 11 postmenopausal women and 9 men) participated in this study. Carotid-femoral pulse wave velocity (cfPWV) and augmentation index at heart rate 75 bpm (AIx@75)—indices of arterial stiffness and wave reflection, respectively—were assessed by SphygmoCor XCEL at baseline (T0), following 8 weeks of normal lifestyle (T1; control condition), and following 8 weeks of supervised home-based HIIT-ANE (T2). Acute cfPWV and AIx@75 responses to HIIT-ANE were assessed at pre-, end-of-, 1-hr post- and 24-hrs post-exercise, in the untrained and trained states. cfPWV increased after 8 weeks of normal lifestyle (T0 vs. T1: 7.9±0.3 vs. 8.2±0.3 m/s, P=0.03), but it decreased following 8 weeks of HIIT-ANE (T1 vs. T2: 8.2±0.3 vs. 7.7±0.3 m/s, P&lt;0.001). AIx@75 decreased after 8 weeks of HIIT-ANE compared to baseline and following 8 weeks of normal lifestyle (T0 vs. T2: 23.7±1.8 vs. 17.8±1.9 %, P&lt;0.001; T1 vs. T2: 24.9±2.2 vs. 17.8±1.9 %, P&lt;0.001). Acute cfPWV and AIx@75 responses to HIIT-ANE were similar in the untrained and trained states ( P for condition×time interaction; cfPWV: P=0.8; AIx@75: P=0.9). cfPWV and AIx@75 responses to chronic HIIT-ANE were not significantly related with acute responses to HIIT-ANE in the untrained (cfPWV: r=0.07, P=0.8; AIx@75: r=-0.32, P=0.2) and trained states (cfPWV: r=0.10, P=0.7; AIx@75: r=-0.32, P=0.2). In conclusion, we have demonstrated that supervised home-based HIIT-ANE has beneficial vascular effects in healthy older adults. We also showed that acute vascular responses to HIIT-ANE do not change from the untrained to trained state and are not predictive of chronic vascular responses to HIIT-ANE. This work was supported by the National Institute of Aging grant AG063143. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Impact of arterial stiffness on cerebrovascular function: a review of evidence from humans and preclincal models.

With advancing age, the cerebral vasculature becomes dysfunctional, and this dysfunction is associated with cognitive decline. However, the initiating cause of these age-related cerebrovascular impairments remains incompletely understood. A characteristic feature of the aging vasculature is the increase in stiffness of the large elastic arteries. This increase in arterial stiffness is associated with elevated pulse pressure and blood flow pulsatility in the cerebral vasculature. Evidence from both humans and rodents supports that increases in large elastic artery stiffness are associated with cerebrovascular impairments. These impacts on cerebrovascular function are wide-ranging and include reductions in global and regional cerebral blood flow, cerebral small vessel disease, endothelial cell dysfunction, and impaired perivascular clearance. Furthermore, recent findings suggest that the relationship between arterial stiffness and cerebrovascular function may be influenced by genetics, specifically APOE and NOTCH genotypes. Given the strength of the evidence that age-related increases in arterial stiffness have deleterious impacts on the brain, interventions that target arterial stiffness are needed. The purpose of this review is to summarize the evidence from human and rodent studies, supporting the role of increased arterial stiffness in age-related cerebrovascular impairments.

Effects of regular exercise on vascular function with aging: Does sex matter?

Vascular aging, featuring endothelial dysfunction and large elastic artery stiffening, is a major risk factor for the development of age-associated cardiovascular diseases (CVDs). Vascular aging is largely mediated by an excessive production of reactive oxygen species (ROS) and increased inflammation leading to reduced bioavailability of the vasodilatory molecule nitric oxide and remodeling of the arterial wall. Other cellular mechanisms (i.e., mitochondrial dysfunction, impaired stress response, deregulated nutrient sensing, cellular senescence), termed "hallmarks" or "pillars" of aging, may also contribute to vascular aging. Gonadal aging, which largely impacts women but also impacts some men, modulates the vascular aging process. Regular physical activity, including both aerobic and resistance exercise, is a first-line strategy for reducing CVD risk with aging. Although exercise is an effective intervention to counter vascular aging, there is considerable variation in the vascular response to exercise training with aging. Aerobic exercise improves large elastic artery stiffening in both middle-aged/older men and women and enhances endothelial function in middle-aged/older men by reducing oxidative stress and inflammation and preserving nitric oxide bioavailability; however, similar aerobic exercise training improvements are not consistently observed in estrogen-deficient postmenopausal women. Sex differences in adaptations to exercise may be related to gonadal aging and declines in estrogen in women that influence cellular-molecular mechanisms, disconnecting favorable signaling in the vasculature induced by exercise training. The present review will summarize the current state of knowledge on vascular adaptations to regular aerobic and resistance exercise with aging, the underlying mechanisms involved, and the moderating role of biological sex.

Cellular Senescence Contributes to Large Elastic Artery Stiffening and Endothelial Dysfunction With Aging: Amelioration With Senolytic Treatment.

Here, we assessed the role of cellular senescence and the senescence associated secretory phenotype (SASP) in age-related aortic stiffening and endothelial dysfunction. We studied young (6-8 mo) and old (27-29 mo) p16-3MR mice, which allows for genetic-based clearance of senescent cells with ganciclovir (GCV). We also treated old C57BL/6N mice with the senolytic ABT-263. In old mice, GCV reduced aortic stiffness assessed by aortic pulse wave velocity (PWV; 477±10 vs. 382±7 cm/s, P<0.05) to young levels (old-GCV vs. young-vehicle, P=0.35); ABT-263 also reduced aortic PWV in old mice (446±9 to 356±11 cm/s, P<0.05). Aortic adventitial collagen was reduced by GCV (P<0.05) and ABT-263 (P=0.12) in old mice. To show an effect of the circulating SASP, we demonstrated that plasma exposure from Old-vehicle p16-3MR mice, but not from Old-GCV mice, induced aortic stiffening assessed ex vivo (elastic modulus; P<0.05). Plasma proteomics implicated glycolysis in circulating SASP-mediated aortic stiffening. In old p16-3MR mice, GCV increased endothelial function assessed via peak carotid artery endothelium-dependent dilation (EDD; Old-GCV, 94±1% vs. Old-vehicle, 84±2%, P<0.05) to young levels (Old-GCV vs. young-vehicle, P=0.98), and EDD was higher in old C57BL/6N mice treated with ABT-263 vs. vehicle (96±1% vs. 82±3%, P<0.05). Improvements in endothelial function were mediated by increased nitric oxide (NO) bioavailability (P<0.05) and reduced oxidative stress (P<0.05). Circulating SASP factors related to NO signaling were associated with greater NO-mediated EDD following senescent cell clearance. Cellular senescence and the SASP contribute to vascular aging and senolytics hold promise for improving age-related vascular function.

Vascular determinants of hippocampal viscoelastic properties in healthy adults across the lifespan

Arterial stiffness and cerebrovascular pulsatility are non-traditional risk factors of Alzheimer’s disease. However, there is a gap in understanding the earliest mechanisms that link these vascular determinants to brain aging. Changes to mechanical tissue properties of the hippocampus (HC), a brain structure essential for memory encoding, may reflect the impact of vascular dysfunction on brain aging. We tested the hypothesis that arterial stiffness and cerebrovascular pulsatility are related to HC tissue properties in healthy adults across the lifespan. Twenty-five adults underwent measurements of brachial blood pressure (BP), large elastic artery stiffness, middle cerebral artery pulsatility index (MCAv PI), and magnetic resonance elastography (MRE), a sensitive measure of HC viscoelasticity. Individuals with higher carotid pulse pressure (PP) exhibited lower HC stiffness (β = −0.39, r = −0.41, p = 0.05), independent of age and sex. Collectively, carotid PP and MCAv PI significantly explained a large portion of the total variance in HC stiffness (adjusted R2 = 0.41, p = 0.005) in the absence of associations with HC volumes. These cross-sectional findings suggest that the earliest reductions in HC tissue properties are associated with alterations in vascular function.

Oral Supplementation with the Short-Chain Fatty Acid Acetate Ameliorates Age-Related Aortic Stiffening in Mice

Aging is the main risk factor for cardiovascular diseases (CVD) due in part to stiffening of large elastic arteries (e.g., aorta). High-fiber diets (H-FIB) are associated with reduced risk of CVD, but most people do not meet guidelines for adequate fiber intake. Short-chain fatty acids (SCFA), which are produced by gut microbiome-dependent fermentation of soluble fiber, are thought to mediate many of the benefits of a H-FIB. Acetate, the most prevalent SCFA in circulation, may be an adherable intervention as an oral supplement for improving age-related arterial stiffening and reducing the risk of CVD. PURPOSE: To determine if oral acetate supplementation can reduce age-related aortic stiffness comparably to a H-FIB. METHODS: Young (Y: 3mo; N=11-12/group) and old (O: 24mo; N=24-27/group) C57Bl/6N mice were split into 3 groups per age: 1) controls (YC/OC): standard chow (15% total, 2.5% soluble fiber) and normal drinking water; 2) acetate supplemented (YA/OA): standard chow and 100mM of calcium acetate in drinking water; and 3) H-FIB (YF/OF): chow supplemented with fiber (20% total, 8% soluble fiber) and normal drinking water. Aortic pulse wave velocity (aPWV; standard reference method of in vivo aortic stiffness) and blood pressure (BP; tail cuff) were measured before and after 8 weeks of intervention. Thoracic aortas were harvested to measure: elastic modulus (aEM) of aortic rings (structural measurement of stiffness dependent on engagement of collagen fibers); aortic wall thickness (structural contributor to arterial stiffening); and collagen abundance by immunofluorescence (pro-stiffening structural protein). RESULTS: Data are mean ± SE. aPWV was higher in old vs. young mice at baseline (O: 404±10 vs. Y: 335±4 cm/sec, p&lt;0.01), and was reduced comparably by both interventions in the old mice (OA: 379±5, p=0.04 vs. OC: 403±8 cm/sec; OF: 379±5 cm/sec, p=0.04 vs. OC). Post-intervention systolic blood pressure (OC: 83.1±3.2, OA: 87.5±4.7, OF: 85.4±5.9 mmHg, p=0.82) and aortic wall thickness (OC: 0.05±0.002, OA: 0.05±0.004, OF: 0.05±0.002 μM, p=0.77) were not different between groups, suggesting that neither factor explained the intervention effects on aPWV. Conversely, aortic collagen abundance (measured in a subset of mice, N=4/group), which was higher in old mice (OC: 964±118 vs. YC: 644±25 AU, p=0.02), was reduced to young levels by acetate supplementation (OA: 671±18 vs. YC: 644±25 A.U., p=0.41). Both acetate and H-FIB reduced aEM in old mice (OC: 3640±229 vs. OA: 2291±274 kPA, p=0.002; OF: 2600±321 kPA, p=0.06 vs. OC). There were no differences across groups in young mice. CONCLUSION: Oral acetate supplementation and H-FIB were similarly effective at mitigating age-related aortic stiffening; effects may be mediated in part by reduced collagen content in the arterial wall. Acetate supplementation may be a promising treatment for preventing age-related aortic stiffening and subsequent CVD risk. FUNDING: K99/R00 HL151818, CU Boulder BSI Scholarship This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Biological sex influences aortic hemodynamic responses to maximal exercise in healthy older adults

Aging is associated with stiffening of large elastic arteries resulting in early wave reflection, which increases aortic systolic blood pressure (BP) and left ventricular afterload. These age-related alterations predispose older adults to cardiovascular disease (CVD). Exercise is recommended for reducing CVD risk in older adults, but the acute aortic hemodynamic responses to exercise have not been fully described. We have previously shown that exercise intensity influences acute aortic hemodynamic responses to submaximal exercise in older adults, however, the responses to maximal exercise have not been investigated. In young adults, the influence of maximal exercise on aortic wave characteristics is impacted by sex. Therefore, the objective of this study was to investigate the acute effects of maximal exercise on aortic wave characteristics in healthy older adults and to test the hypothesis that the acute aortic hemodynamic responses to maximal exercise will be influenced by sex. Twenty-two older men and postmenopausal women (66.4±1.0 yrs, mean±SE, 11M/11W) completed the study. Research participants were free of major clinical disease, were not using hormone replacement therapy or participating in endurance exercise training. Aortic wave characteristics were assessed using wave separation analysis (SphygmoCor XCEL) before and immediately after maximal exercise, based on a modified Balke treadmill test. We found that wave reflection, assessed as augmentation index (AIx) at heart rate of 75 bpm (AIx@75), was not different between older men and women prior to maximal exercise ( P=0.2). Following maximal exercise, AIx@75 increased in older men (21.1±2.6 vs. 28.2±2.4 %, pre- vs. post-exercise, P=0.02) and women (27.4±3.3 vs. 33.9±3.2 %, P=0.03), but the response was not influenced by sex ( P=0.9 for sex × time interaction). Aortic systolic and diastolic BP (AoSBP and AoDBP) were not different in older men compared with women prior to maximal exercise ( P≥0.4). In response to maximal exercise, AoSBP and AoDBP significantly increased in older men (AoSBP: 113±3 vs. 118±2 mmHg, P=0.01 and AoDBP: 75±2 vs. 80±2 mmHg, P&lt;0.01), but not in women (AoSBP: 113±4 vs. 113±4 mmHg, P=0.9; P=0.04 for sex × time interaction and AoDBP: 73±2 vs. 74±2 mmHg, P=0.054; P=0.02 for sex × time interaction). In conclusion, sex influences the aortic BP response to maximal exercise, but not the wave reflection response in older adults. This finding suggests that left ventricular afterload remains elevated during recovery from maximal exercise in older men which may differentially expose them to a transient risk of experiencing a cardiac complication. This work was supported by National Institute of Aging grant AG063143. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Attenuated hyaluronan synthesis impairs glycocalyx integrity and leads to arterial dysfunction

The glycocalyx (GC) is a semi-solid layer lining the endothelium that plays a key role in maintaining barrier function and mechanosensing shear forces. With advanced age and pathological conditions, the GC deteriorates, and this is accompanied by arterial dysfunction characterized by impaired endothelial-dependent dilation (EDD) and large elastic artery stiffening. Alterations in hyaluronan (HA), a primary component of the GC, may contribute to the development of a dysfunctional artery phenotype. Here, we sought to determine the role of HA in GC integrity and arterial function. We have generated a tamoxifen-inducible, endothelial cell-specific, knockout mouse model of the hyaluronan producing enzyme, hyaluronan synthase 2 (HAS2, HAS2 f/f- Vecad-CreERT2). Endothelial HAS2 knockout (HAS2 f/f- Vecad-creERT2+: ecHAS2 KO, n=10) and wildtype (HAS2 +/+- Vecad-creERT2+: ecHAS2 WT, n=10) young mice were injected intraperitoneally with 4 mg of tamoxifen for 5 consecutive days. HAS2 mRNA expression was reduced by ~47% in carotid endothelial cells of ecHAS2 KO mice (P=0.004). GC barrier function (perfused boundary region [PBR]) was evaluated in vivo in the mesenteric microcirculation using an intravital microscope equipped with an automated capture and analysis system. PBR was 8.9% higher in ecHAS2 KO compared to ecHAS2 WT (P&lt;0.0001). Subsequently, video recordings acquired were used to manually determine GC thickness from individual microvascular segments. GC thickness was significantly reduced in ecHAS2 KO vs ecHAS2 WT (7.9μm±0.02 vs 0.37μm±0.02, P&lt;0.0001). Together, these results indicated that GC integrity was deteriorated in response to a reduction in endothelial HAS2. This GC deterioration impairs EDD, as evidenced by a 43.4% reduction in flow-induced dilation in isolated carotid arteries from ecHAS2 KO compared to ecHAS2 WT (P=0.013). To directly assess the role of GC plays in the differences in flow-induced EDD observed, the lumen of the arteries was infused with hyaluronidase, a HA degrading enzyme, and this abolished the differences in EDD between groups (P&gt;0.05). Endothelial-independent dilation in response to sodium nitroprusside was not different between groups (P&gt;0.05). Furthermore, aortic pulse wave velocity, a measure of large elastic artery stiffness, as well as systolic, diastolic, and mean arterial blood pressure were all greater in ecHAS2 KO compared to ecHAS2 WT (all P≤0.033). These results demonstrate that endothelial cell-specific impairment in HA synthesis compromises GC integrity and leads to arterial dysfunction and elevated blood pressure. Funded in part by awards from National Institutes of Health Awards R01 AG060395, R01 AG048366, T32 HL007576, T32 HL139451 and Veteran's Affairs Merit Review Award I01 BX004492. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sex-specific effects of mild to moderate renal dysfunction on vascular endothelial function and large elastic artery stiffness

BACKGROUND: Cardiovascular disease (CVD) risk is elevated in patients with advanced chronic kidney disease (CKD). Vascular dysfunction, including vascular endothelial dysfunction and large elastic artery stiffening, is a key contributor to increased CVD risk in advanced CKD. Individuals with mild to moderately reduced renal function may also be at increased risk for CVD, but endothelial function and arterial stiffness are not well characterized in this group. Further, women with CKD have lower risk for CVD than men. Whether women are protected from renal dysfunction-related decreases in vascular function is unknown. PURPOSE: We sought to determine: i) whether individuals with mild to moderate renal dysfunction (MRD) have lower endothelial function and greater arterial (aortic) stiffness compared to healthy controls (HC) and ii) if the presence of vascular dysfunction in individuals with MRD is influenced by sex. METHODS &amp; RESULTS: Fifty-nine adults were split into two groups based on renal function. Thirty-two adults (mean±SEM: 66±2 years; 16 women) were identified with MRD, characterized as an estimated glomerular filtration rate (eGFR) of 45-89 (CKD-EPI; 75.0±2.0 mL/min/1.73m2) and/or the presence of microalbuminuria (albumin: creatinine ratio between 30-300 mg/g). Twenty-seven adults (63±2 years; 13 women) were identified as HC with an eGFR &gt;90 (CKD-EPI; 98.7±0.9 mL/min/1.73m2). Subject characteristics known to influence vascular function (e.g., blood pressure, cholesterol, blood glucose, etc.) were not different between groups (all p&gt;0.05). Endothelial function, assessed by brachial artery flow mediated dilation, was not different between groups (MRD: 4.4±0.5%, HC: 4.6±0.5%, p=0.75). Aortic stiffness, assessed via carotid-femoral pulse wave velocity, also was not different (MRD: 950.7±50.6 cm/s, HC: 864.3±33.1 cm/s, p=0.18). When analyzed by sex, men with MRD had lower endothelial function (MRD: 2.8±0.4%, HC: 4.4±0.6%, p=0.04) and tended to have stiffer arteries (MRD: 879.0±42.7 cm/s, HC: 787.7±35.5 cm/s, p=0.11) compared to HC men. In women with MRD, there were no differences in endothelial function (MRD: 5.9±0.8%, HC: 4.8±0.8%, p=0.36) or aortic stiffness (MRD: 1022.3±89.9 cm/s, HC: 953.6±49.4 cm/s, p=0.55) versus HC women. CONCLUSIONS: Men with MRD exhibit vascular dysfunction, while women appear to be protected from MRD-related vascular dysfunction. The lower risk of CVD in women versus men with CKD may, in part, be due to resistance against renal dysfunction-related vascular dysfunction. NIH K01DK115524 to MJR; 5T32DK007135-46 to KOM; K01HL153326 to DHC This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

NIH Toolbox Cognitive Battery in non-Hispanic Black individuals: role of cerebral vascular function, pulse wave velocity, and psychosocial stress exposure

Non-Hispanic Black (BL) individuals are ~ 2 times more likely to develop cognitive impairment, Alzheimer’s disease, and related dementias (ADRD) relative to other populations. ADRD prevalence is expected to double by 2060, with a greater increase in BL and Hispanic populations. Reduced cerebral vascular function and large elastic artery health increases risk for cognitive decline and ADRD. In addition, psychosocial stress exposure, including at a young age, is a significant predictor of intellectual function and executive attention. However, the relationship between 1) cerebral &amp; peripheral vascular function/health and indices of cognitive function, and 2) psychosocial stress exposure and indices of cognitive function in relatively young, healthy BL individuals are incompletely understood. We tested the hypothesis that cerebral vascular function and large elastic artery health are blunted in BL individuals, which will be associated with reduced cognitive performance. We also hypothesized that psychosocial stress exposure in the BL individuals is negatively associated with cognitive performance. METHODS: Eight BL (2 males; age: 20±1 yr; BMI: 22±3 kg/m2) and 8 WH (4 males; age: 20±3 yr; BMI: 23±2 kg/m2) individuals participated. Cognitive function was indexed using the NIH Toolbox Cognitive Battery which compiles a fluid score (i.e., capacity for new learning and information processing in novel situations), a crystallized score (i.e., past learning experiences), and a total cognition score. Cerebral vascular function was assessed as the % increase in cerebral vascular conductance (CVCi = middle cerebral artery blood velocity/mean arterial pressure) during hypercapnia (6% CO2). Large elastic artery health was assessed as aortic pulse wave velocity (PWV). Psychosocial stress exposure was assessed as adverse childhood experiences (ACEs). RESULTS: The national percentile and age-adjusted fluid and total scores were lower in the BL individuals ( P&lt;0.05 for each), whereas the crystallized score was not different ( P=0.79). The % increase in CVCi during hypercapnia (BL: 32±15, WH: 54±50%, P=0.26) and PWV (BL: 5.7±0.9, WH: 5.7±0.9 m·s-1, P=0.96) was similar between groups. Within the BL individuals there was not a significant correlation between %CVCi or PWV and the fluid, crystallized, or total scores ( P&gt;0.05 for each) while ACEs tended to be negatively associated with total ( P=0.06) but not fluid or crystallized scores ( P&gt;0.05 for each). CONCLUSION: These preliminary data suggest that young, healthy BL individuals may have reduced indices of cognitive function, particularly in the fluid domain, which may be associated with ACEs. This does not appear to be related to cerebral vascular function or large elastic artery stiffness. Future work will continue to assess these relationships in a population with a wider age range and more diverse life experiences. NIH R15 (HL156128, RMB) &amp; Peanut Institute (982307, RMB) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Senolytic administration following doxorubicin chemotherapy prevents large elastic artery stiffening and endothelial dysfunction

Doxorubicin (DOXO) chemotherapy induces vascular dysfunction (aortic stiffening and endothelial dysfunction). Cellular senescence and the related increase in oxidative stress, notably mitochondrial reactive oxygen species (mtROS), are implicated in DOXO-induced vascular dysfunction. Hypothesis. Targeting cellular senescence, via administration of a senolytic (senescent cell clearing drug), following exposure to DOXO chemotherapy will prevent aortic stiffening and endothelial dysfunction by suppressing excess mtROS bioactivity and preserving nitric oxide (NO) bioavailability. Methods/Results Animals. Young (6 mo) male and female C57BL/6 mice received a single intraperitoneal injection of Sham (saline) or DOXO (10 mg/kg in Sham). One week later, mice received the vehicle (V; 10% EtOH, 30% PEG400, 60% Phosal 50 PG) or the senolytic ABT263 (ABT; 50 mg/kg/day in V) by oral gavage (1 week on; 2 weeks off; 1 week on). There were 4 groups/sex (Sham-V; Sham-ABT; DOXO-V; DOXO-ABT; n=10-12/group). There were no sex differences, so results were combined. Data are mean±SEM. Aortic Stiffness. Aortic stiffness (aortic pulse wave velocity [aPWV, cm/sec]) was assessed pre and post intervention. There were no group differences at baseline ( P=.63). After the dosing period, aPWV increased by 15% in the DOXO-V group (pre: 353±2 vs post: 414±6, P&lt;.05) whereas no differences were observed in the Sham-V, Sham-ABT or DOXO-ABT groups (DOXO-V vs all groups, P&lt;.05). Endothelial Function. DOXO-V animals had impaired endothelial function ( ex vivo carotid artery endothelium dependent dilation [EDD] to acetylcholine) relative to the Sham-V and Sham-ABT groups, and ABT prevented the DOXO-induced reduction in peak EDD (Peak EDD [%]: Sham-V, 92±1; Sham-ABT, 90±2; DOXO-V, 75±4; DOXO-ABT, 95±1; P&lt;.05). To determine the influence of NO in mediating differences in EDD, we assessed EDD in the presence of the NO-synthase inhibitor L-NAME. With L-NAME group differences were abolished. Oxidative Stress. We assessed if ABT prevented the increase in aortic oxidative stress following DOXO by quantifying (immunofluorescence) nitrotyrosine (NT; marker of oxidative stress). Aortic NT was 21% higher with DOXO-V vs Sham-V (877±29 vs 726±73 Arbitrary Units [AU]; P&lt;.05); ABT administration after DOXO prevented the increase in NT (799±19 AU, P&lt;.05 vs DOXO-V). We then interrogated the specific role of mtROS in mediating differences in oxidative stress with ABT. MtROS. DOXO-V mice had 38% higher mtROS (EPR spectroscopy) vs Sham-V (12.8±1.3 vs 9.2±1.1 AU, P&lt;.05). The DOXO-induced increase in mtROS was mitigated by ABT (9.1±1.1 AU; P&lt;.05 vs DOXO-V). Incubation of carotid arteries with MitoQ (mtROS scavenger) restored peak EDD in the DOXO-V group but had no effect on other groups. Conclusion. Senolytic administration following DOXO chemotherapy may be a strategy to prevent aortic stiffening and NO-mediated endothelial dysfunction by preventing the increase in oxidative stress, particularly excess mtROS. NIH K99 HL159241 and NIH R21 AG078408 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Mitochondrial-targeted antioxidant supplementation for improving age-related vascular dysfunction in humans: A study protocol.

Background: Cardiovascular disease (CVD) is the leading cause of death worldwide and aging is the primary risk factor for the development of CVD. The increased risk of CVD with aging is largely mediated by the development of vascular dysfunction. Excessive production of mitochondrial reactive oxygen species (mtROS) is a key mechanism of age-related vascular dysfunction. Therefore, establishing the efficacy of therapies to reduce mtROS to improve vascular function with aging is of high biomedical importance. Previously, in a small, randomized, crossover-design pilot clinical trial, our laboratory obtained initial evidence that chronic oral supplementation with the mitochondrial-targeted antioxidant MitoQ improves vascular function in healthy older adults. Here, we describe the protocol for an ongoing R01-funded phase IIa clinical trial to establish the efficacy of MitoQ as a therapy to improve vascular function in older adults (ClinicalTrials.gov Identifier: NCT04851288). Outcomes: The primary outcome of the study is nitric oxide (NO)-mediated endothelium-dependent dilation (EDD) as assessed by brachial artery flow-mediated dilation (FMDBA). Secondary outcomes include mtROS-mediated suppression of EDD, aortic stiffness as measured by carotid-femoral pulse wave velocity, carotid compliance and β-stiffness index, and intima media thickness. Other outcomes include the assessment of endothelial mitochondrial health and oxidative stress in endothelial cells obtained by endovascular biopsy; the effect of altered circulating factors following MitoQ treatment on endothelial cell NO bioavailability and whole cell and mitochondrial reactive oxygen species production ex vivo; and circulating markers of oxidative stress, antioxidant status, and inflammation. Methods: We are conducting a randomized, placebo-controlled, double-blind, parallel group, phase IIa clinical trial in 90 (45/group) healthy older men and women 60 years of age or older. Participants complete baseline testing and are then randomized to either 3 months of oral MitoQ (20 mg; once daily) or placebo supplementation. Outcome measures are assessed at the midpoint of treatment, i.e., 6 weeks, and again at the conclusion of treatment. Discussion: This study is designed to establish the efficacy of chronic supplementation with the mitochondrial-targeted antioxidant MitoQ for improving vascular endothelial function and reducing large elastic artery stiffness in older adults, and to investigate the mechanisms by which MitoQ supplementation improves endothelial function.

Effect of Arterial Stiffness and Cerebral Pulsatility on Hippocampal Tissue Integrity in Healthy Adults

Elevated large elastic artery (i.e. aorta and common carotid) stiffness has emerged as a risk factor of cognitive impairment in older adults. Stiffening of these arteries leads to increased pulsatile energy transmission into the brain, which may result in structural damage to neuronal tissue, and potentially precipitate cognitive decline. In this regard, changes to microstructural integrity of the hippocampus (HC), a brain structure essential for memory encoding, may reflect the impact of age‐related increases in arterial stiffness and pulsatile blood flow through the middle cerebral artery (MCA). Therefore, the purpose of this study was to determine whether large elastic artery stiffness and associated pulsatile hemodynamics are related with HC integrity in healthy adults across the lifespan. We included 25 participants (16M/9F, age: 44±16 y; age range: 22‐69 y; BMI: 27±5 kg/m2; BP: 115±11/71±10 mmHg) in this study. Aortic stiffness was assessed as carotid‐femoral pulse wave velocity (PWV) using applanation tonometry (AtCor Medical, Sydney, Australia). Common carotid artery (CCA) stiffness was measured using duplex ultrasound (Logiq e, GE Healthcare, Chicago, IL) and analyzed with an offline wall‐tracking software (Cardiovascular Suite, Pisa, Italy). CCA blood pressures were acquired from applanation tonometry. Transcranial Doppler ultrasound was used to measure basal mean blood flow velocity of the MCA (MCAv) from which Gosling’s pulsatility index (PI) was calculated as the difference between peak systolic MCAv and end‐diastolic MCAv over mean MCAv. HC tissue integrity was measured using magnetic resonance elastography (MRE), which was acquired using a Siemens 3T Prisma MRI scanner coupled with shear waves generated via a pneumatic actuator (Resoundant, Rochester, MN) at 50 Hz. Bilateral HC stiffness (µ) and HC damping ratio (ξ) were estimated from MRE displacement data using a nonlinear inversion algorithm. A correlation matrix was used to determine if arterial stiffness, vascular hemodynamics, and other lifestyle factors (e.g., age, sex, BMI) were related with HC integrity. BMI (r=‐0.40, p=0.048), CCA pulse pressure (PP) (r=‐0.61, p=0.001), and MCAv PI (r=‐0.48, p=0.01) were associated with HC µ while age (r=0.66, p=0.0004), BMI (r=0.45, p=0.02), SBP (r=0.52, p= 0.008), aortic PWV (r=0.65, p=0.0004), and CCA stiffness (r=0.60, p=0.002) were associated with HC ξ. Next, multiple linear regressions were performed to determine the independent associations among arterial stiffness, vascular hemodynamics of interest, and HC integrity while correcting for age and BMI. HC µ remained significantly associated with CCA PP (β=‐0.52, p=0.03) and was trending towards negative association with MCAv PI (β=‐0.37, p=0.06). There were no significant independent associations among the variables of interest and HC ξ, however, together these variables significantly explained variance in HC ξ (R2=0.37, p=0.03). Our results suggest increased pulsatile pressure through the carotid artery along with elevated cerebral pulsatility negatively impacts HC tissue integrity. Future studies should consider how our current findings affect functional outcomes like memory and age‐related neurological conditions.

Non-Invasive Assessment of Arterial Stiffness: Pulse Wave Velocity, Pulse Wave Analysis and Carotid Cross-Sectional Distensibility: Comparison between Methods.

Background: The stiffening of large elastic arteries is currently estimated in research and clinical practice by propagative and non-propagative models, as well as parameters derived from aortic pulse waveform analysis. Methods: Common carotid compliance and distensibility were measured by simultaneously recording the diameter and pressure changes during the cardiac cycle. The aortic and upper arm arterial distensibility was estimated by measuring carotid–femoral and carotid–radial pulse wave velocity (PWV), respectively. The augmentation index and blood pressure amplification were derived from the analysis of central pulse waveforms, recorded by applanation tonometry directly from the common carotid artery. Results: 75 volunteers were enrolled in this study (50 females, average age 53.5 years). A significant inverse correlation was found between carotid distensibility and carotid–femoral PWV (r = −0.75; p < 0.001), augmentation index (r = −0.63; p < 0.001) and central pulse pressure (r = −0.59; p < 0.001). A strong correlation was found also between the total slope of the diameter/pressure rate carotid curves and aortic distensibility, quantified from the inverse of the square of carotid–femoral PWV (r = 0.67). No correlation was found between carotid distensibility and carotid–radial PWV. Conclusions: This study showed a close correlation between carotid–femoral PWV, evaluating aortic stiffness by using the propagative method, and local carotid cross-sectional distensibility.

Vascular Ageing and Aerobic Exercise.

Impairment of vascular function, in particular endothelial dysfunction and large elastic artery stiffening, represents a major link between ageing and cardiovascular risk. Clinical and experimental studies identified numerous mechanisms responsible for age-related decline of endothelial function and arterial compliance. Since most of these mechanisms are related to oxidative stress or low-grade inflammation, strategies that suppress oxidative stress and inflammation could be effective for preventing age-related changes in arterial function. Indeed, aerobic physical activity, which has been shown to improve intracellular redox balance and mitochondrial health and reduce levels of systemic inflammatory markers, also improves endothelial function and arterial distensibility and reduces risk of cardiovascular diseases. The present paper provides a brief overview of processes underlying age-related changes in arterial function, as well as the mechanisms through which aerobic exercise might prevent or interrupt these processes, and thus attenuate vascular ageing.

MMP-2 knockdown blunts age-dependent carotid stiffness by decreasing elastin degradation and augmenting eNOS activation.

Arterial stiffness is a hallmark of vascular ageing that precedes and strongly predicts the development of cardiovascular diseases. Age-dependent stiffening of large elastic arteries is primarily attributed to increased levels of matrix metalloproteinase-2 (MMP-2). However, the mechanistic link between age-dependent arterial stiffness and MMP-2 remains unclear. Thus, we aimed to investigate the efficacy of MMP-2 knockdown using small-interfering RNA (siRNA) on age-dependent arterial stiffness. Pulse wave velocity (PWV) was assessed in right carotid artery of wild-type (WT) mice from different age groups. MMP-2 levels in the carotid artery and plasma of young (3 months) and old (20-25 months) WT mice were determined. Carotid PWV as well as vascular and circulating MMP-2 were elevated with increasing age in mice. Old WT mice (18- to 21-month old) were treated for 4 weeks with either MMP-2 or scrambled (Scr) siRNA via tail vein injection. Carotid PWV was assessed at baseline, 2 and 4 weeks after start of the treatment. MMP-2 knockdown reduced vascular MMP-2 levels and attenuated age-dependent carotid stiffness. siMMP-2-treated mice showed increased elastin-to-collagen ratio, lower plasma desmosine (DES), enhanced phosphorylation of endothelial nitric oxide synthase (eNOS), and higher levels of vascular cyclic guanosine monophosphate (cGMP). An age-dependent increase in direct protein-protein interaction between MMP-2 and eNOS was also observed. Lastly, DES, an elastin breakdown product, was measured in a patient cohort (n = 64, 23-86 years old), where carotid-femoral PWV was also assessed; here, plasma levels of DES directly correlated with age and arterial stiffness. MMP-2 knockdown attenuates age-dependent carotid stiffness by blunting elastin degradation and augmenting eNOS bioavailability. Given the increasing clinical use of siRNA technology, MMP2 knockdown should be investigated further as a possible strategy to mitigate age-dependent arterial stiffness and related CV diseases.

Apigenin restores endothelial function by ameliorating oxidative stress, reverses aortic stiffening, and mitigates vascular inflammation with aging.

We assessed the efficacy of oral supplementation with the flavanoid apigenin on arterial function during aging and identified critical mechanisms of action. Young (6 mo) and old (27 mo) C57BL/6N mice (model of arterial aging) consumed drinking water containing vehicle (0.2% carboxymethylcellulose; 10 young and 7 old) or apigenin (0.5 mg/mL in vehicle; 10 young and 9 old) for 6 wk. In vehicle-treated animals, isolated carotid artery endothelium-dependent dilation (EDD), bioassay of endothelial function, was impaired in old versus young (70% ± 9% vs. 92% ± 1%, P < 0.0001) due to reduced nitric oxide (NO) bioavailability. Old mice had greater arterial reactive oxygen species (ROS) production and oxidative stress (higher nitrotyrosine) associated with greater nicotinamide adenine dinucleotide phosphate oxidase (oxidant enzyme) and lower superoxide dismutase 1 and 2 (antioxidant enzymes); ex vivo administration of Tempol (antioxidant) restored EDD to young levels, indicating ROS-mediated suppression of EDD. Old animals also had greater aortic stiffness as indicated by higher aortic pulse wave velocity (PWV, 434 ± 9 vs. 346 ± 5 cm/s, P < 0.0001) due to greater intrinsic aortic wall stiffness associated with lower elastin levels and higher collagen, advanced glycation end products (AGEs), and proinflammatory cytokine abundance. In old mice, apigenin restored EDD (96% ± 2%) by increasing NO bioavailability, normalized arterial ROS, oxidative stress, and antioxidant expression, and abolished ROS inhibition of EDD. Moreover, apigenin prevented foam cell formation in vitro (initiating step in atherosclerosis) and mitigated age-associated aortic stiffening (PWV 373 ± 5 cm/s) by normalizing aortic intrinsic wall stiffness, collagen, elastin, AGEs, and inflammation. Thus, apigenin is a promising therapeutic for arterial aging.NEW & NOTEWORTHY Our study provides novel evidence that oral apigenin supplementation can reverse two clinically important indicators of arterial dysfunction with age, namely, vascular endothelial dysfunction and large elastic artery stiffening, and prevents foam cell formation in an established cell culture model of early atherosclerosis. Importantly, our results provide extensive insight into the biological mechanisms of apigenin action, including increased nitric oxide bioavailability, normalization of age-related increases in arterial ROS production and oxidative stress, reversal of age-associated aortic intrinsic mechanical wall stiffening and adverse remodeling of the extracellular matrix, and suppression of vascular inflammation. Given that apigenin is commercially available as a dietary supplement in humans, these preclinical findings provide the experimental basis for future translational studies assessing the potential of apigenin to treat arterial dysfunction and reduce cardiovascular disease risk with aging.

Mitochondrial contributions to vascular endothelial dysfunction, arterial stiffness, and cardiovascular diseases.

Cardiovascular disease (CVD) affects one in three adults and remains the leading cause of death in America. Advancing age is a major risk factor for CVD. Recent plateaus in CVD-related mortality rates in high-income countries after decades of decline highlight a critical need to identify novel therapeutic targets and strategies to mitigate and manage the risk of CVD development and progression. Vascular dysfunction, characterized by endothelial dysfunction and large elastic artery stiffening, is independently associated with an increased CVD risk and incidence and is therefore an attractive target for CVD prevention and management. Vascular mitochondria have emerged as an important player in maintaining vascular homeostasis. As such, age- and disease-related impairments in mitochondrial function contribute to vascular dysfunction and consequent increases in CVD risk. This review outlines the role of mitochondria in vascular function and discusses the ramifications of mitochondrial dysfunction on vascular health in the setting of age and disease. The adverse vascular consequences of increased mitochondrial-derived reactive oxygen species, impaired mitochondrial quality control, and defective mitochondrial calcium cycling are emphasized, in particular. Current evidence for both lifestyle and pharmaceutical mitochondrial-targeted strategies to improve vascular function is also presented.