A high-resolution view of the heterogeneous aging endothelium.

Vascular endothelial cell (EC) aging has a strong impact on tissue perfusion and overall cardiovascular health. While studies confined to the investigation of aging-associated vascular readouts in one or a few tissues have already drastically expanded our understanding of EC aging, single-cell omics and other high-resolution profiling technologies have started to illuminate the intricate molecular changes underlying endothelial aging across diverse tissues and vascular beds at scale. In this review, we provide an overview of recent insights into the heterogeneous adaptations of the aging vascular endothelium. We address critical questions regarding tissue-specific and universal responses of the endothelium to the aging process, EC turnover dynamics throughout lifespan, and the differential susceptibility of ECs to acquiring aging-associated traits. In doing so, we underscore the transformative potential of single-cell approaches in advancing our comprehension of endothelial aging, essential to foster the development of future innovative therapeutic strategies for aging-associated vascular conditions.

Validation of an early vascular aging construct model for comprehensive cardiovascular risk assessment using external risk indicators for improved clinical utility: data from the EVasCu study.

BACKGROUND: Cardiovascular diseases (CVDs) remain a major global health concern, necessitating advanced risk assessment beyond traditional factors. Early vascular aging (EVA), characterized by accelerated vascular changes, has gained importance in cardiovascular risk assessment. METHODS: The EVasCu study in Spain examined 390 healthy participants using noninvasive measurements. A construct of four variables (Pulse Pressure, Pulse Wave Velocity, Glycated Hemoglobin, Advanced Glycation End Products) was used for clustering. K-means clustering with principal component analysis revealed two clusters, healthy vascular aging (HVA) and early vascular aging (EVA). External validation variables included sociodemographic, adiposity, glycemic, inflammatory, lipid profile, vascular, and blood pressure factors. RESULTS: EVA cluster participants were older and exhibited higher adiposity, poorer glycemic control, dyslipidemia, altered vascular properties, and higher blood pressure. Significant differences were observed for age, smoking status, body mass index, waist circumference, fat percentage, glucose, insulin, C-reactive protein, diabetes prevalence, lipid profiles, arterial stiffness, and blood pressure levels. These findings demonstrate the association between traditional cardiovascular risk factors and EVA. CONCLUSIONS: This study validates a clustering model for EVA and highlights its association with established risk factors. EVA assessment can be integrated into clinical practice, allowing early intervention and personalized cardiovascular risk management.

Dietary NO3- does not enhance endothelial dependent cutaneous vascular conductance in older women.

Prior work has yet to determine whether the reduction of dietary nitrate (NO3-) to NO, via the enterosalivary pathway, may modify cutaneous vascular conductance (CVC) responses to local heating in older women. Changes occurring with the transition to menopause related to hormonal flux, increased adiposity, and/or decreased physical activity may further compound the negative influence of aging on nitric oxide (NO)-dependent CVC. Herein, we characterized changes in NO-dependent CVC following acute ingestion of 140 mL of NO3--rich beetroot juice in 24 older women (age: 65 ± 5 y, BMI: 31.2 ± 3.7 kg/m2). Red blood cell (RBC) flux was measured continuously via laser-Doppler flowmetry on the dorsal aspect of the forearm during local skin heating to 39 °C/44 °C before and 3 h after NO3- ingestion. NO-dependent changes in CVC were calculated as RBC flux/mean arterial blood pressure at 39 °C and normalized as a proportion of maximal CVC at 44 °C (%CVCmax). Changes (Δ) in fractional exhaled NO (FeNO) following NO3- ingestion were used an index of NO bioavailability. Despite increased FeNO (+81 ± 70 %, P < 0.001), %CVCmax at 39 °C was reduced (-16 ± 10 %, P < 0.001) following NO3- ingestion. A greater reduction in %CVCmax was weakly to moderately associated with higher body fat% (r = 0.45 [0.05-0.72], P = 0.029), central adiposity% (r = 0.50 [0.13-0.75], P = 0.012), neutrophil% (r = 0.42 [0.02-0.70], P = 0.041), and higher neutrophil to lymphocyte ratio (r = 0.49 [0.11-0.75], P = 0.016). These findings demonstrate a single dose of dietary NO3- does not promote CVC responses to local heating in sedentary older women with overweight and obesity. Correlation with multiple biomarkers suggest systemic inflammation may be involved.

Spinster homolog 2 (SPNS2) deficiency drives endothelial cell senescence and vascular aging via promoting pyruvate metabolism mediated mitochondrial dysfunction.

Endothelial cell (EC) senescence and vascular aging are important hallmarks of chronic metabolic diseases. An improved understanding of the precise regulation of EC senescence may provide novel therapeutic strategies for EC and vascular aging-related diseases. This study examined the potential functions of Spinster homolog 2 (SPNS2) in EC senescence and vascular aging. We discovered that the expression of SPNS2 was significantly lower in older adults, aged mice, hydrogen peroxide-induced EC senescence models and EC replicative senescence model, and was correlated with the expression of aging-related factors. in vivo experiments showed that the EC-specific knockout of SPNS2 markedly aggravated vascular aging by substantially, impairing vascular structure and function, as evidenced by the abnormal expression of aging factors, increased inflammation, reduced blood flow, pathological vessel dilation, and elevated collagen levels in a naturally aging mouse model. Moreover, RNA sequencing and molecular biology analyses revealed that the loss of SPNS2 in ECs increased cellular senescence biomarkers, aggravated the senescence-associated secretory phenotype (SASP), and inhibited cell proliferation. Mechanistically, silencing SPNS2 disrupts pyruvate metabolism homeostasis via pyruvate kinase M (PKM), resulting in mitochondrial dysfunction and EC senescence. Overall, SPNS2 expression and its functions in the mitochondria are crucial regulators of EC senescence and vascular aging.

Perivascular fat tissue and vascular aging: A sword and a shield.

The understanding of the function of perivascular adipose tissue (PVAT) in vascular aging has significantly changed due to the increasing amount of information regarding its biology. Adipose tissue surrounding blood vessels is increasingly recognized as a key regulator of vascular disorders. It has significant endocrine and paracrine effects on the vasculature and is mediated by the production of a variety of bioactive chemicals. It also participates in a number of pathological regulatory processes, including oxidative stress, immunological inflammation, lipid metabolism, vasoconstriction, and dilation. Mechanisms of homeostasis and interactions between cells at the local level tightly regulate the function and secretory repertoire of PVAT, which can become dysregulated during vascular aging. The PVAT secretion group changes from being reducing inflammation and lowering cholesterol to increasing inflammation and increasing cholesterol in response to systemic or local inflammation and insulin resistance. In addition, the interaction between the PVAT and the vasculature is reciprocal, and the biological processes of PVAT are directly influenced by the pertinent indicators of vascular aging. The architectural and biological traits of PVAT, the molecular mechanism of crosstalk between PVAT and vascular aging, and the clinical correlation of vascular age-related disorders are all summarized in this review. In addition, this paper aims to elucidate and evaluate the potential benefits of therapeutically targeting PVAT in the context of mitigating vascular aging. Furthermore, it will discuss the latest advancements in technology used for targeting PVAT.

Efficacy of a mixed extract of Salvia miltiorrhiza and Paeonia lactiflora in inhibiting the aging of vascular wall through in vitro and in vivo experiments.

Vascular wall aging has been strongly associated with cardiovascular diseases. Thus, this study aimed to investigate the efficacy of USCP-GVH-014, a mixed extract of Salvia miltiorrhiza Bunge and Paeonia lactiflora Pall., in inhibiting vascular wall aging through in vitro and in vivo experiments. The results revealed that USCP-GVH-014 inhibited abnormal cell proliferation, collagen overproduction, and MMP-2 and MMP-9 overexpression caused by various stimuli and recovered the antioxidant enzyme superoxide dismutase on human aortic smooth muscle cells. In addition, it inhibited the increase in ICAM-1 and VCAM-1 expression induced by tumor necrosis factor alpha on human aortic endothelial cells and prevented the aging of the vascular wall by regulating related proteins such as epidermal growth factor and interleukin-1ß. Furthermore, it reduced vascular aging in in vivo studies. These results demonstrate that USCP-GVH-014 effectively reduces vascular aging, thereby rendering it a potential therapeutic candidate for cardiovascular diseases.

BANP Participates in the Chronic Intermittent Hypoxia-Induced Senescence of Vascular Endothelial Cells by Promoting P53 Phosphorylation and Nuclear Retention.

INTRODUCTION: The objective of this study was to examine the potential induction of senescence in vascular endothelial cells (VECs) by chronic intermittent hypoxia (CIH), a defining characteristic of obstructive sleep apnea (OSA). This investigation seeks to elucidate the underlying mechanisms that contribute to the development of cardiovascular diseases in patients with OSA, with a particular focus on CIH-induced vascular aging. METHODS: The BioSpherix-OxyCycler system was used to establish models of CIH in both rats and human umbilical vein endothelial cells (HUVECs). To assess VECs' senescence, various methods were employed including EdU incorporation assay, cell cycle analysis, senescence-associated ß-galactosidase (SA-ß-gal) staining, and senescence protein testing. Vascular aging was evaluated through measurements of carotid-femoral pulse wave velocity, intima-media thickness, and Ki67 immunohistochemical staining. In order to identify the molecular mechanisms associated with CIH-induced senescence in VECs, a bioinformatics study was conducted utilizing the Gene Expression Omnibus database. RESULTS: Under conditions of CIH, HUVECs exhibited inhibited proliferation, arrested cell cycle, increased activity of SA-ß-gal, and elevated expression levels of p53 and p21 compared to HUVECs under normoxic conditions. Similarly, rats exposed to CIH displayed increased carotid-femoral pulse wave velocity, intima-media thickness, vascular permeability, and SA-ß-gal activity in VECs, along with decreased expression of arterial Ki67. BTG3-associated protein (BANP) was found to be highly expressed in CIH-induced VECs. Furthermore, the overexpression of BANP resulted in the senescence of VECs, along with elevated levels of p53 phosphorylation and nuclear localization. CONCLUSIONS: These findings demonstrate that CIH can induce VECs senescence and contribute to vascular aging. Additionally, BANP can induce VECs senescence by promoting p53 phosphorylation and nuclear retention. These discoveries offer novel insights into the increased cardiovascular risk associated with OSA, thereby presenting new possibilities for therapeutic intervention.

Early vascular aging in acute ischemic stroke: A systematic review and meta-analysis.

BACKGROUND: While arterial stiffening is a known risk factor for cardiovascular diseases, it remains unclear whether there is an early vascular aging (EVA) in patients who have experienced acute ischemic stroke (AIS). This systematic review and meta-analysis aims to investigate whether patients with AIS exhibit EVA through pulse wave velocity (PWV) measurements shortly after the stroke onset, shedding light on the relationship between arterial stiffness, hypertension, and stroke. METHODS: Thirteen case-control studies were included, comparing PWV measurements between AIS patients and non-AIS individuals. A meta-analysis was performed to compare PWV levels, age, blood pressure, and the prevalence of different cardiovascular risk factors among 1711 AIS patients and 1551 controls. RESULTS: Despite AIS patients showing higher PWV compared to controls (mean difference: 1.72 m/s, 95 % CI: 1.05-2.38, p < 0.001; I2 = 88.3 %), their age did not significantly differ (95 % CI: -0.47-0.94, p = 0.519; I2 = 0 %), suggesting EVA in AIS patients. Moreover, AIS patients exhibited elevated systolic and diastolic blood pressure and had higher odds of smoking, hypertension, diabetes, and male gender compared to controls. CONCLUSIONS: This study's findings underscore the presence of EVA in AIS patients, evident through increased PWV measurements shortly after stroke onset. Notably, smoking, hypertension, and diabetes mellitus emerge as substantial factors contributing to accelerated arterial stiffness within this population.

Correlation between obesity and early vascular aging in middle-aged and young adult health check-up populations. / ä¸­é’å¹´å¥åº·ä½“æ£€äººç¾¤è‚¥èƒ–ä¸Žæ—©å‘è¡€ç®¡è€åŒ–çš„ç›¸å ³æ€§.

OBJECTIVES: The obesity rate among middle-aged and young adults in China is increasing annually, and the incidence of cardiovascular diseases is becoming more prevalent in younger populations. However, it has not yet been reported whether obesity is associated with early vascular aging (EVA). This study aims to explore the correlation between obesity and EVA in middle-aged and young adult health check-up populations, providing a reference for the prevention of cardiovascular diseases. METHODS: A total of 15 464 middle-aged and young adults aged 18-59 who completed brachial-ankle pulse wave velocity (baPWV) test in the Third Xiangya Hospital of Central South University from January to December 2020 were included. Among them, 1 965 individuals with normal blood pressure and no cardiovascular risk factors were selected as the healthy population. The baPWV thresholds for determining EVA in each age group for males and females were calculated based on the baPWV values of the healthy population. The number and percentage of individuals meeting the EVA criteria in the middle-aged and young adult health check-up populations were statistically analyzed by age and gender. The differences in obesity indicators [visceral adiposity index (VAI), body mass index (BMI), waist circumference (WC)] between the EVA and non-EVA groups for males and females were compared. Using EVA as the dependent variable, VAI, BMI, and WC were included as independent variables in a Logistic model to analyze the correlation between each obesity indicator and EVA before and after adjusting for other influencing factors. Furthermore, the correlation between each obesity indicator and EVA in each age group was analyzed. RESULTS: In the health check-up populations, the detection rate of EVA in different age groups was 1.65%-10.92% for males, and 1.16%-10.50% for females, the detection rate of EVA increased with age in both males and females. Except for the 40-<50 age group, the EVA detection rate was higher in males than in females in all other age groups. Regardless of gender, obesity indicators VAI, BMI, and WC were significantly higher in the EVA group than in the non-EVA group (all P<0.01). Before and after adjusting for other influencing factors, VAI and WC were both correlated with EVA (both P<0.05). BMI was a risk factor for EVA before adjusting for other influencing factors (P<0.01), but after adjustment, the correlation between BMI and EVA was not statistically significant (P=0.05). After adjusting for other influencing factors, the correlation between VAI and EVA was statistically significant in the 18-<40 and 50-<60 age groups (both P<0.05), while the correlation between BMI and WC with EVA was not statistically significant (both P>0.05). In the 40-<50 age group, the correlation between VAI and BMI with EVA was not statistically significant (both P>0.05), but the correlation between WC and EVA was statistically significant (P<0.01). CONCLUSIONS: VAI is closely related to the occurrence of EVA in middle-aged and young adults aged 18-<40 and 50-<60 years, while WC is closely related to the occurrence of EVA in those aged 40-<50 years.

Role of Notch signaling in neurovascular aging and Alzheimer's disease.

The Notch signaling pathway is an evolutionarily conserved cell signaling system known to be involved in vascular development and function. Recent evidence suggests that dysfunctional Notch signaling could play a critical role in the pathophysiology of neurodegenerative diseases. We reviewed current literature on the role of Notch signaling pathway, and specifically Notch receptor genes and proteins, in aging, cerebrovascular disease and Alzheimer's disease. We hypothesize that Notch signaling may represent a key point of overlap between age-related vascular and Alzheimer's pathophysiology contributing to their comorbidity and combined influence on cognitive decline and dementia. Numerous findings from studies of genetics, neuropathology and cell culture models all suggest a link between altered Notch signaling and Alzheimer's pathophysiology. Age-related changes in Notch signaling may also trigger neurovascular dysfunction, contributing to the development of neurodegenerative diseases; however, additional studies are warranted. Future research directly exploring the influence of aberrant Notch signaling in the development of Alzheimer's disease is needed to better understand this mechanism.

Urinary Peptidomics and Pulse Wave Velocity: The African-PREDICT Study.

Increased arterial stiffness is related to early vascular aging and is an independent predictor for cardiovascular disease and mortality. Molecular mechanisms underlying increased arterial stiffness are largely unexplored, especially at the proteome level. We aimed to explore the relationship between pulse wave velocity and urinary proteomics. We included 919 apparently healthy (no chronic illnesses) Black and White men and women (equally distributed) between 20 and 30 years from the African-PREDICT study. Capillary electrophoresis time-of-flight mass spectrometry was used to analyze the urinary proteome. We measured the carotid-femoral pulse wave velocity to estimate arterial stiffness. In the total group, pulse wave velocity correlated positively with collagen-derived peptides including collagen types I, II, III, IV, V, and IX and inversely with collagen type XI (adjusted for mean arterial pressure). Regarding noncollagen-derived peptides, pulse wave velocity positively correlated with polymeric immunoglobulin receptor peptides (n = 2) (all q-value ≤0.05). In multivariable adjusted analyses, pulse wave velocity associated positively and independently with seven urinary peptides (collagen type I, n = 5) (all p-value ≤0.05). We found significant positive and independent associations between pulse wave velocity and the collagen type I-derived peptides, suggesting that dysregulation of collagen type I in the extracellular matrix scaffold could lead to early onset of increased arterial stiffness.

Oxidative stress and epigenetics in ocular vascular aging: an updated review.

Vascular aging is an inevitable process with advancing age, which plays a crucial role in the pathogenesis of cardiovascular and microvascular diseases. Diabetic retinopathy (DR) and age-related macular degeneration (AMD), characterized by microvascular dysfunction, are the common causes of irreversible blindness worldwide, however there is still a lack of effective therapeutic strategies for rescuing the visual function. In order to develop novel treatments, it is essential to illuminate the pathological mechanisms underlying the vascular aging during DR and AMD progression. In this review, we have summarized the recent discoveries of the effects of oxidative stress and epigenetics on microvascular degeneration, which could provide potential therapeutic targets for DR and AMD.

Arterial stiffness preceding metabolic syndrome in 3,862 adolescents: a mediation and temporal causal longitudinal birth cohort study.

The temporal longitudinal associations of carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, with the risk of incident metabolic syndrome, were examined in youth. A total of 3,862 adolescents, aged 17.7 yr and followed up for 7 yr, from the Avon Longitudinal Study of Parents and Children were included. cfPWV was assessed by Vicorder at baseline and follow up. Metabolic syndrome was determined by the presence of three or more of dual-energy X-ray absorptiometry-measured trunk fat obesity; decreased high-density lipoprotein cholesterol, elevated triglyceride, hyperglycemia, and elevated/hypertensive blood pressure at both measurement time points. Analyses were conducted using generalized logit mixed-effect models and autoregressive cross-lagged and mediation structural equation models. Among 3,862 adolescents [2,143 (55.5%) female], 5% of male and 1.1% of female participants had metabolic syndrome at baseline, whereas 8.8% of male and 2.4% of female participants had metabolic syndrome at follow-up. In the mixed-model analysis, a 7-yr progressive increase in cfPWV was associated with a cumulatively increased risk of incident metabolic syndrome from baseline through follow-up in the total cohort (odds ratio 1.04 [confidence interval, 1.02-1.06], P = 0.002) and in males (1.09 [1.06-1.12], P < 0.001) but not in females (1.01 [0.95-1.06], P = 0.885). In the cross-lagged model, higher cfPWV at baseline was associated with a higher metabolic syndrome score (ß = 0.08, standard error = 0.39, P < 0.0001) at follow-up but metabolic syndrome score at baseline was not associated with cfPWV at follow-up. Cumulatively increased fasting insulin and low-density lipoprotein cholesterol had 12.4 and 9.4% respective mediation effects on the positive relationships between cumulative arterial stiffness and metabolic syndrome score. In conclusion, arterial stiffness temporally preceded incident and progressive metabolic syndrome in youth in a potential causal path, but experimental studies are warranted.NEW & NOTEWORTHY Participants at risk of metabolic syndrome increased twofold during growth from late adolescence to young adulthood. The cumulative increase in arterial stiffness independently predicted the progressive risk of incident metabolic syndrome. Arterial stiffness temporally preceded metabolic syndrome. Increased fasting insulin and low-density lipoprotein cholesterol partly mediated the direct associations between arterial stiffness and metabolic syndrome. Age 17 yr may be an optimal arterial stiffness intervention timing for attenuating metabolic syndrome risks.

Does arterial stiffness mediate or suppress the associations of blood pressure with cardiac structure and function in adolescents?

There is limited understanding of the role of arterial stiffness in cardiovascular disease risk in the pediatric population, lagging behind strong evidence in the adult population. Arterial stiffness progression among adolescents with hypertension has been considered hypertension-mediated vascular damage. However, emerging pediatric reports suggest that arterial stiffness may precede increased blood pressure and hypertension, whereas increased blood pressure from childhood has been associated with signs of cardiac damage in mid-adulthood. Thus, this study used a third variable analytical approach to examine whether arterial stiffness mediates or suppresses the effects of increasing blood pressure on cardiac structure and function in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort of 1,778 adolescents. After an adjustment for cardiometabolic and lifestyle factors, arterial stiffness measured as carotid-femoral pulse wave velocity partly suppressed the association of higher systolic blood pressure with higher left ventricular mass (standardized regression coefficient, ß = -0.012; P = 0.017; suppression effect = 4%), partly mediated the associations of higher systolic and diastolic blood pressure with higher relative ventricular wall thickness, and partly suppressed the association of higher diastolic blood pressure with lower left ventricular diastolic function (ß = -0.021; P = 0.003; suppression effect = 14.5%). In conclusion, increasing arterial stiffness could attenuate some of the adverse effects of increased blood pressure on cardiac structure and function in adolescents possibly by modifying the Windkessel effects.NEW & NOTEWORTHY The present study demonstrates that the associations of blood pressure with cardiac function and structure in adolescents may be mediated or suppressed by arterial stiffness depending on the blood pressure phenotype: systolic or diastolic. Arterial stiffness may be considered as an intermediate pathway to attenuate the effect of increased blood pressure on altered cardiac structure and function in youth.

Noninvasive hemodynamic indices of vascular aging: an in silico assessment.

Vascular aging (VA) involves structural and functional changes in blood vessels that contribute to cardiovascular disease. Several noninvasive pulse wave (PW) indices have been proposed to assess the arterial stiffness component of VA in the clinic and daily life. This study investigated 19 of these indices, identified in recent review articles on VA, by using a database comprising 3,837 virtual healthy subjects aged 25-75 yr, each with unique PW signals simulated under various levels of artificial noise to mimic real measurement errors. For each subject, VA indices were calculated from filtered PW signals and compared with the precise theoretical value of aortic Young's modulus (EAo). In silico PW indices showed age-related changes that align with in vivo population studies. The cardio-ankle vascular index (CAVI) and all pulse wave velocity (PWV) indices showed strong linear correlations with EAo (Pearson's rp > 0.95). Carotid distensibility showed a strong negative nonlinear correlation (Spearman's rs < -0.99). CAVI and distensibility exhibited greater resilience to noise compared with PWV indices. Blood pressure-related indices and photoplethysmography (PPG)-based indices showed weaker correlations with EAo (rp and rs < 0.89, |rp| and |rs| < 0.84, respectively). Overall, blood pressure-related indices were confounded by more cardiovascular properties (heart rate, stroke volume, duration of systole, large artery diameter, and/or peripheral vascular resistance) compared with other studied indices, and PPG-based indices were most affected by noise. In conclusion, carotid-femoral PWV, CAVI and carotid distensibility emerged as the superior clinical VA indicators, with a strong EAo correlation and noise resilience. PPG-based indices showed potential for daily VA monitoring under minimized noise disturbances.NEW & NOTEWORTHY For the first time, 19 noninvasive pulse wave indices for assessing vascular aging were examined together in a single database of nearly 4,000 subjects aged 25-75 yr. The dataset contained precise values of the aortic Young's modulus and other hemodynamic measures for each subject, which enabled us to test each index's ability to measure changes in aortic stiffness while accounting for confounding factors and measurement errors. The study provides freely available tools for analyzing these and additional indices.

Impact of aging on vascular ion channels: perspectives and knowledge gaps across major organ systems.

Individuals aged ≥65 yr will comprise ∼20% of the global population by 2030. Cardiovascular disease remains the leading cause of death in the world with age-related endothelial "dysfunction" as a key risk factor. As an organ in and of itself, vascular endothelium courses throughout the mammalian body to coordinate blood flow to all other organs and tissues (e.g., brain, heart, lung, skeletal muscle, gut, kidney, skin) in accord with metabolic demand. In turn, emerging evidence demonstrates that vascular aging and its comorbidities (e.g., neurodegeneration, diabetes, hypertension, kidney disease, heart failure, and cancer) are "channelopathies" in large part. With an emphasis on distinct functional traits and common arrangements across major organs systems, the present literature review encompasses regulation of vascular ion channels that underlie blood flow control throughout the body. The regulation of myoendothelial coupling and local versus conducted signaling are discussed with new perspectives for aging and the development of chronic diseases. Although equipped with an awareness of knowledge gaps in the vascular aging field, a section has been included to encompass general feasibility, role of biological sex, and additional conceptual and experimental considerations (e.g., cell regression and proliferation, gene profile analyses). The ultimate goal is for the reader to see and understand major points of deterioration in vascular function while gaining the ability to think of potential mechanistic and therapeutic strategies to sustain organ perfusion and whole body health with aging.

Early vascular aging as an index of cardiovascular risk in healthy adults: confirmatory factor analysis from the EVasCu study.

BACKGROUND: The concept of early vascular aging (EVA) represents a potentially beneficial model for future research into the pathophysiological mechanisms underlying the early manifestations of cardiovascular disease. For this reason, the aims of this study were to verify by confirmatory factor analysis the concept of EVA on a single factor based on vascular, clinical and biochemical parameters in a healthy adult population and to develop a statistical model to estimate the EVA index from variables collected in a dataset to classify patients into different cardiovascular risk groups: healthy vascular aging (HVA) and EVA. METHODS: The EVasCu study, a cross-sectional study, was based on data obtained from 390 healthy adults. To examine the construct validity of a single-factor model to measure accelerated vascular aging, different models including vascular, clinical and biochemical parameters were examined. In addition, unsupervised clustering techniques (using both K-means and hierarchical methods) were used to identify groups of patients sharing similar characteristics in terms of the analysed variables to classify patients into different cardiovascular risk groups: HVA and EVA. RESULTS: Our data show that a single-factor model including pulse pressure, glycated hemoglobin A1c, pulse wave velocity and advanced glycation end products shows the best construct validity for the EVA index. The optimal value of the risk groups to separate patients is K = 2 (HVA and EVA). CONCLUSIONS: The EVA index proved to be an adequate model to classify patients into different cardiovascular risk groups, which could be valuable in guiding future preventive and therapeutic interventions.

Association of Accelerometer-Measured Sedentary Time and Physical Activity with Arterial Stiffness and Vascular Aging in the General Spanish Population, Analyzed by Sex.

Background: In this study we analyzed the association between physical activity and sedentary lifestyle with vascular aging in Spanish populations aged 35-75 years. Methods: A cross-sectional study was developed, in which 501 subjects aged 35-75 years were recruited. Physical activity and sedentary time were measured with an accelerometer (Actigraph GTX3) for a week. We measured carotid-femoral pulse wave velocity (cfPWV) by a Sphygmo Cor® device and carotid intima-media thickness (cIMT) by ultrasound (Sonosite Micromax®). The vascular aging index (VAI) was calculated as described in the literature. Vascular aging was defined considering the 25th and 75th percentiles by age and sex of cfPWV and VAI, presence of vascular injury, type-2 diabetes mellitus or arterial hypertension. Individuals were classified into three groups: healthy, normal, and early vascular aging. Results: The mean age of the sample was 55.90 ± 14.24 years, 50% being women. Total physical activity was negatively associated with cfPWV ( ß = -0.454) and VAI ( ß = -1.845). Similarly, the number of steps per day obtained a negative association with cfPWV ( ß = -0.052) and VAI ( ß = -0.216), while sedentary time showed a positive association with cfPWV ( ß = 0.028) and VAI ( ß = 0.117). In the analysis by sex, the results showed similar values. The odds ratio (OR) of total physical activity of subjects classified as early vascular aging (EVA) with regarding those classified as healthy vascular aging (HVA) was 0.521 (95% confidence interval [CI] 0.317 to 0.856) for cfPWV, and 0.565 (95% CI 0.324 to 0.986) for VAI. In terms of the number of steps per day, the OR was 0.931 (95% CI 0.875 to 0.992) for cfPWV and 0.916 (95% CI 0.847 to 0.990) for VAI and for sedentary time the OR was 1.042 (95% CI 1.011 to 1.073) for cfPWV and 1.037 (95% CI 1.003 to 1.072) for VAI. The OR of subjects classified as vigorous physical activity was 0.196 (95% CI 0.041 to 0.941) using cfPWV and 0.161 (95% CI 0.032 to 0.820) using VAI. In the analysis by sex, the results showed an association in men when cfPWV was used and an association in women when VAI was used to define vascular aging. Conclusions: The results of this study indicate that the more time spent performing physical activity and the less sedentary time, the lower the arterial stiffness and the probability of developing early vascular aging. Clinical Trial Registration: The study was registered in ClinicalTrials.gov (number: NCT02623894).

IL-17A promotes endothelial cell senescence by up-regulating the expression of FTO through activating JNK signal pathway.

Endothelial aging is a sign of vascular aging that predisposes patients to vascular disease. We explored the effects of IL-17A on endothelial cell aging and determined the potential underlying mechanisms. In human umbilical vein endothelial cells, IL-17A promoted senescence, evidenced as increased positive staining of senescence-associated ß-galactosidase, increased proportion of cells arrested at G0/G1 stage, and upregulated p21 and p16 expression. IL-17A increased the expression of the m6A methylase FTO. We then investigated the relationship between FTO and endothelial cell aging. After interfering with FTO expression by siRNA, we observed that FTO induced endothelial cell aging. An increase in the expression of p-Jun N-terminal kinases (JNK) increased after IL-17A treatment indicated, that the JNK signaling pathway affected FTO expression. Moreover, the addition of the JNK signaling pathway inhibitor SP600125 blocked the effect of IL-17A on FTO expression. In conclusion, our findings revealed that IL-17A can promote endothelial cell aging by activating the JNK signaling pathway and upregulating FTO expression. This discovery can help in the identification of new therapeutic targets against endothelial cell aging and related vascular complications.

Orthostatic blood pressure adaptations, aortic stiffness, and central hemodynamics in the general population: insights from the Malmö Offspring Study (MOS).

PURPOSE: Arterial stiffness is independently associated with orthostatic hypotension in older individuals. The relationship between orthostatic blood pressure adaptation and aortic stiffness has not been thoroughly examined in a younger population. We investigated the relationship between orthostatic blood pressure adaptations, central aortic hemodynamics, and aortic stiffness in a cohort of predominantly younger and middle-aged adults. METHODS: We analyzed an observational, population-based study of 5259 individuals living in Malmö, Sweden. We related aortic stiffness and central hemodynamics assessed by carotid-femoral pulse wave velocity and pulse wave analysis at the arteria radialis using Sphygmocor to orthostatic blood pressure adaptation after 3 min standing. RESULTS: The mean age of the population was 41.9 ± 14.5 years, and 52.1% were women. We observed the highest aortic stiffness and central aortic blood pressure measurements in the lowest and highest quartiles of orthostatic systolic blood pressure differences (p < 0.001). Aortic stiffness and central aortic blood pressure gradually decreased across increasing quartiles of orthostatic diastolic blood pressure difference (p < 0.001). After full adjustment, orthostatic diastolic blood pressure remained significantly associated with aortic stiffness (p = 0.001) and central aortic blood pressure (p < 0.001), whereas orthostatic systolic blood pressure was significantly associated only with central aortic systolic blood pressure (p = 0.009). No significant associations were found between subclinical orthostatic hypotension, aortic stiffness, and central hemodynamics. CONCLUSIONS: Our findings demonstrate that altered blood pressure responses to orthostatic challenges, both blood pressure reductions and blood pressure increases, are independently and inversely associated with markers of aortic stiffness (vascular aging) in a predominantly young to middle-aged population.