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Females outperform males in a mouse model of exertional heat stroke (EHS). Here, we show for the first time the impact of ovariectomy (OVX) on EHS pathophysiology. OVX resulted in a shorter exercise capacity in the heat, greater intestinal damage, and lower heat shock response following EHS.

One of the most important lifestyle factors that contributes to cardiovascular disease risk is excess dietary salt intake. In the US, ~90% of adults consume too much salt, and the average salt intake is ~2.3x higher than recommended by the American Heart Association. Excess salt consumption contributes to cardiovascular disease risk by elevating systolic blood pressure (BP) and inducing arterial dysfunction in humans. However, this arterial phenotype is not typically observed in inbred, genetically identical mouse strains that consume a high-salt (HS) diet, which may be due to strain-specific resistance to HS diet. Thus, we sought to determine the effects of HS diet consumption on systolic BP and arterial function in UM-HET3 mice, an outbred, genetically diverse strain of mice. Male and female UM-HET3 mice underwent a low-salt (1% NaCl [LS]) or HS (4% NaCl) diet for 12 weeks. Systolic BP was increased after 2 weeks and aortic stiffness, determined by pulse wave velocity (PWV), was increased after 4 weeks in HS mice compared to baseline (P0.05). Histological analysis revealed that aortic collagen content was ~81% higher in HS compared to LS mice (P0.05). Endothelium‑dependent dilation (EDD), determine by carotid artery vasodilation to acetylcholine (ACh), was ~10% lower in HS compared to LS mice (P0.05). There was a tendency for NO-mediated vasodilation, determined by subtracting ACh+L-NAME max vasodilation from ACh max vasodilation, to be higher in LS compared to HS mice (P=0.057). Endothelium-independent dilation (EID), determined by carotid artery vasodilation to sodium nitroprusside, was similar between groups (P>0.05). Lastly, there was a strong relationship between systolic BP and PWV (r2=0.40, P0.05). Lastly, we observed no sex-related difference in any measurement of arterial function (P>0.05 for all). Taken together, these findings provide evidence that a HS diet in UM-HET3 mice induces progressive elevations in systolic BP and aortic stiffness, which are accompanied by impaired EDD. These data suggest that outbred, genetically diverse mice may provide unique translational insight into HS diet-induced elevations in systolic BP and arterial dysfunction in humans living in industrialized societies. This study was funded in part by a grant from the National Institutes of Health (R00 AT010017). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Many individuals in industrialized societies consume a high-salt, Western diet(WD); however, the effects of this diet on microcirculatory properties and glycocalyx barrier function are unknown. Young genetically heterogeneous male and female mice underwent 12 wk of normal chow (NC) diet, NC diet with 4% salt (NC4%), Western diet (WD), or WD with 4% salt (WD4%). Microcirculatory properties and glycocalyx barrier function were evaluated in the mesenteric microcirculation, using an intravital microscope equipped with an automated capture and analysis system. Total microvascular density summed across 4- to 25-μm microvessel segment diameters was lower in NC4% than in NC and WD (P < 0.05). Perfused boundary region (PBR), a marker of glycocalyx barrier function, averaged across 4- to 25-μm microvessel segment diameters was similar between NC and NC4%, as well as between WD and WD4% (P > 0.05). PBR was lower in WD and WD4% than in NC and NC4% (P < 0.05), indicating augmented glycocalyx barrier function in WD and WD4%. There were strong, inverse relationships between PBR and adiposity and blood glucose (r = −0.44 to −0.61, P < 0.05). In summary, NC4% induces deleterious effects on microvascular density, whereas WD augments glycocalyx barrier function. Interestingly, the combination of high-salt, Western diet in WD4% resulted in lower total microvascular density like NC4% and augmented glycocalyx barrier function like WD. These data suggest distinct microcirculatory adaptations to high-salt and Western diets that coincide when these diets are combined in young genetically heterogeneous male and female mice. NEW & NOTEWORTHY Many individuals in industrialized societies consume a combination of high-salt and Western diet; however, the effects of this diet on microcirculatory and glycocalyx properties are unknown. This study reveals that a high-salt diet lowers microcirculatory and glycocalyx properties, whereas a Western diet augments glycocalyx barrier function and thickness. Taken together, these data indicate that there are distinct microcirculatory adaptations to high-salt and Western diets that coincide when high-salt and Western diets are combined.

Advanced age is accompanied by arterial dysfunction, as well as a diminished glycocalyx, which may be linked to reduced high molecular weight-hyaluronan (HMW-HA) synthesis. However, the impact of glycocalyx deterioration in age-related arterial dysfunction is unknown. We sought to determine if manipulations in glycocalyx properties would alter arterial function. Tamoxifen-induced hyaluronan synthase 2 (Has2) reduction was used to decrease glycocalyx properties. Three weeks post-tamoxifen treatment, glycocalyx thickness was lower in Has2 knockout compared to wild-type mice (P0.05). Has2 reduction phenocopies age-related arterial dysfunction, while 10 weeks of glycocalyx-targeted therapy that restores the glycocalyx also ameliorates age-related arterial dysfunction. These findings suggest that the glycocalyx may be a viable therapeutic target to ameliorate age-related arterial dysfunction.

Age-related increases in large artery stiffness are associated with cerebrovascular dysfunction and cognitive impairment. Pyridoxamine treatment prevents large artery stiffening with advancing age, but the effects of pyridoxamine treatment on the cerebral vasculature or cognition is unknown. The purpose of this study was to investigate the effects of pyridoxamine on blood pressure, large artery stiffness, cerebral artery function, and cognitive function in old mice. Old male C57BL/6 mice consumed either pyridoxamine (2 g/L) or vehicle control in drinking water for ∼7.5 months and were compared with young male C57BL/6 mice. From pre- to post-treatment, systolic blood pressure increased in old control mice, but was maintained in pyridoxamine treated mice. Large artery stiffness decreased in pyridoxamine-treated mice but was unaffected in control mice. Pyridoxamine-treated mice had greater cerebral artery endothelium-dependent dilation compared with old control mice, and not different from young mice. Old control mice had impaired cognitive function; however, pyridoxamine only partially preserved cognitive function in old mice. In summary, pyridoxamine treatment in old mice prevented age-related increases in blood pressure, reduced large artery stiffness, preserved cerebral artery endothelial function, and partially preserved cognitive function. Taken together, these results suggest that pyridoxamine treatment may limit vascular aging.

Background: Systemic inhibition of mammalian target of rapamycin (mTOR) improves age-related arterial and metabolic dysfunction. Although the mechanisms and tissues involved in this amelioration remain unknown, endothelial cells (ECs), key regulators of arterial and metabolic function, may be responsible for these effects. Hypothesis: The beneficial effects of systemic mTOR inhibition will be recapitulated after EC specific mTOR deletion in old mice. Methods: We studied 22-24 mo old wildtype (WT) and EC specific tamoxifen-inducible mTOR knockout (KO) mice. The arterial function was determined by assessing aortic stiffness by measuring pulse wave velocity (PWV) using Doppler ultrasound as well as endothelium-dependent dilation (EDD) and nitric oxide (NO) bioavailability using pressure myography. Carotid artery superoxide production was measured using electric paramagnetic resonance. Glucose (2g/kg, ip) and lipid (3mL/kg, oral) tolerance tests were performed to examine metabolic function. Results: Two weeks after tamoxifen administration (4mg/day, 4 days, oral), we found a ~ 60% reduction in EC mTOR protein (p=0.04). Aortic PWV was lower in KO compared to WT mice (Fig A), indicating lower aortic stiffness. EDD to acetylcholine (ACh) was higher in mesenteric arteries from KO compared to WT mice (Fig B) due to an increase in NO bioavailability (31.6 ± 8.6 vs 8.4 ± 2.3; p=0.01). Superoxide scavenger, TEMPOL, increased EDD in both WT and KO mice (Fig C), eliminating differences between groups. Superoxide was lower in carotid arteries of KO compared to WT (Fig D), suggesting that oxidative stress impairs EDD in WT mice and ablation of EC selective mTOR ameliorates this effect. Aged KO mice demonstrated greater glucose and lipid tolerance compared to WT (Fig E, F). Conclusions: Our findings demonstrate that EC specific deletion of mTOR provides beneficial effects on arterial function via reductions in oxidative stress and prevents metabolic dysfunction in old mice.

Age-related vascular dysfunction in large elastic and resistance arteries is associated with reductions in microvascular perfusion and elevations in blood pressure. Recent evidence indicates that telomere uncapping-induced senescence in vascular cells may be an important source of oxidative stress and vascular dysfunction in aging, but the causal relationship between these processes has yet to be elucidated. To test this important unexplored hypothesis, we measured arterial senescence signaling and oxidative stress, carotid and mesenteric artery endothelium-dependent vasodilatory capacity, markers of mesenteric microvascular perfusion and endothelial glycocalyx deterioration, and blood pressure in a novel mouse model of Cre-inducible whole body Trf2 deletion and telomere uncapping. Trf2 deletion led to a 320% increase in arterial senescence signaling (P < 0.05). There was a concurrent 29% and 22% reduction in peak endothelium-dependent vasodilation in carotid and mesenteric arteries, respectively, as well as a 63% reduction in mesenteric microvascular endothelial glycocalyx thickness (all P ≤ 0.01). Mesenteric microvascular perfusion was reduced by 8% and systolic blood pressure was increased by 9% following Trf2 deletion (both P < 0.05). Trf2 deletion also led to a pro-oxidative arterial phenotype characterized by increased in NADPH oxidase gene expression; a 210% increase in superoxide levels that was partly dependent on NADPH oxidase activity; and an oxidative stress-mediated reduction in carotid artery vasodilation (all P ≤ 0.05). Collectively, our findings demonstrate that induced Trf2 deletion leads to telomere uncapping, increased senescence signaling, and oxidative-stress mediated functional impairments in the vasculature similar to those seen in human aging.

Increased arterial stiffness is a cardiovascular disease risk factor in the setting of advancing age and high-fat (HF) diet induced obesity. Increases in large artery stiffness, as measured by pulse wave velocity (PWV), occur within 8 weeks of HF feeding in mice. Sirtuin-1 (Sirt1), a NAD-dependent deacetylase, regulates cellular metabolic activity and activation of this protein has been associated with vasoprotection in aged mice. The aim of the present study was to elucidate the effect of global Sirt1 overexpression (Sirttg) on HF diet-induced arterial stiffening. Sirt1 overexpression did not influence PWV in normal chow (NC) fed mice (Sirttg: 263 ± 6 vs WT: 274 ± 7, p=0.28). However, PWV was higher in wild-type (WT) mice (376 ± 22, ptg(304 ± 2 cm/s, p=0.07), after 12 weeks of HF diet. Despite no effect of Sirt1 overexpression on aortic collagen content in NC (p=0.71), aortic elastin content was higher in Sirttgmice compared with WT mice fed NC diet (Ptgmice. Likewise, there was no difference in wall thickness in NC (Sirttg: 40.7 ± 2 vs WT: 41.6 ± 2, p= 0.78). However, wall thickness was higher in mice WT mice fed a HF diet (51.7 ± 2, ptgmice after HF diet (p=0.66). Similarly, there was no difference in wall-to-lumen ratio in mice fed NC diet (Sirttg: 0.08 vs WT: 0.08, p=0.48) was higher in HF diet fed WT mice (ptgmice fed HF diet (0.08, p=0.59). These findings demonstrate a vasoprotective effect of Sirt1 overexpression that limits increases in arterial stiffness and protects against alterations in vessel morphology in response to HF feeding. As such, activation of Sirt1 may be a novel therapeutic target to prevent elevated CVD risk associated with HF-induced aortic stiffening.

Aging adipose tissues (ATs) manifest reduced vascularity and increased hypoxia and inflammation that contribute to local and systemic metabolic dysfunction. However, the mechanisms that underlie these age-related changes are incompletely understood. In this study, we sought to examine insulin-stimulated vasodilation and angiogenesis in the arterial vasculature from three major AT depots, perigonadal white (pgWAT), subcutaneous white (scWAT) and brown (BAT) from young and old mice. Here, we demonstrate that in young mice, insulin-stimulated vasodilation is lower in feed arteries from pgWAT compared to scWAT (p 0.05), but no differences were found between feed arteries in other AT depots (p 0.05). Insulin-stimulated vasodilation was lower in old compared to young feed arteries from all three AT depots (p 0.05 for all). In the presence of endothelial nitric oxide synthase inhibitor, L-NAME, insulin-stimulated vasodilation was decreased in young (p 0.05), but was unaffected in old (p 0.05) from all AT depots. We also observed no age-related differences in endothelium-independent dilation, as assessed by sodium nitroprusside (p 0.05). We next investigated angiogenic capacity of the vasculature in these AT depots. In young mice, BAT vasculature demonstrated the highest angiogenic potential, followed by pgWAT and scWAT. We found that aging decreased angiogenic sprout formation in pgWAT and BAT (both p 0.05), but increased angiogenic potential in scWAT (p 0.05), indicating dissimilar impact of aging on angiogenesis in different AT depots. Collectively, these data suggest that aging leads to a consistent impairment in insulin-stimulated vasodilation and reduction in NO bioavailability in all three AT, although aging differentially impacts angiogenic capacity across different AT depots.

BACKGROUND Elevated android body fat increases the risk of developing cardiometabolic diseases. Postprandial hyperglycemia contributes to the proatherogenic metabolic state evident in android adiposity. Due to the insulinotropic effect of milk‐derived proteins, postprandial hyperglycemia has been shown to be reduced with the addition of dairy products. The purpose of this study was to determine whether one serving of nonfat milk added to an oral glucose tolerance test (OGTT ) could attenuate postprandial hyperglycemia in individuals with elevated android adiposity and whether these improvements would be associated with metabolic and/or peripheral hemodynamic effects. METHODS In this placebo‐controlled, randomized, crossover experimental study, 29 overweight/obese adults (26 ± 1 year) consumed an OGTT beverage (75 g glucose) combined with either nonfat milk (227 g) or a placebo control (12 g lactose + 8 g protein + 207 g water) that was matched for both carbohydrate and protein quantities. RESULTS In the whole sample, blood glucose and insulin concentrations increased over time in both trials with no significant differences between trials. Relative increases in peak blood glucose response were significantly related to android body fat (p < 0.05). The subjects in the highest tertiles of android body fat displayed attenuated hyperglycemic responses as well as improvements in flow‐mediated dilation (FMD) after milk intake. CONCLUSIONS A single serving of nonfat milk may attenuate acute hyperglycemia in individuals with elevated android body fat offering a simple and convenient option for managing elevations in blood glucose.

NEW FINDINGS What is the central question of this study? Do systemic sclerosis patients exhibit impaired nitric oxide-mediated vascular function of the lower limb and are these decrements correlated with plasma biomarkers for inflammation and oxidative stress? What is the main finding and its importance? Findings indicate impaired nitric oxide-mediated vascular function, linked to the incidence of digital ulcers and a milieu of inflammation and oxidative stress. However, the absence of significant correlations between individual biomarkers and blood flow responses suggests that the vasculopathy observed in systemic sclerosis may not be solely the result of derangements in the redox balance or inflammatory signalling. ABSTRACT Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, which may be the consequence of inflammation and oxidative stress that ultimately leads to a reduced nitric oxide (NO) bioavailability. Passive leg movement (PLM) is a novel methodology for assessing lower limb vascular function that is predominantly NO dependent. We combined this vascular assessment with a comprehensive panel of plasma biomarkers to assess the axis of inflammation, oxidative stress and NO in SSc patients (n = 12; 62 ± 11 years of age) compared with healthy control subjects (n = 17; 60 ± 16 years of age). The PLM-induced changes in leg blood flow (LBF; 191 ± 104 versus 327 ± 217 ml min-1 ) and LBF area under the curve (39 ± 104 versus 125 ± 131 ml) were reduced in SSc compared with control subjects. Stratification of patients according to history of digital ulcer (DU) formation revealed a further reduction in LBF area under the curve in DU (-13 ± 83 ml) versus non-DU (91 ± 102 ml) patients. Biomarkers of inflammation (C-reactive protein) and oxidative stress (malondialdehyde and protein carbonyl) were all elevated in SSc (C-reactive protein, 3299 ± 2372 versus 984 ± 565 ng ml-1 ; malondialdehyde, 3.2 ± 1.1 versus 1.1 ± 0.7 μm; and protein carbonyl, 0.15 ± 0.05 versus 0.12 ± 0.03 nmol mg-1 ), and C-reactive protein was further elevated in patients with a history of DU (4551 ± 2752 versus 2047 ± 1019 ng ml-1 ) compared with non-DU, although these were not individually correlated with changes in LBF. These findings of impaired NO-mediated vascular function, linked to DU and a milieu of inflammation and oxidative stress, suggest that redox balance plays an important, but not necessarily deterministic, role in the vascular pathophysiology of SSc.

Background: Repeated exposure to elevated postprandial triglycerides, as seen with typical Western diets, contributes to atherosclerosis and vascular disease. We determined if a single serving of non-fat milk added to a high fat tolerance test could attenuate postprandial hypertriglyceridemia in individuals who consume a high fat diet. Methods: In this placebo-controlled, randomized, crossover experimental study, 30 overweight/obese adults consumed a high-fat tolerance test meal combined with either non-fat milk, carbohydrate control drink, or caloric control drink. Results: Plasma triglycerides increased over time with no significant differences between interventions. Peak plasma triglyceride levels during HFTT were significantly related to dietary fat intake (r = 0.30, p

Objective.The aim of our study was to determine whether an automated capture and analysis system could detect differences in structure and function of sublingual microvessels in patients with systemic sclerosis (SSc) compared to healthy controls.Methods.Intravital microscopy of the sublingual microcirculation was automatically captured and analyzed in 40 patients with SSc and 10 age-matched healthy controls.Results.Total and perfused microvascular density were lower in patients with SSc compared with controls (total microvascular density: 2471 ± 134 µm/mm2 vs 3067 ± 197 µm/mm2, p = 0.020; perfused microvascular density: 1708 ± 92 µm/mm2 vs 2192 ± 144 µm/mm2, p = 0.009). However, the relative percentage of perfused to total microvascular density was similar between SSc and controls (72 ± 2% vs 71 ± 2%, respectively, p = 0.429). Mean red blood cell (RBC) fraction, which indicates the longitudinal tube hematocrit of microvessel segments, was lower in patients with SSc compared with controls (69 ± 1% vs 77 ± 1%, respectively, p < 0.001). Perfused boundary region (PBR), a marker of endothelial glycocalyx barrier properties, was higher in patients with SSc compared with controls (2.1 ± 0.0 µm vs 1.9 ± 0.0 µm, respectively, p = 0.012), suggestive of a dysfunctional glycocalyx. There was an inverse association of PBR with perfused microvascular density (r = −0.40, p = 0.004) and RBC fraction (r = −0.80, p < 0.001).Conclusion.Our results indicate that automated capture and analysis of sublingual microvessel segments produces detailed, objective microvascular structural and functional data that have allowed us to distinguish patients with SSc from controls. These data suggest that microvascular structural and functional abnormalities present in patients with SSc could be at least partly due to a dysfunctional glycocalyx.

Large elastic artery stiffening and endothelial dysfunction, and associated reductions in nitric oxide (NO) bioavailability, are central features of vascular aging. We have recently demonstrated th...

Atherogenic remodeling often occurs at arterial locations with disturbed blood flow (i.e., low or oscillatory) and both aging and western diet (WD) increase the likelihood for pro-atherogenic remodeling. However, it is unknown if old age and/or a WD modify the pro-atherogenic response to disturbed blood flow. We induced disturbed blood flow by partial carotid ligation (PCL) of the left carotid artery in young and old, normal chow (NC) or WD fed male B6D2F1 mice. Three weeks post-PCL, ligated carotid arteries had greater intima media thickness, neointima formation, and macrophage content compared with un-ligated arteries. WD led to greater remodeling and macrophage content in the ligated artery compared with NC mice, but these outcomes were similar between young and old mice. In contrast, nitrotyrosine content, a marker of oxidative stress, did not differ between WD and NC fed mice, but was greater in old compared with young mice in both ligated and un-ligated carotid arteries. In primary vascular smooth muscle cells, aging reduced proliferation, whereas conditioned media from fatty acid treated endothelial cells increased proliferation. Taken together, these findings suggest that the remodeling and pro-inflammatory response to disturbed blood flow is increased by WD, but is not increased by aging.

Swimming exercise is an ideal and excellent form of exercise for patients with osteoarthritis (OA). However, there is no scientific evidence that regular swimming reduces vascular dysfunction and inflammation and elicits similar benefits compared with land-based exercises such as cycling in terms of reducing vascular dysfunction and inflammation in patients with OA. Forty-eight middle-aged and older patients with OA were randomly assigned to swimming or cycling training groups. Cycling training was included as a non-weight-bearing land-based comparison group. After 12 weeks of supervised exercise training, central arterial stiffness, as determined by carotid-femoral pulse wave velocity, and carotid artery stiffness, through simultaneous ultrasound and applanation tonometry, decreased significantly after both swimming and cycling training. Vascular endothelial function, as determined by brachial flow-mediated dilation, increased significantly after swimming but not after cycling training. Both swimming and cycling interventions reduced interleukin-6 levels, whereas no changes were observed in other inflammatory markers. In conclusion, these results indicate that regular swimming exercise can exert similar or even superior effects on vascular function and inflammatory markers compared with land-based cycling exercise in patients with OA who often has an increased risk of developing cardiovascular disease.

Although the associations between chronic levels of arterial stiffness and blood pressure (BP) have been fairly well studied, it is not clear whether and how much arterial stiffness is influenced by acute perturbations in BP. The primary aim of this study was to determine magnitudes of BP dependence of various measures of arterial stiffness during acute BP perturbation maneuvers. Fifty apparently healthy subjects, including 25 young (20–40 yr) and 25 older adults (60–80 yr), were studied. A variety of BP perturbations, including head-up tilt, head-down tilt, mental stress, isometric handgrip exercise, and cold pressor test, were used to encompass BP changes induced by physical, mental, and/or mechanical stimuli. When each index of arterial stiffness was plotted with mean BP, all arterial stiffness indices, including cardio-ankle vascular index or CAVI ( r = 0.50), carotid-femoral pulse wave velocity or cfPWV ( r = 0.51), brachial-ankle pulse wave velocity or baPWV ( r = 0.61), arterial compliance ( r = −0.42), elastic modulus ( r = 0.52), arterial distensibility ( r = −0.32), β-stiffness index ( r = 0.19), and Young's modulus ( r = 0.35) were related to mean BP (all P < 0.01). Changes in CAVI, cfPWV, baPWV, and elastic modulus were significantly associated with changes in mean BP in the pooled conditions, while changes in arterial compliance, arterial distensibility, β-stiffness index, and Young's modulus were not. In conclusion, this study demonstrated that BP changes in response to various forms of pressor stimuli were associated with the corresponding changes in arterial stiffness indices and that the strengths of associations with BP varied widely depending on what arterial stiffness indices were examined.

The endothelial glycocalyx is a gel-like structure that is bound to the luminal surface of the vascular endothelium. At the interface between flowing blood and endothelial cells, the glycocalyx has several functions that are critical for the maintenance of a healthy vasculature, particularly in regard to the vascular endothelium. Within the vasculature, the glycocalyx modulates vascular resistance to maintain blood flow homogeneity in the microcirculation, mechanotransduces fluid shear stress to the endothelium, and buffers endothelial cells from plasma oxidants, cytokines, and circulating immune cells. In advanced age and cardiovascular disease (CVD), the glycocalyx is deteriorated. Moreover, glycocalyx deterioration may precede traditional measurements of age-related vascular dysfunction, such as impaired endothelium-dependent dilation and large artery stiffness, suggesting that a deteriorated glycocalyx could initiate age-related CVD pathology.

OBJECTIVE: Accumulating evidence suggests the vascular endothelium plays a fundamental role in the pathophysiology of obesity by regulating the functional status of white adipose and systemic metabolism. Roundabout guidance 4 (Robo4) is expressed specifically in endothelial cells and increases vascular stability and inhibits angiogenesis. We sought to determine the role of Robo4 in modulating cardio-metabolic function in response to high fat feeding. METHODS: We examined exercise capacity, glucose tolerance, and white adipose tissue artery gene expression, endothelium-dependent dilation and angiogenesis in wild type and Robo4 knockout mice fed normal chow or a high fat diet (HFD). RESULTS: We found Robo4 deletion enhances exercise capacity in normal chow fed mice and HFD markedly increased the expression of Robo4 ligand Slit2 in white adipose tissue. Deletion of Robo4 increased angiogenesis in white adipose tissue and protected against HFD-induced impairments in white adipose artery vasodilation and glucose intolerance. CONCLUSIONS: We demonstrate a novel functional role for Robo4 in endothelial cell function and metabolic homeostasis in white adipose tissue, with Robo4 deletion protecting against endothelial and metabolic dysfunction associated with a HFD. Our findings suggest that Robo4-dependent signaling pathways may be a novel target in anti-obesity therapy.

Advancing age promotes cardiovascular disease (CVD), the leading cause of death in the United States and many developed nations. Two major age-related arterial phenotypes, large elastic artery stiffening and endothelial dysfunction, are independent predictors of future CVD diagnosis and likely are responsible for the development of CVD in older adults. Not limited to traditional CVD, these age-related changes in the vasculature also contribute to other age-related diseases that influence mammalian health span and potential life span. This review explores mechanisms that influence age-related large elastic artery stiffening and endothelial dysfunction at the tissue level via inflammation and oxidative stress and at the cellular level via Klotho and energy-sensing pathways (AMPK [AMP-activated protein kinase], SIRT [sirtuins], and mTOR [mammalian target of rapamycin]). We also discuss how long-term calorie restriction—a health span- and life span-extending intervention—can prevent many of these age-related vascular phenotypes through the prevention of deleterious alterations in these mechanisms. Lastly, we discuss emerging novel mechanisms of vascular aging, including senescence and genomic instability within cells of the vasculature. As the population of older adults steadily expands, elucidating the cellular and molecular mechanisms of vascular dysfunction with age is critical to better direct appropriate and measured strategies that use pharmacological and lifestyle interventions to reduce risk of CVD within this population.

Regular consumption of low- and nonfat dairy products reduces blood pressure (BP) in adults with elevated BP. Currently, it is unknown if conventional full-fat dairy products exert similar hypotensive effects. We hypothesized that adding full-fat dairy products to the normal routine diet would reduce seated office and ambulatory BP (primary outcome) in adults with elevated BP when compared with a no dairy control. Using a randomized controlled crossover design, 60 adults with elevated systolic BP (systolic/diastolic BP: 120-159/

Age-related microvascular dysfunction is well characterized in rodents and humans, but little is known about the properties of the microvascular endothelial glycocalyx in advanced age. We examined the glycocalyx in microvessels of young and old male C57BL6 mice (young: 6.1 ± 0.1 mo vs. old: 24.6 ± 0.2 mo) using intravital microscopy and transmission electron microscopy and in human participants (young: 29 ± 1 yr vs. old: 60 ± 2 yr) using intravital microscopy. Glycocalyx thickness in mesenteric and skeletal muscle microvessels was 51–54% lower in old compared with young mice. We also observed 33% lower glycocalyx thickness in the sublingual microcirculation of humans in advanced age. The perfused boundary region, a marker of glycocalyx barrier function, was also obtained using an automated capture and analysis system. In advanced age, we observed a 10–22% greater perfused boundary region in mice and humans, indicating a more penetrable glycocalyx. Finally, using this automated analysis system, we examined perfused microvascular density and red blood cell (RBC) fraction. Perfused microvascular density is a marker of microvascular function that reflects the length of perfused microvessel segments in a given area; RBC fraction represents the heterogeneity in RBC presence between microvessel segments. Compared with young, the perfused microvascular density was 16–21% lower and RBC fraction was 5–14% lower in older mice and in older humans. These data provide novel evidence that, across mammalian species, a diminished glycocalyx is present in advanced age and is accompanied by markers of impaired microvascular perfusion. Age-related glycocalyx deterioration may be an important contributor to microvascular dysfunction in older adults and subsequent pathophysiology. NEW & NOTEWORTHY Advanced age is characterized by microvascular dysfunction that contributes to age-related cardiovascular diseases, but little is known about endothelial glycocalyx properties in advanced age. This study reveals, for the first time, lower glycocalyx thickness and barrier function that is accompanied by impaired microvascular perfusion in both mice and humans in advanced age.

Hispanics are at increased risk of acquiring cardiovascular risk factors that contribute to cognitive dysfunction. To compare indices of vascular health to measures of cerebral gray matter integrity, 60 middle-aged Hispanic and non-Hispanic Caucasian participants were matched across age, gender, years of education, and mental status. Arterial stiffness was characterized via β-stiffness index and carotid-femoral pulse-wave velocity, and magnetic resonance imaging estimated cortical thickness in a priori regions of interest known to be susceptible to vascular risk factors. Measures of arterial stiffness were significantly higher in Hispanics than in non-Hispanic Caucasians. Hispanics exhibited thinner left inferior frontal gyrus (LIFG) cortical thickness (p=0.04) with concurrently lower language (p=0.02), memory (p=0.03), and attention-executive functioning (p=0.02). These results suggest that compromised vascular health may occur simultaneously with cortical thinning of the LIFG as an early neuropathological alteration in Hispanics.

Purpose: Ischemic preconditioning (IPC) has been used to protect myocardial cells against ischemia- reperfusion injury and is recently utilized for improving exercise performance. It is unknown whether remote IPC (RIPC) to tissues not involved in exercise can induce similar exercise improvements and what "dose" of IPC is necessary to induce exercise performance benefits. This study determined if unilateral and bilateral upper limb RIPC improves lower body anaerobic power output. Methods: Using two randomized, sham-controlled, crossover study designs, we studied 43 recreationally-active adults. For study 1, unilateral RIPC was used, while for study 2, the ischemic stimuli was increased to bilateral occlusion. After either the RIPC or sham control treatment, subjects completed four 30 s Wingate anaerobic tests on a Monark cycle ergometer with 2 min passive rest between trials. Results: In the unilateral occlusion trial, peak power, mean power, and fatigue index were not different between the two conditions at every Wingate test. In the bilateral occlusion trial, mean power was greater in the RIPC condition during the first Wingate test compared with the sham control (both p

In the present review, we describe the dysfunction in arteries that occurs with advanced aging and review how increased dairy product consumption ameliorates age-related arterial dysfunction and lowers the risk of cardiovascular disease (CVD) as well as type 2 diabetes. High consumption of low- and nonfat dairy products is inversely related to key markers of arterial dysfunction, including elevated blood pressure, arterial stiffening, and endothelial dysfunction. Importantly, adoption of a diet that is high in low- and nonfat dairy products is able to lower blood pressure and reduce arterial stiffness and ameliorate endothelial dysfunction in humans. More importantly, simply adding nonfat dairy products to the normal routine diet results in the amelioration of age-related arterial dysfunction. Consumption of a diet that is high in dairy products is also inversely related to risk of type 2 diabetes, which itself is a major risk factor for the development of CVD. Indeed, there is a substantial overlap of risk factors between type 2 diabetes and CVD, most of which are affected by age-related arterial dysfunction. These risk factors also appear to be ameliorated by high consumption of low- and nonfat dairy products. Nevertheless, the information pertaining to the relation between dairy intake and arterial dysfunction is currently limited, and it is clear that more research is warranted.

AB Acute endurance exercise has been shown to lower postprandial plasma triglyceride (PPTG) concentrations; however, whether this is due to the negative energy and/or CHO deficit from the exercise bout is not well understood. Purpose: This study aimed to examine the effects of a postexercise meal consisting of either high or low CHO content on PPTG and postprandial fat oxidation the morning after an exercise bout. Methods: Healthy young men (n = 6) performed each of four experimental treatments: 1) nonexercise control (CON), 2) 80 min of cycling with either no meal replacement (EX), 3) a high-CHO postexercise meal (EX+HCHO), or a 4) low-CHO postexercise meal (EX+LCHO). A standardized meal for PPTG determination was provided (16.0 kcal[middle dot]kg-1 body mass, 1.02 g fat[middle dot]kg-1, 1.36 g CHO[middle dot]kg-1, 0.31 g protein[middle dot]kg-1) 12 h after the exercise, and measurements of plasma triglyceride (TG) concentration and whole-body resting fat oxidation were made in the fasted condition and during the 4-h postprandial period. Results: The total area under the curve for plasma TG was significantly lower in EX+LCHO (325 (63) mg[middle dot]dL-1 per 4 h) compared with that in EX+HCHO (449 (118) mg[middle dot]dL-1 per 4 h, P = 0.03). Postprandial fat oxidation during this period was significantly greater in EX+LCHO (257 (58) kcal per 4 h, P = 0.003) compared with that in EX+HCHO (209 (56) kcal per 4 h). The change in total postprandial fat oxidation (kcal per 4 h) relative to CON was significantly and inversely correlated with the change in the total TG area under the curve relative to CON (mg[middle dot]dL-1 per 4 h, [DELTA]TG AUC, R2 = 0.37, P = 0.008). Conclusions: The low CHO composition of the postexercise meal contributes to lower PPTG and increased fat oxidation, with lower PPTG related to an increase in fat oxidation.

Dietary supplementation with pomegranate juice improves isometric strength recovery after unaccustomed eccentric exercise. The purpose of this study was to determine if there is a dose response effect of pomegranate juice supplementation after eccentric exercise isometric strength recovery. Forty-five nonresistance trained, recreationally active men were assigned once-daily pomegranate juice, twice-daily pomegranate juice, or placebo supplementation. On day four of supplementation, 20 min of downhill running and 40 maximal eccentric elbow flexion repetitions were performed. Isometric knee extensor and elbow flexor strength, muscular soreness, and serum myoglobin concentrations were measured prior to exercise and 2, 24, 48, 72, and 96 h after exercise. Throughout the postexercise time period, while isometric knee extensor and elbow flexor strength were similar between once-daily and twice-daily pomegranate juice supplementation groups, isometric strength was significantly higher in pomegranate juice groups than placebo. Knee extensor soreness, elbow flexor soreness, and myoglobin increased in response to exercise but were similar between groups. It is apparent that pomegranate juice supplementation improves strength recovery in leg and arm muscles following eccentric exercise; however, no dose response effect was present. We conclude that once-daily pomegranate juice supplementation is not different from twice-daily supplementation in regards to strength recovery after eccentric exercise.

Acute exercise has been shown to attenuate postprandial plasma triglyceride elevation (PPTG). However, the direct contribution of exercise intensity is less well understood. The purpose of this study was to examine the effects of exercise intensity on PPTG and postprandial fat oxidation. One of three experimental treatments was performed in healthy young men ( n = 6): nonexercise control (CON), moderate-intensity exercise (MIE; 50% V̇o2peak for 60 min), or isoenergetic high-intensity exercise (HIE; alternating 2 min at 25% and 2 min at 90% V̇o2peak). The morning after the exercise, a standardized meal was provided (16 kcal/kg BM, 1.02 g fat/kg, 1.36 g CHO/kg, 0.31 g PRO/kg), and measurements of plasma concentrations of triglyceride (TG), glucose, insulin, and β-hydroxybutyrate were made in the fasted condition and hourly for 6 h postprandial. Indirect calorimetry was used to determine fat oxidation in the fasted condition and 2, 4, and 6 h postprandial. Compared with CON, both MIE and HIE significantly attenuated PPTG [incremental AUC; 75.2 (15.5%), P = 0.033, and 54.9 (13.5%), P = 0.001], with HIE also significantly lower than MIE ( P = 0.03). Postprandial fat oxidation was significantly higher in MIE [83.3 (10.6%) of total energy expenditure] and HIE [89.1 (9.8) %total] compared with CON [69.0 (16.1) %total, P = 0.039, and P = 0.018, respectively], with HIE significantly greater than MIE ( P = 0.012). We conclude that, despite similar energy expenditure, HIE was more effective than MIE for lowering PPTG and increasing postprandial fat oxidation.

Arterial vasodilation to increases in wall shear rate is indicative of vascular endothelial function. In humans, the non-invasive measurement of endothelial function can be achieved by employing the flow-mediated dilation technique, typically performed in the brachial or superficial femoral artery. Briefly, a blood pressure cuff placed distal to an ultrasound probe is inflated to a suprasystolic pressure, which results in limb ischemia. After 5 min of occlusion the cuff is deflated, resulting in reactive hyperemia and increases in wall shear rate that signal vasodilatory molecules to be released from the endothelium eliciting vasodilation. Despite the thousands of studies performing flow-mediated dilation in humans, surprisingly, no studies have performed this technique non-invasively in living rats. Considering the recent shift in focus to translational research, the establishment of guidelines for non-invasive measurement of flow-mediated dilation in rats and other rodents would be extremely valuable. In the following article, a protocol is presented for the non-invasive measurement of flow-mediated dilation in brachial and superficial femoral arteries of rats, as those sites are most commonly measured in humans.

Systemic sclerosis (SSc) is a rare autoimmune disease characterized by debilitating fibrosis and vascular dysfunction; however, little is known about the circulatory response to exercise in this population. Therefore, we examined the peripheral hemodynamic and vasodilatory responses to handgrip exercise in 10 patients with SSc (61 ± 4 yr) and 15 age-matched healthy controls (56 ± 5 yr). Brachial artery diameter, blood flow, and mean arterial pressure (MAP) were determined at rest and during progressive static-intermittent handgrip exercise. Patients with SSc and controls were similar in body stature, handgrip strength, and MAP; however, brachial artery blood flow at rest was nearly twofold lower in patients with SSc compared with controls (22 ± 4 vs. 42 ± 5 ml/min, respectively; P < 0.05). Additionally, SSc patients had an ∼18% smaller brachial artery lumen diameter with an ∼28% thicker arterial wall at rest ( P < 0.05). Although, during handgrip exercise, there were no differences in MAP between the groups, exercise-induced hyperemia and therefore vascular conductance were ∼35% lower at all exercise workloads in patients with SSc ( P < 0.05). Brachial artery vasodilation, as assessed by the relationship between Δbrachial artery diameter and Δshear rate, was significantly attenuated in the patients with SSc ( P < 0.05). Finally, vascular dysfunction in the patients with SSc was accompanied by elevated blood markers of oxidative stress and attenuated endogenous antioxidant activity ( P < 0.05). Together, these findings reveal attenuated exercise-induced brachial artery blood flow and conduit arterial vasodilatory dysfunction during handgrip exercise in SSc and suggest that elevated oxidative stress may play a role.

Objective.Arthritis and its associated joint pain act as significant barriers for adults attempting to perform land-based physical activity. Swimming can be an ideal form of exercise for patients with arthritis. Yet there is no information on the efficacy of regular swimming exercise involving patients with arthritis. The effect of a swimming exercise intervention on joint pain, stiffness, and physical function was evaluated in patients with osteoarthritis (OA).Methods.Using a randomized study design, 48 sedentary middle-aged and older adults with OA underwent 3 months of either swimming or cycling exercise training. Supervised exercise training was performed for 45 min/day, 3 days/week at 60–70% heart rate reserve for 12 weeks. The Western Ontario and McMaster Universities Arthritis Index was used to measure joint pain, stiffness, and physical limitation.Results.After the exercise interventions, there were significant reductions in joint pain, stiffness, and physical limitation accompanied by increases in quality of life in both groups (all p < 0.05). Functional capacity as assessed by maximal handgrip strength, isokinetic knee extension and flexion power (15–30% increases), and the distance covered in the 6-min walk test increased (all p < 0.05) in both exercise groups. No differences were observed in the magnitude of improvements between swimming and cycling training.Conclusion.Regular swimming exercise reduced joint pain and stiffness associated with OA and improved muscle strength and functional capacity in middle-aged and older adults with OA. Additionally, the benefits of swimming exercise were similar to the more frequently prescribed land-based cycling training. Trial registration: clinicaltrials.govNCT01836380.

It was reported in 1980s that ages at which peak performance was observed had remained remarkably stable in the past century, although absolute levels of athletic performance increased dramatically for the same time span. The emergence of older (masters) athletes in the past few decades has changed the demographics and age-spectrum of Olympic athletes. The primary aim of the present study was to determine whether the ages at which peak performance was observed had increased in the recent decades. The data spanning 114 years from the first Olympics (1898) to the most recent Olympics (2014) were collected using the publically available data. In the present study, ages at which Olympic medals (gold, silver, and bronze) were won were used as the indicators of peak performance age. Track and field, swimming, rowing, and ice skating events were analyzed. In men, peak performance age did not change significantly in most of the sporting events (except in 100 m sprint running). In contrast, peak performance ages in women have increased significantly since 1980s and consistently in all the athletic events examined. Interestingly, as women's peak performance age increased, they became similar to men's peak ages in many events. In the last 20-30 years, ages at which peak athletic performance is observed have increased in women but not in men.