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The “biomechanical hypothesis” stipulates that with aging, the cumulative mechanical damages to the cerebral microvasculature, magnified by risk factors for vascular diseases, contribute to a breach in cerebral homeostasis producing neuronal losses. In other words, vascular dysfunction affects brain structure and function, and leads to cognitive failure. This is gathered under the term Vascular Cognitive Impairment and Dementia (VCID). One of the main culprits in the occurrence of cognitive decline could be the inevitable rise in arterial pulse pressure due to the age-dependent stiffening of large conductance arteries like the carotids, which in turn, could accentuate the penetration of the pulse pressure wave deeper into the fragile microvasculature of the brain and damage it. In this review, we will discuss how and why the vascular and brain cells communicate and are interdependent, describe the deleterious impact of a vascular dysfunction on brain function in various neurodegenerative diseases and even of psychiatric disorders, and the potential chronic deleterious effects of the pulsatile blood pressure on the cerebral microcirculation. We will also briefly review data from antihypertensive clinical trial aiming at improving or delaying dementia. Finally, we will debate how the aging process, starting early in life, could determine our sensitivity to risk factors for vascular diseases, including cerebral diseases, and the trajectory to VCID.

Background Aerobic exercise training is associated with beneficial ventricular remodeling and an improvement in cardiac biomarkers in chronic stable heart failure. High‐intensity interval training (HIIT) is a time‐efficient method to improve V˙O2peak in stable coronary heart disease patients. This pilot study aimed to compare the effect of HIIT on ventricular remodeling in patients with a recent acute myocardial infarction (AMI). Methods Nineteen post‐AMI patients were randomized to either HIIT (n = 9) or usual care (n = 10). A cardiopulmonary exercise test (CPET), transthoracic echocardiography, and cardiac biomarker assessment (ie, N‐terminal pro B‐type natriuretic peptide levels and G protein‐coupled receptor kinase 2 expression) were performed before and after a 12‐week training intervention. CPET parameters including oxygen uptake efficiency slope (OUES) and V˙O2 at the first ventilatory threshold (V˙O2 VT1) were calculated. left ventricular (LV) structural and functional echocardiographic parameters including myocardial strain imaging were assessed. Results V˙O2peak and OUES improved solely in the HIIT group (P

Introduction: Age-related and atherosclerosis-related vascular dysfunction contributes to neuro-vascular uncoupling, which induces neuronal damage and leads to precocious cognitive loss. This dysfunction could be partially explained by the accumulation of senescent cells (SnC) that remain metabolically active and release many pro-inflammatory factors. Hypothesis: Targeted elimination of SnC with a senolytic restores cerebrovascular function, maintains neuro-vascular coupling and slows cognitive decline. Methods and Results: Nine-month old male atherosclerotic mice (ATX, LDLR -/- ;hApoB +/+ ) were treated (n=13), or not (n=11), for 3 months with navitoclax (50mg/kg), a Bcl2 inhibitor that stimulates global elimination of SnC overexpressing this antiapoptotic pathway. Twelve-month old vehicle-treated ATX mice developed atheroma plaques up to the upper neck portion of the carotid arteries, but not in the cerebral circulation. Three months treatment with navitoclax reduced aortic plaques size (-32%, pex vivo ; navitoclax improved endothelium-dependent dilatation by 50% (for example, FMD at 20 dyn/cm 2 : 58±10%) compared to vehicle-treated mice (FMD: 29±7%; p Conclusion: Global elimination of SnC slowed atherosclerotic plaque development and restored cerebral endothelial function, demonstrating that senescence contributes to vascular dysfunction. The absence of cognitive improvement with navitoclax suggests an irreversible state of neuronal damage that could not be affected by the late senolytic treatment. To demonstrate the role of SnC in cognitive impairment, an earlier senolytic therapy will be needed.

A chronic and gradual increase in pulse pressure (PP) is associated with cognitive decline and dementia in older individuals, but the mechanisms remain ill-defined. We hypothesized that a chronic elevation of PP would cause brain microvascular endothelial mechanical stress, damage the neurovascular unit, and ultimately induce cognitive impairment in mice, potentially contributing to the progression of vascular dementia and Alzheimer disease. To test our hypothesis, male control wild-type mice and Alzheimer disease model APP/PS1 (amyloid precursor protein/presenilin 1) mice were exposed to a transverse aortic constriction for 6 weeks, creating a PP overload in the right carotid (ipsilateral). We show that the transverse aortic constriction procedure associated with high PP induces a cascade of vascular damages in the ipsilateral parenchymal microcirculation: in wild-type mice, it impairs endothelial dilatory and blood brain barrier functions and causes microbleeds, a reduction in microvascular density, microvascular cell death by apoptosis, leading to severe hypoperfusion and parenchymal cell senescence. These damages were associated with brain inflammation and a significant reduction in learning and spatial memories. In APP/PS1 mice, that endogenously display severe cerebral vascular dysfunctions, microbleeds, parenchymal inflammation and cognitive dysfunction, transverse aortic constriction–induced high PP further aggravates cerebrovascular damage, Aβ (beta-amyloid) accumulation, and prevents learning. Our study, therefore, demonstrates that brain microvessels are vulnerable to a high PP and mechanical stress associated with transverse aortic constriction, promoting severe vascular dysfunction, disruption of the neurovascular unit, and cognitive decline. Hence, chronic elevated amplitude of the PP could contribute to the development and progression of vascular dementia including Alzheimer disease.

The vascular endothelium occupies a catalog of functions that contribute to the homeostasis of the cardiovascular system. It is a physically active barrier between circulating blood and tissue, a regulator of the vascular tone, a biochemical processor and a modulator of coagulation, inflammation, and immunity. Given these essential roles, it comes to no surprise that endothelial dysfunction is prodromal to chronic age-related diseases of the heart and arteries, globally termed cardiovascular diseases (CVD). An example would be ischemic heart disease (IHD), which is the main cause of death from CVD. We have made phenomenal advances in treating CVD, but the aging endothelium, as it senesces, always seems to out-run the benefits of medical and surgical therapies. Remarkably, many epidemiological studies have detected a correlation between a flavonoid-rich diet and a lower incidence of mortality from CVD. Quercetin, a member of the flavonoid class, is a natural compound ubiquitously found in various food sources such as fruits, vegetables, seeds, nuts, and wine. It has been reported to have a wide range of health promoting effects and has gained significant attention over the years. A growing body of evidence suggests quercetin could lower the risk of IHD by mitigating endothelial dysfunction and its risk factors, such as hypertension, atherosclerosis, accumulation of senescent endothelial cells, and endothelial-mesenchymal transition (EndoMT). In this review, we will explore these pathophysiological cascades and their interrelation with endothelial dysfunction. We will then present the scientific evidence to quercetin's anti-atherosclerotic, anti-hypertensive, senolytic, and anti-EndoMT effects. Finally, we will discuss the prospect for its clinical use in alleviating myocardial ischemic injuries in IHD.

Aims/hypothesis: Tenascin-C (TN-C) is an extracellular matrix glycoprotein highly expressed in inflammatory and cardiovascular (CV) diseases. Serum TN-C has not yet been specifically studied in individuals with type 2 diabetes, a condition associated with chronic low-grade inflammation and increased CV disease risk. In this study, we hypothesised that elevated serum TN-C at enrolment in participants with type 2 diabetes would be associated with increased risk of death and major adverse CV events (MACE) during follow-up.Methods: We used a prospective, monocentric cohort of consecutive type 2 diabetes participants (the SURDIAGENE [SUivi Rénal, DIAbète de type 2 et GENEtique] cohort) with all-cause death as a primary endpoint and MACE (CV death, non-fatal myocardial infarction or stroke) as a secondary endpoint. We used a proportional hazard model after adjustment for traditional risk factors and the relative integrated discrimination improvement (rIDI) to assess the incremental predictive value of TN-C for these risk factors.Results: We monitored 1321 individuals (58% men, mean age 64 ± 11 years) for a median of 89 months. During follow-up, 442 individuals died and 497 had MACE. Multivariate Cox analysis showed that serum TN-C concentrations were associated with an increased risk of death (HR per 1 SD: 1.27 [95% CI 1.17, 1.38]; p < 0.0001) and MACE (HR per 1 SD: 1.23 [95% CI 1.13, 1.34]; p < 0.0001). Using TN-C concentrations on top of traditional risk factors, prediction of the risk of all-cause death (rIDI: 8.2%; p = 0.0006) and MACE (rIDI: 6.7%; p = 0.0014) improved significantly, but modestly.Conclusions/interpretation: In individuals with type 2 diabetes, increased serum TN-C concentrations were independently associated with death and MACE. Therefore, including TN-C as a prognostic biomarker could improve risk stratification in these individuals.

Aging is a modern concept: human life expectancy has more than doubled in less than 150 yr in Western countries. Longer life span, however, reveals age-related diseases, including cerebrovascular diseases. The vascular system is a prime target of aging: the “wear and tear” of large elastic arteries exposed to a lifelong pulsatile pressure causes arterial stiffening by fragmentation of elastin fibers and replacement by stiffer collagen. This arterial stiffening increases in return the amplitude of the pulse pressure (PP), its wave penetrating deeper into the microcirculation of low-resistance, high-flow organs such as the brain. Several studies have associated peripheral arterial stiffness responsible for the sustained increase in PP, with brain microvascular diseases such as cerebral small vessel disease, cortical gray matter thinning, white matter atrophy, and cognitive dysfunction in older individuals and prematurely in hypertensive and diabetic patients. The rarefaction of white matter is also associated with middle cerebral artery pulsatility that is strongly dependent on PP and artery stiffness. PP and brain damage are likely associated, but the sequence of mechanistic events has not been established. Elevated PP promotes endothelial dysfunction that may slowly develop in parallel with the accumulation of proinflammatory senescent cells and oxidative stress, generating cerebrovascular damage and remodeling, as well as brain structural changes. Here, we review data suggesting that age-related increased peripheral artery stiffness may promote the penetration of a high PP to cerebral microvessels, likely causing functional, structural, metabolic, and hemodynamic alterations that could ultimately promote neuronal dysfunction and cognitive decline.

Angiopoietin-like 2 (ANGPTL2) is a proinflammatory protein belonging to the angiopoietin-like family. ANGPTL2 is secreted and detected in the systemic circulation. Different observational clinical studies reported that circulating levels of ANGPTL2 increase significantly in various chronic inflammatory diseases and showed associations between ANGPTL2 levels and diagnosis and/or prognosis of cardiovascular diseases, diabetes, chronic kidney disease, and various types of cancers. However, these studies did not address the following questions: (a) what are the sources of circulating ANGPTL2? (b) How and by which mechanisms an increase in circulating ANGPTL2 contributes to the pathogenesis of chronic inflammatory diseases? (c) Does an increase in circulating levels of ANGPTL2 measured in a well-defined chronic medical condition originate from a specific cell type? Mechanistic hypotheses have been proposed based on studies performed in mice and cultured cells, and proinflammatory, prooxidative, proangiogenic, proliferative, and antiapoptotic properties of ANGPTL2 have been reported. The aim of this review is to propose answers concerning the potential sources of circulating ANGPTL2 and its common pathological properties associated with various chronic inflammatory diseases and death in humans. We believe that high circulating ANGPTL2 levels are more than an inflammatory marker and may reflect the senescent cellular load of an individual.

Cognitive functions are dependent upon intercommunications between the cellular components of the neurovascular unit (NVU). Vascular risk factors are associated with a more rapid rate of cognitive decline with aging and cerebrovascular diseases magnify both the incidence and the rate of cognitive decline. The causal relationship between vascular risk factors and injury to the NVU is, however, lacking. We hypothesized that vascular risk factors, such as hypertension and dyslipidemia, promote disruption of the NVU leading to early cognitive impairment. We compared brain structure and cerebrovascular functions of 1-year old (middle-aged) male wild-type (WT) and atherosclerotic hypertensive (LDLr(−/−):hApoB(+/+), ATX) mice. In addition, mice were subjected, or not, to a transverse aortic constriction (TAC) for 6 weeks to assess the acute impact of an increase in systolic blood pressure on the NVU and cognitive functions. Compared with WT mice, ATX mice prematurely developed cognitive decline associated with cerebral micro-hemorrhages, loss of microvessel density and brain atrophy, cerebral endothelial cell senescence and dysfunction, brain inflammation, and oxidative stress associated with blood-brain barrier leakage and brain hypoperfusion. These data suggest functional disturbances in both vascular and parenchymal components of the NVU. Exposure to TAC-induced systolic hypertension promoted cerebrovascular damage and cognitive decline in WT mice, similar to those observed in sham-operated ATX mice; TAC exacerbated the existing cerebrovascular dysfunctions and cognitive failure in ATX mice. Thus, a hemodynamic stress such as systolic hypertension could initiate the cascade involving cerebrovascular injury and NVU deregulation and lead to cognitive decline, a process accelerated in atherosclerotic mice.

The arterial wall is under a huge mechanical constraint imposed by the cardiac cycle that is bound to generate damage with time. Each heartbeat indeed imposes a pulsatile pressure that generates a vascular stretch. Lifetime accumulation of pulsatile stretches will eventually induce fatigue of the elastic large arterial walls, such as aortic and carotid artery walls, promoting their stiffening that will gradually perturb the normal blood flow and local pressure within the organs, and lead to organ failure. The augmented pulse pressure induced by arterial stiffening favours left ventricular hypertrophy because of the repeated extra work against stiff high-pressure arteries, and tissue damage as a result of excessive pulsatile pressure transmitted into the microcirculation, especially in low resistance/high-flow organs such as the brain and kidneys. Vascular aging is therefore characterized by the stiffening of large elastic arteries leading to a gradual increase in pulse pressure with age. In this review we focus on the effect of age-related stiffening of large elastic arteries. We report the clinical evidence linking arterial stiffness and organ failure and discuss the molecular pathways that are activated by the increase of mechanical stress in the wall. We also discuss the possible interventions that could limit arterial stiffening with age, such as regular aerobic exercise training, and some pharmacological approaches.

Circulating levels of angiopoietin-like 2 (ANGPTL2), a proinflammatory and proatherogenic protein, are elevated in patients with coronary artery disease (CAD). We hypothesized that high-intensity intermittent exercise (HIIE), known to be beneficial in patients with CAD, would reduce circulating ANGPTL2 levels.Plasma levels of ANGPTL2 were measured before and 20 minutes, 24 hours, and 72 hours after an acute exercise session in a crossover study comparing HIIE to moderate-intensity continuous exercise (MICE) in 14 patients with CAD and 20 age-matched and 20 young healthy controls.Pre-exercise ANGPTL2 levels were 3-fold higher in patients with CAD than in age-matched controls (P0.05) and correlated negatively with Vo2max/lean body mass (P0.0001). In healthy controls, ANGPTL2 levels were low and not affected by HIIE or MICE. In patients with CAD, ANGPTL2 levels decreased significantly by 41% after 20 minutes of HIIE, a reduction that was maintained after 24 and 72 hours (P0.05). In contrast, although ANGPTL2 levels decreased by 47% after 20 minutes of MICE, they increased by 104% after 24 hours and returned to baseline values after 72 hours (P0.05). A negative correlation was observed between this increase in ANGPTL2 levels and the mean rate-pressure product (heart rate × systolic blood pressure; index of myocardial O2 consumption) measured during MICE, suggesting that subclinical ischemia might promote ANGPTL2 expression.In patients with CAD, circulating ANGPTL2 levels are acutely reduced after HIIE and transiently increased after MICE. A sustained reduction in circulating ANGPTL2 levels could contribute to the chronic beneficial cardiometabolic effects of HIIE in patients with CAD.

Background Tenascin-C (TNC) is an extracellular matrix glycoprotein highly expressed in inflammatory and cardiovascular (CV) pathologies. In heart failure or after myocardial infarction, elevated TNC is associated with adverse outcomes. Serum TNC has not yet been studied specifically in patients with type II diabetes, a condition associated with chronic low-grade inflammation and increased CV risk. We hypothesized that high serum TNC measured at enrolment in a large cohort of type II diabetic patients is associated with major adverse CV events (MACE) and death during follow-up. Methods A prospective, monocentric cohort of consecutive type 2 diabetes patients (the SURDIAGENE cohort; total of 1338 patients; 58% men, mean ± SD age 64 ± 11 years) was followed for a median of 89 months for death as primary endpoint and MACE (i.e. CV death, myocardial infarction or stroke) as a secondary endpoint. Patients with stage ≥ 4 renal disease were excluded. Results During follow-up, 448 patients (representing 4.4% of the total person-years) died and 506 patients (representing 5.2% of the total person-years) presented with MACE. Cox multivariate analysis showed that increased serum TNC concentrations were significantly associated with death (HR per 10 ng/mL: 1.03 (1.01–1.05) P = 0.0095) and MACE (HR per 10 ng/mL: 1.02 (1.00–1.04) P = 0.0162), after adjustment for sex, age, established modifiable CV risk factors (active smoking, hypertension, hypercholesterolemia) and NT-proBNP levels. Conclusions In patients with type 2 diabetes, we show for the first time that increased serum TNC concentrations are independently associated with MACE and death. These findings suggest that elevated TNC expression might be implicated in the increased CV risk associated with diabetes, and might be useful for CV risk stratification in this context.

Background Patients with type 2 diabetes (T2D) face a high amputation rate. We investigated the relationship between the level of amputation and the presence of micro or macro-vascular disease and related circulating biomarkers, Tumor Necrosis Factor Receptor 1 (TNFR1) and Angiopoietin like-2 protein (ANGPTL2). Methods We have analyzed data from 1468 T2D participants in a single center prospective cohort (the SURDIAGENE cohort). Our outcome was the occurrence of lower limb amputation categorized in minor (below-ankle) or major (above ankle) amputation. Microvascular disease was defined as a history of albuminuria [microalbuminuria: uACR (urinary albumine-to-creatinine ratio) 30–299 mg/g or macroalbuminuria: uACR ≥ 300 mg/g] and/or severe diabetic retinopathy or macular edema. Macrovascular disease at baseline was divided into peripheral arterial disease (PAD): peripheral artery revascularization and/or major amputation and in non-peripheral macrovascular disease: coronary artery revascularization, myocardial infarction, carotid artery revascularization, stroke. We used a proportional hazard model considering survival without minor or major amputation. Results During a median follow-up period of 7 (0.5) years, 79 patients (5.5%) underwent amputation including 29 minor and 50 major amputations. History of PAD (HR 4.37 95% CI [2.11–9.07]; p

Angiopoietin-like 2 (ANGPTL2) is an inflammatory adipokine linking obesity to insulin resistance. Intermittent fasting, on the other hand, is a lifestyle intervention able to prevent obesity and diabetes but difficult to implement and maintain. Our objectives were to characterize a link between ANGPTL2 and intermittent fasting and to investigate whether the knockdown of ANGPTL2 reproduces the benefits of intermittent fasting on weight gain and insulin responsiveness in knockdown and wild-type littermates mice. Intermittent fasting, access to food ad libitum once every other day, was initiated at the age of three months and maintained for four months. Intermittent fasting decreased by 63% (p Impact statement Intermittent fasting is an efficient diet pattern to prevent weight gain and improve insulin sensitivity. It is, however, a difficult regimen to follow and compliance is expected to be very low. In this work, we demonstrate that knockdown of ANGPTL2 in mice fed ad libitum mimics the beneficial effects of intermittent fasting on weight gain and insulin sensitivity in wild-type mice. ANGPTL2 is a cytokine positively associated with fat mass in humans, which inactivation in mice improves resistance to a high-fat metabolic challenge. This study provides a novel pathway by which IF acts to limit obesity despite equivalent energy intake. The development of a pharmacological ANGPTL2 antagonist could provide an efficient tool to reduce the burden of obesity.

A strong relationship between high circulating angiopoietin-like 2 (ANGPTL2) levels, a proinflammatory adipokine, and cardiovascular diseases has been reported. Our objective was to determine whether plasma ANGPTL2 and high-sensitivity C-reactive protein (hs-CRP) levels change postoperatively in patients who underwent heart valve surgery and/or coronary artery bypass grafting. We hypothesized that a corrective cardiac surgery would decrease ANGPTL2 levels.In 47 prospectively recruited patients who underwent coronary artery bypass grafting (n = 16), valve replacement (n = 16), or both (n = 15), we measured plasma ANGPTL2 and hs-CRP levels preoperatively, at 24 hours, at 3 to 5 days (hospital discharge), and at 30 to 90 days (follow-up) after surgery. Mediastinal adipose tissue and distal fragments of the left internal mammary artery (IMA) were harvested during surgery and mRNA expression of inflammatory and senescence markers was assessed using real-time quantitative polymerase chain reaction.ANGPTL2 and hs-CRP levels were elevated 24 hours after surgery and then returned to baseline levels. We noted, however, a dichotomy among patients: compared with baseline, plasma ANGPTL2 levels either significantly decreased (n = 21/47) or increased (n = 26/47) after surgery. In contrast, hs-CRP levels were identical between groups (P = .997). Patients in the increased group were older (P = .002) with a higher systolic blood pressure (P = .038) at baseline. Moreover, changes in ANGPTL2 levels (ΔANGPTL2 = final minus initial levels) positively correlated with mRNA expression of tumor necrosis factor α and interleukin 8 in mediastinal adipose tissue and IMA (P .05) and with the senescence-associated marker cyclin-dependent kinase inhibitor 1 in IMA (P = .009).In younger patients with lower levels of tissue inflammation and arterial senescence load, ANGPTL2, but not hs-CRP levels decreased after cardiac surgery, suggesting that circulating ANGPTL2 reflects tissue inflammation and senescence.

Cognitive performances are tightly associated with the maximal aerobic exercise capacity, both of which decline with age. The benefits on mental health of regular exercise, which slows the age-dependent decline in maximal aerobic exercise capacity, have been established for centuries. In addition, the maintenance of an optimal cerebrovascular endothelial function through regular exercise, part of a healthy lifestyle, emerges as one of the key and primary elements of successful brain aging. Physical exercise requires the activation of specific brain areas that trigger a local increase in cerebral blood flow to match neuronal metabolic needs. In this review, we propose three ways by which exercise could maintain the cerebrovascular endothelial function, a premise to a healthy cerebrovascular function and an optimal regulation of cerebral blood flow. First, exercise increases blood flow locally and increases shear stress temporarily, a known stimulus for endothelial cell maintenance of Akt-dependent expression of endothelial nitric oxide synthase, nitric oxide generation, and the expression of antioxidant defenses. Second, the rise in circulating catecholamines during exercise not only facilitates adequate blood and nutrient delivery by stimulating heart function and mobilizing energy supplies but also enhances endothelial repair mechanisms and angiogenesis. Third, in the long term, regular exercise sustains a low resting heart rate that reduces the mechanical stress imposed to the endothelium of cerebral arteries by the cardiac cycle. Any chronic variation from a healthy environment will perturb metabolism and thus hasten endothelial damage, favoring hypoperfusion and neuronal stress.

BACKGROUND Angiopoietin-like-2 (ANGPTL2) is a secreted proinflammatory glycoprotein that promotes endothelial dysfunction, atherosclerosis, and cardiovascular disease (CVD). Circulating ANGPTL2 is increased in chronic kidney disease (CKD), where the risk of CVD is amplified. The objectives of the present study were to (i) examine whether kidney transplantation (KTx) reduces ANGPTL2 levels, (ii) identify the determinants of ANGPTL2 after KTx, (iii) study the association of ANGPTL2 with aortic stiffness, and (iv) assess the impact of ANGPTL2 on mortality after KTx. METHODS In 75 patients, serum ANGPTL2 levels were measured at baseline and 3 months after KTx. Aortic stiffness was determined by carotid-femoral pulse wave velocity, glomerular filtration rate was estimated by CKD-EPI formula, and serum cytokines and endothlin-1 levels were determined 3 months after KTx. Survival analysis was performed using Kaplan-Meier and Cox regression after a median follow-up of 90 months. RESULTS After 3 months of KTx, ANGPTL2 levels decreased from 71 ng/ml (53-95) to 11 ng/ml (9-15) (P < 0.001). In multivariate analysis, age, lower renal function, and endothelin-1 were independently associated with higher post-KTx ANGPTL2 levels. ANGPTL2 was positively associated with aortic stiffness after KTx, even when adjusted for mean blood pressure (standardized β = 0.314; P = 0.008). During follow-up, 13 deaths occurred. The group of patients with higher post-KTx ANGPTL2 levels had a hazard ratio for mortality of 3.9 (95% confidence interval: 1.07-14.4; P = 0.039). CONCLUSION KTx significantly reduced serum ANGPTL2 levels. The positive association between post-KTx ANGPTL2, aortic stiffness and mortality, suggests that ANGPTL2 may play a biological role in CKD-related CVD.

Plasma angiopoietin-like 2 (Angptl2), a proinflammatory protein, has been associated with obesity and diabetes. Whether weight loss induced by bariatric surgery and associated improvement of the cardiometabolic risk profile influence circulating Angptl2 levels is unknown. We tested whether biliopancreatic diversion with duodenal switch (BPD-DS) surgery alters plasma Angptl2 concentrations.Severely obese patients (n = 73; body mass index: 49.8 ± 7.1) underwent BPD-DS. Plasma levels of Angptl2 and metabolic biomarkers were obtained acutely (days 1 and 5) and at 6 and 12 months after surgery, and compared with results in an age- and sex-matched control group (n = 33) remaining on the waiting list.Preoperative Angptl2 levels were high (median: 12.3 ng/mL) and correlated with metabolic and anthropometric parameters. A significant (P0.01) increase in Angptl2 levels, fasting glucose, insulin, and interleukin-6 levels was observed acutely postoperatively (day 1) followed by a progressive decline from day 5. Besides weight loss, Angptl2 levels were decreased at the 12-month follow-up (11.5 ± 4.7 vs 14.0 ± 4.0 ng/mL, P0.0001), but not at the 6-month time point. Long-term changes in plasma Angptl2 levels showed significant positive correlations with changes in fasting glucose, insulin resistance, and tumour necrosis factor-α levels, and negative correlation with changes in leptin concentration (P0.05). No significant correlation was observed between changes in anthropometric parameters and Angptl2.Plasma Angptl2 levels decreased after BPD-DS in severely obese patients; no changes occurred in control participants. Lowered circulating levels of the inflammatory factor Angptl2 because of BPD-DS were closely related to favourable changes in glucose-insulin homeostasis and inflammatory profiles.

Pro-inflammatory angiopoietin-like 2 (angptl2) promotes endothelial dysfunction in mice and circulating angptl2 is higher in patients with cardiovascular diseases. We previously reported that a single bout of physical exercise was able to reduce angptl2 levels in coronary patients. We hypothesized that chronic exercise would reduce angptl2 in patients with post-acute coronary syndrome (ACS) and endothelial dysfunction. Post-ACS patients (n = 40, 10 women) were enrolled in a 3-month exercise-based prevention program. Plasma angptl2, hs-CRP, and endothelial function assessed by scintigraphic forearm blood flow, were measured before and at the end of the study. Exercise increased VO2peak by 10% (p

DNA methylation is believed to regulate gene expression during adulthood in response to the constant changes in environment. The methylome is therefore proposed to be a biomarker of health through age. ANGPTL2 is a circulating pro-inflammatory protein that increases with age and prematurely in patients with coronary artery diseases; integrating the methylation pattern of the promoter may help differentiate age- vs. disease-related change in its expression. We believe that in a pro-inflammatory environment, ANGPTL2 is differentially methylated, regulating ANGPTL2 expression. To test this hypothesis we investigated the changes in promoter methylation of ANGPTL2 gene in leukocytes from patients suffering from post-acute coronary syndrome (ACS). DNA was extracted from circulating leukocytes of post-ACS patients with cardiovascular risk factors and from healthy young and age-matched controls. Methylation sites (CpGs) found in the ANGPTL2 gene were targeted for specific DNA methylation quantification. The functionality of ANGPTL2 methylation was assessed by an in vitro luciferase assay. In post-ACS patients, C-reactive protein and ANGPTL2 circulating levels increased significantly when compared to healthy controls. Decreased methylation of specific CpGs were found in the promoter of ANGPTL2 and allowed to discriminate age vs. disease associated methylation. In vitro DNA methylation of specific CpG lead to inhibition of ANGPTL2 promoter activity. Reduced leukocyte DNA methylation in the promoter region of ANGPTL2 is associated with the pro-inflammatory environment that characterizes patients with post-ACS differently from age-matched healthy controls. Methylation of different CpGs in ANGPTL2 gene may prove to be a reliable biomarker of coronary disease.

Endothelial dysfunction and oxidative stress contribute to the atherosclerotic process that includes stiffening of large peripheral arteries. In contrast, our laboratory previously reported a paradoxical increase in cerebrovascular compliance in LDLr−/−:hApoB+/+ atherosclerotic (ATX) mice ( 7 ). We hypothesized that prevention of cerebral artery endothelial dysfunction with a chronic dietary antioxidant intake would normalize the changes in cerebral artery wall structure and biomechanics and prevent the decline in basal cerebral blood flow associated with atherosclerosis. Three-month-old ATX mice were treated, or not, for 3 mo with the polyphenol (+)-catechin (CAT; 30 mg·kg−1·day−1) and compared with wild-type controls. In isolated, pressurized cerebral arteries from ATX mice, CAT prevented endothelial dysfunction (deterioration of endothelium-dependent, flow-mediated dilations; P < 0.05), the inward hypertrophic structural remodeling (increase in the wall-to-lumen ratio; P < 0.05), and the rise in cerebrovascular compliance (rightward shift of the stress-strain curve measured in passive conditions, reflecting mechanical properties of the arterial wall; P < 0.05). Doppler optical coherence tomography imaging in vivo confirmed these findings, showing that cerebral compliance was higher in ATX mice and normalized by CAT ( P < 0.05). CAT also prevented basal cerebral hypoperfusion in ATX mice ( P < 0.05). Active remodeling of the cerebrovascular wall in ATX mice was further suggested by the increase ( P < 0.05) in pro-metalloproteinase-9 activity, which was normalized by CAT. We conclude that, by preserving the endothelial function, a chronic treatment with CAT prevents the deleterious effect of severe dyslipidemia on cerebral artery wall structure and biomechanical properties, contributing to preserving resting cerebral blood flow.

Background: Angiopoietin-like 2 (angptl2) is a circulating protein promoting vascular inflammation and endothelial dysfunction in mice, but little is known on its impact on cardiac function. Our previous results suggest that knocking down angptl2 in mice (KD) worsens pressure overload-induced cardiac dysfunction while preserving cerebral artery structure and endothelial function. As NADPH oxidase NOX4 is known to produce H2O2, a deleterious hypertrophic stimulus in cardiomyocytes but also a vasodilatory factor, we hypothesized that increased expression of NOX4 contributes to the aggravated cardiac dysfunction observed in KD mice. Methods/Results: Cardiac function was measured in vivo by Millar catheter in KD mice versus their wild-type (WT) littermates in response to a 6-week pressure overload induced by transverse aortic constriction (TAC). Concomitantly to a worsened cardiac remodeling and an aggravated cardiac dysfunction compared to WT-TAC mice, only KD-TAC mice displayed an increase in cardiac mRNA and protein expression of NOX4 (p Conclusion: Angptl2 knockdown worsens cardiac hypertrophy and contractile dysfunction induced by pressure overload: cardiac up-regulation of NOX4 could contribute to these deleterious effects in angptl2 KD mice.

The cardiac cycle imposes a mechanical stress that dilates elastic carotid arteries, while shear stress largely contributes to the endothelium-dependent dilation of downstream cerebral arteries. In the presence of dyslipidemia, carotid arteries stiffen while the endothelial function declines. We reasoned that stiffening of carotid arteries would be prevented by reducing resting heart rate (HR), while improving the endothelial function would regulate cerebral artery compliance and function. Thus we treated or not 3-mo-old male atherosclerotic mice (ATX; LDLr-/−:hApoB+/+) for 3 mo with the sinoatrial pacemaker current inhibitor ivabradine (IVA), the β-blocker metoprolol (METO), or subjected mice to voluntary physical training (PT). Arterial (carotid and cerebral artery) compliance and endothelium-dependent flow-mediated cerebral dilation were measured in isolated pressurized arteries. IVA and METO similarly reduced ( P < 0.05) 24-h HR by ≈15%, while PT had no impact. As expected, carotid artery stiffness increased ( P < 0.05) in ATX mice compared with wild-type mice, while cerebral artery stiffness decreased ( P < 0.05); this paradoxical increase in cerebrovascular compliance was associated with endothelial dysfunction and an augmented metalloproteinase-9 (MMP-9) activity ( P < 0.05), without changing the lipid composition of the wall. Reducing HR (IVA and METO) limited carotid artery stiffening, but plaque progression was prevented by IVA only. In contrast, IVA maintained and PT improved cerebral endothelial nitric oxide synthase-dependent flow-mediated dilation and wall compliance, and both interventions reduced MMP-9 activity ( P < 0.05); METO worsened endothelial dysfunction and compliance and did not reduce MMP-9 activity. In conclusion, HR-dependent mechanical stress contributes to carotid artery wall stiffening in severely dyslipidemic mice while cerebrovascular compliance is mostly regulated by the endothelium.

We previously reported that in healthy mouse cerebral arteries, endothelial nitric oxide synthase (eNOS) produces H2O2, leading to endothelium-dependent dilation. In contrast, thromboxane A2 (TXA2), a potent pro-oxidant and pro-inflammatory endogenous vasoconstrictor, is associated with eNOS dysfunction. Our objectives were to elucidate whether (1) the cerebrovascular eNOS–H2O2 pathway was sensitive to oxidative stress associated with aging and dyslipidemia and (2) TXA2 contributed to cerebral eNOS dysfunction. Atherosclerotic (ATX = LDLR−/−; hApoB+/+) and wild-type (WT) control mice were used at 3 and 12 months old (m/o). Three-m/o ATX mice were treated with the cardio-protective polyphenol catechin for 9 months. Dilations to ACh and the simultaneous eNOS-derived H2O2 production were recorded in isolated pressurized cerebral arteries. The age-associated decrease in cerebral eNOS–H2O2 pathway observed in WT was premature in ATX mice, decreasing at 3 m/o and abolished at 12 m/o. Thromboxane synthase inhibition by furegrelate increased dilations at 12 months in WT and at 3 and 12 months in ATX mice, suggesting an anti-dilatory role of TXA2 with age hastened by dyslipidemia. In addition, the non-selective NADP(H) oxidase inhibitor apocynin improved the eNOS–H2O2 pathway only in 12-m/o ATX mice. Catechin normalized the function of this pathway, which became sensitive to L-NNA and insensitive to furegrelate or apocynin; catechin also prevented the rise in TXA2 synthase expression. In conclusion, the age-dependent cerebral endothelial dysfunction is precocious in dyslipidemia and involves TXA2 production that limits eNOS activity. Preventive catechin treatment reduced the impact of endogenous TXA2 on the control of cerebral tone and maintained eNOS function.

Differents mecanismes cellulaires de reparation, de defense et de maintien de l’homeostasie sont continuellement actives au cours de la vie. Ils permettent d’etablir un equilibre temporaire face aux agressions successives endogenes et exogenes. Le principe d’hormesis, selon lequel l’exposition a un faible stress induit une meilleure resistance a un stress ulterieur, permet d’amplifier ces mecanismes d’adaptation cellulaire. Le vieillissement, la senescence et finalement la mort cellulaire, resultent de l’epuisement des ressources qui maintiennent l’equilibre et reparent les dommages moleculaires. L’endothelium vasculaire est dynamique et tres sensible au stress oxydant. Avec l’âge, le changement graduel de l’environnement redox vers un etat pro-oxydant contribue a une redistribution progressive des facteurs endotheliaux menant a la dysfonction endotheliale. Nous suggerons qu’une exposition moderee au stress oxydant durant la phase de maturation de l’endothelium determine la longevite vasculaire, selon le principe benefique d’hormesis.

Endogenous endothelin-1-dependent (ET-1) tone in coronary arteries depends on the balance between ETAand ETBreceptor-mediated effects and on parameters such as receptor distribution and endothelial integrity. Numerous studies highlight the striking functional interactions that exist between nitric oxide (NO) and ET-1 in the regulation of vascular tone. Many of the cardiovascular complications associated with cardiovascular risk factors and aging are initially attributable, at least in part, to endothelial dysfunction characterized by a dysregulation between NO and ET-1. The contribution of the imbalance between smooth muscle ETA/Band endothelial ETBreceptors to this process is poorly understood. An increased contribution of ET-1 that is associated with a proportional decrease in that of NO accompanies the development of coronary endothelial dysfunction, coronary vasospasm, and atherosclerosis. These data form the basis for the rationale of testing therapeutic approaches counteracting ET-1-induced cardiovascular dysfunction. It remains to be determined whether the beneficial role of endothelial ETBreceptors declines with age and risk factors for cardiovascular diseases, revealing smooth muscle ETBreceptors with proconstricting and proinflammatory activities.

The vascular endothelium starts to age at the first heartbeat. There is no longer a need to demonstrate that an increased resting heart rate--above 70 b.p.m.--is associated with the onset of cardiovascular events and reduces lifespan in humans. Each cardiac cycle imposes a mechanical constraint on the arteries, and we would like to propose that this mechanical stress damages the vascular endothelium, its dysfunction being the prerequisite for atherogenesis. Consequently, reducing heart rate could protect the endothelium and slow the onset of atherosclerosis. The potential mechanisms by which reducing heart rate could be beneficial to the endothelium are likely a combination of a reduction in mechanical stress and tissue fatigue and a prolongation of the period of steady laminar flow, and thus sustained shear stress, between each systole. With age, irreparable damage accumulates in endothelial cells and leads to senescence, which is characterized by a pro-atherogenic phenotype. In the body, the highest mechanical stress occurs in the coronary vessels, where blood only flows during diastole and even reverses during systole; thus, coronary arteries are the prime site of atherosclerosis. All classical risk factors for cardiovascular diseases add up, to accelerate atherogenesis, but hypertension, which further raises mechanical stress, is likely the most damaging. By inducing flow through the arteries, the heart rate determines shear stress and its stability: mechanical stress and the associated damage induced by each systole are efficiently counteracted by the repair capacities of a healthy endothelium. The maintenance of a physiological, low heart rate may be key to prolonging the endothelial healthy lifespan and thus, vascular health.

Endothelial senescence may contribute to the pathogenesis of age-related vascular disorders. Furthermore, chronic exposure to risk factors for cardiovascular disease (CVD) accelerates the effects of chronological aging by generating stress-dependent damages, including oxidative stress, therefore promoting stress-induced premature senescence. Our objective was to determine whether a chronic treatment with an antioxidant (N-acetyl-cystein, NAC) could delay senescence of endothelial cells (EC) isolated and cultured from arterial segments of patients with severe coronary artery disease. If EC were considered as one population (n = 26), chronic NAC treatment slightly shortened telomere attrition rate associated with senescence but did not significantly delay the onset of endothelial senescence. However, in a subgroup of NAC-treated EC (n = 15) cellular senescence was significantly delayed, NAC decreased lipid peroxidation (HNE), activated the catalytic subunit of telomerase (hTERT) and inhibited telomere attrition. In contrast, in another subgroup of EC (n = 11) characterized by initial short telomeres, no effect of NAC on HNE and high levels of DNA damages, the antioxidant was not beneficial on senescence, suggesting an irreversible stress-dependent damage. In conclusion, chronic exposure to NAC can delay senescence of diseased EC via hTERT activation and transient telomere stabilization, unless oxidative stress-associated cell damage has become irreversible.

Risk factors for cardiovascular diseases (CVD) increase oxidative stress, and they are proposed to hasten endothelial cell (EC) damage and dysfunction. Our objective was to elucidate the impact of chronic exposure to risk factors for CVD on senescence of EC isolated and cultured from internal mammary arterial segments of patients with severe coronary artery disease. Senescence induced by serial passages resulted in progressive telomere shortening, and short initial telomeres predicted early appearance of senescence in culture. Neither time course of senescence nor telomere length was age-dependent, suggesting that biological age, rather than chronological age, determined the dynamics. Senescence appeared earlier in patients with longer history of risk factor for CVD, and multivariate analysis suggested that hypertension hastened the onset of senescence. Risk factors for CVD override the effects of chronological aging likely by generating stress-dependent damage: senescent EC exhibited oxidative stress (increase in lipid peroxydation and caveolin-1 gene expression) and cell damage markers (loss of eNOS expression and increase in Cox2 mRNA, lower TRF1 protein level). Thus, cell senescence was triggered both by telomere-dependent and -independent pathways. In conclusion, chronic exposure to risk factors for CVD accelerated the development of endothelial senescence that could contribute to the pathogenesis of CVD.

Objective: Hydrogenperoxide(H2O2)producedbythevascularendotheliumisasignalingmoleculeregulatingvasculartone.Wehypothesized that H2O2 derived from eNOS activity could play a physiological role in endothelium-dependent dilation of mouse cerebral arteries. Methods: Simultaneous endothelium-dependent dilation and fluorescence-associated free radical (DCF-DA) or NO (DAF-2) production were recorded in isolated and pressurized (60 mm Hg) cerebral artery of C57Bl/6 male mice. Results: Without synergism, N-nitro-L-arginine (L-NNA) or the H2O2 scavengers catalase, PEG-catalase and pyruvate reduced (Pb0.05) by 50% the endothelium-dependent dilation induced by acetylcholine (ACh). Simultaneously with the dilation, H2O2 – but not NO – production, sensitive to either L-NNA or catalase, was detected. In cerebral arteries from C57Bl/6·eNOS �/� mice, catalase had no effect on ACh-induced dilation and no H2O2-associated fluorescence was observed. In C57Bl/6 mice, silver diethyldithiocarbamate (DETC), a superoxide dismutase (SOD) inhibitor, but not the specific NO scavenger 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl3-oxide (PTIO), prevented ACh-induced dilation and H2O2 production suggesting that eNOS-derived superoxide is an intermediate in the production of H2O2. The catalase-sensitive ACh-induced dilation was restored by the eNOS cofactor tetrahydrobiopterin (BH4). This reversal was associated with a NO-associated fluorescence sensitive to PTIO but not to catalase. Soluble guanylate cyclase inhibition with 1H-[1,2,4]oxadiazole-4,3-aquinoxalin-1-one (ODQ) prevented the dilation induced by ACh and by exogenous H2O2. Lastly, L-NNA, PTIO and ODQ – but not DETC, catalase or pyruvate – increased the pressure-dependent myogenic tone, suggesting that eNOS produces NO at rest, but leads to H2O2 during muscarinic stimulation. Conclusion: H2O2-dependent dilation in mouse cerebral arteries appears to be a physiological eNOS-derived mechanism.

Angiopoietin like-2 (angptl2) is a circulating pro-inflammatory and pro-oxidative protein, but its role in regulating cerebral endothelial function remains unknown. We hypothesized that in mice knockdown (KD) of angptl2, cerebral endothelial function would be protected against ANG II-induced damage. Subcutaneous infusion of ANG II (200 ng·kg−1·min−1, n = 15) or saline ( n = 15) was performed in 20-wk-old angptl2 KD mice and wild-type (WT) littermates for 14 days. In saline-treated KD and WT mice, the amplitude and the sensitivity of ACh-induced dilations of isolated cerebral arteries were similar. However, while endothelial nitric oxide (NO) synthase (eNOS)-derived O2−/H2O2 contributed to dilation in WT mice, eNOS-derived NO ( P < 0.05) was involved in KD mice. ANG II induced cerebral endothelial dysfunction only in WT mice ( P < 0.05), which was reversed ( P < 0.05) by either N-acetyl-l-cysteine, apocynin, gp91ds-tat, or indomethacin, suggesting the contribution of reactive oxygen species from Nox2 and Cox-derived contractile factors. In KD mice treated with ANG II, endothelial function was preserved, likely via Nox-derived H2O2, sensitive to apocynin and PEG-catalase ( P < 0.05), but not to gp91ds-tat. In the aorta, relaxation similarly and essentially depended on NO; endothelial function was maintained after ANG II infusion in all groups, but apocynin significantly reduced aortic relaxation in KD mice ( P < 0.05). Protein expression levels of Nox1/2 in cerebral arteries were similar among all groups, but that of Nox4 was greater ( P < 0.05) in saline-treated KD mice. In conclusion, knockdown of angptl2 may be protective against ANG II-induced cerebral endothelial dysfunction; it favors the production of NO, likely increasing endothelial cell resistance to stress, and permits the expression of an alternative vasodilatory Nox pathway.

Recent studies have demonstrated the tissue-specific effect of Na+/K+ pump inhibition by ouabain and other cardiac glycosides on cell viability. The vascular endothelium is an initial target of cardiac glycosides employed for the management of congestive heart failure as well as circulating endogenous ouabain-like substances (EOLS), the production of which is augmented in volume-expanded hypertension. This study examined the role of the Na+/K+ pump in the survival of cultured porcine aortic endothelial cells (PAEC). Complete Na+/K+ pump inhibition with ouabain led to PAEC death, indicated by cell detachment and decreased staining with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Based on cell swelling and resistance to benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD.fmk) a pan-caspase inhibitor, this type of cell death was classified as necrosis. In contrast to ouabain, Na+/K+ pump inhibition in K+-free medium did not affect PAEC viability and sharply attenuated apoptosis triggered by 3H decay-induced DNA damage. Necrosis evoked by ouabain was preserved after dissipation of the transmembrane gradient of K+ and Na+, whereas dissipation of the Na+ gradient abolished the antiapoptotic action of K+-free medium. Comparative analysis of these results and modulation of intracellular Na+ and K+ content by the above-listed stimuli showed that interaction of ouabain with Na+/K+-ATPase triggered necrosis independently of inhibition of Na+/K+ pump-mediated ion fluxes and inversion of the [Na+]i/[K+]i ratio, whereas protection against apoptosis under Na+/K+ pump inhibition in K+-depleted medium was mediated by [Na+]i elevation. The role of Na+/K+ pump-mediated regulation of endothelial cell survival and vascular remodelling seen in hypertension should be investigated further in context of EOLS and chronic treatment with digitalis.

Shrinkage is the earliest hallmark of cells undergoing apoptosis. This study examines the role of this phenomenon in the onset of vascular smooth muscle cell (VSMC) apoptosis triggered by growth factor withdrawal. In hyperosmotic media, VSMC showed the same amplitude of shrinkage but were more resistant to apoptosis than endothelial, epithelial and immune system cells. As with growth factor withdrawal, apoptosis in hyperosmotically-shrunken VSMC was sharply potentiated by transfection with E1A-adenoviral protein and was suppressed by activation of cAMP signaling as well as by the pan-caspase inhibitor z-VAD.fmk. Both cell shrinkage and apoptosis in VSMC-E1A treated with hyperosmotic medium were potentiated under sustained Na+, K+ pump inhibition with ouabain that was in contrast to inhibition of apoptosis documented in ouabain-treated, serum-deprived cells. After 1-hr incubation in serum-deprived medium, VSMC-E1A volume declined by approximately 15%. Transfer from hypotonic to control medium decreased VSMC-E1A volume by approximately 25% without any induction of apoptosis. Neither swelling in hyposmotic medium nor dissipation of the transmembrane gradient of K+ and major organic osmolytes protected serum-deprived VSMC-E1A from apoptosis. Thus, our results show that similarly to immune system, endothelial and epithelial cells, extensive VSMC shrinkage in hyperosmotic medium leads to the development of apoptosis. In contrast to hyperosmotic medium, the modest cell volume decrease occurring in serum-deprived VSMC does not contribute to triggering of the apoptotic machinery.

Background Angiopoietin‐like‐2 (angptl2) is produced by several cell types including endothelial cells, adipocytes and macrophages, and contributes to the inflammatory process in cardiovascular diseases. We hypothesized that angptl2 impairs endothelial function, and that lowering angptl2 levels protects the endothelium against high‐fat diet ( HFD )‐induced fat accumulation and hypercholesterolemia. Methods and Results Acute recombinant angptl2 reduced ( P WT ) mouse femoral artery, an effect reversed ( P N ‐acetylcysteine. Accordingly, in angptl2 knockdown ( KD ) mice, AC h‐mediated endothelium‐dependent vasodilation was greater ( P WT mice. In arteries from KD mice, prostacyclin contributed to the overall dilation unlike in WT mice. After a 3‐month HFD , overall vasodilation was not altered, but dissecting out the endothelial intrinsic pathways revealed that NO production was reduced in arteries isolated from HFD ‐fed WT mice ( P NO release was maintained in KD mice. Similarly, endothelium‐derived hyperpolarizing factor ( EDHF ) was preserved in mesenteric arteries from HFD ‐fed KD mice but not in those from WT mice. Finally, the HFD increased ( P WT mice only, while glycemia remained similar in the 2 strains. KD mice displayed less triglyceride accumulation in the liver ( P WT ), and adipocyte diameters in mesenteric and epididymal white adipose tissues were smaller ( P KD than in WT fed an HFD , while inflammatory gene expression increased ( P WT mice only. Conclusions Lack of angptl2 expression limits the metabolic stress induced by an HFD and maintains endothelial function in mice.