Thromboxane-induced cerebral microvascular rarefaction predicts depressive symptom emergence in metabolic disease.

Previous studies have suggested that the loss of microvessel density in the peripheral circulation with evolving metabolic disease severity represents a significant contributor to impaired skeletal muscle oxygenation and fatigue-resistance. Based on this and our recent work, we hypothesized that cerebral microvascular rarefaction was initiated from the increased prooxidant and proinflammatory environment with metabolic disease and is predictive of the severity of the emergence of depressive symptoms in obese Zucker rats (OZRs). In male OZR, cerebrovascular rarefaction followed the emergence of elevated oxidant and inflammatory environments characterized by increased vascular production of thromboxane A2 (TxA2). The subsequent emergence of depressive symptoms in OZR was associated with the timing and severity of the rarefaction. Chronic intervention with antioxidant (TEMPOL) or anti-inflammation (pentoxifylline) therapy blunted the severity of rarefaction and depressive symptoms, although the effectiveness was limited. Blockade of TxA2 production (dazmegrel) or action (SQ-29548) resulted in a stronger therapeutic effect, suggesting that vascular production and action represent a significant contributor to rarefaction and the emergence of depressive symptoms with chronic metabolic disease (although other pathways clearly contribute as well). A de novo biosimulation of cerebrovascular oxygenation in the face of progressive rarefaction demonstrates the increased probability of generating hypoxic regions within the microvascular networks, which could contribute to impaired neuronal metabolism and the emergence of depressive symptoms. The results of the present study also implicate the potential importance of aggressive prodromic intervention in reducing the severity of chronic complications arising from metabolic disease.NEW & NOTEWORTHY With clinical studies linking vascular disease risk to depressive symptom emergence, we used obese Zucker rats, a model of chronic metabolic disease, to identify potential mechanistic links between these two negative outcomes. Depressive symptom severity correlated with the extent of cerebrovascular rarefaction, after increased vascular oxidant stress/inflammation and TxA2 production. Anti-TxA2 interventions prevasculopathy blunted rarefaction and depressive symptoms, while biosimulation indicated that cerebrovascular rarefaction increased hypoxia within capillary networks as a potential contributing mechanism.

Leptin-dependent differential remodeling of visceral and pericardial adipose tissue following chronic exercise and psychosocial stress.

Obesity is driven by an imbalance between caloric intake and energy expenditure, causing excessive storage of triglycerides in adipose tissue at different sites around the body. Increased visceral adipose tissue (VAT) is associated with diabetes, while pericardial adipose tissue (PAT) is associated with cardiac pathology. Adipose tissue can expand either through cellular hypertrophy or hyperplasia, with the former correlating with decreased metabolic health in obesity. The aim of this study was to determine how VAT and PAT remodel in response to obesity, stress, and exercise. Here we have used the male obese Zucker rats, which carries two recessive fa alleles that result in the development of hyperphagia with reduced energy expenditure, resulting in morbid obesity and leptin resistance. At 9 weeks of age, a group of lean (Fa/Fa or Fa/fa) Zucker rats (LZR) and obese (fa/fa) Zucker rats (OZR) were treated with unpredictable chronic mild stress or exercise for 8 weeks. To determine the phenotype for PAT and VAT, tissue cellularity and gene expression were analyzed. Finally, leptin signaling was investigated further using cultured 3T3-derived adipocytes. Tissue cellularity was determined following hematoxylin and eosin (H&E) staining, while qPCR was used to examine gene expression. PAT adipocytes were significantly smaller than those from VAT and had a more beige-like appearance in both LZR and OZR. In the OZR group, VAT adipocyte cell size increased significantly compared with LZR, while PAT showed no difference. Exercise and stress resulted in a significant reduction in VAT cellularity in OZR, while PAT showed no change. This suggests that PAT cellularity does not remodel significantly compared with VAT. These data indicate that the extracellular matrix of PAT is able to remodel more readily than in VAT. In the LZR group, exercise increased insulin receptor substrate 1 (IRS1) in PAT but was decreased in the OZR group. In VAT, exercise decreased IRS1 in LZR, while increasing it in OZR. This suggests that in obesity, VAT is more responsive to exercise and subsequently becomes less insulin resistant compared with PAT. Stress increased PPAR-γ expression in the VAT but decreased it in the PAT in the OZR group. This suggests that in obesity, stress increases adipogenesis more significantly in the VAT compared with PAT. To understand the role of leptin signaling in adipose tissue remodeling mechanistically, JAK2 autophosphorylation was inhibited using 5 µM 1,2,3,4,5,6-hexabromocyclohexane (Hex) in cultured 3T3-derived adipocytes. Palmitate treatment was used to induce cellular hypertrophy. Hex blocked adipocyte hypertrophy in response to palmitate treatment but not the increase in lipid droplet size. These data suggest that leptin signaling is necessary for adipocyte cell remodeling, and its absence induces whitening. Taken together, our data suggest that leptin signaling is necessary for adipocyte remodeling in response to obesity, exercise, and psychosocial stress.

Effects of electronic cigarette E-liquid and device wattage on vascular function.

Electronic cigarettes (e-cigs) are customizable tobacco products that allow users to select e-liquid composition, flavors, and (in some devices) adjust wattage or heat used to generate e-cig aerosol. This study compared vascular outcomes in a conducting vessel (thoracic aorta) and a resistance artery (middle cerebral artery, MCA) in C57Bl/6 mice exposed to e-cig aerosol generated from either pure vegetable glycerin (VG) or pure propylene glycol (PG) over 60-min (Study 1), and separately the effect of using 5- vs. 30-watt settings with an exposure of 100-min (Study 2). In Study 1, aortic endothelial-dependent-dilation (EDD) was only impaired with PG- exposure (p < 0.05) compared with air. In the MCA, EDD response was impaired by ∼50% in both VG and PG groups compared with air (p < 0.05). In Study 2, the aortic EDD responses were not different for either 5- or 30-watt exposed groups compared with air controls; however, in the MCA, both 5- and 30-watt groups were impaired by 32% and 55%, respectively, compared with air controls (p < 0.05). These pre-clinical data provide evidence that chronic exposure to aerosol produced by either VG or PG, and regardless of the wattage used, leads to vascular dysfunction at multiple levels within the arterial system. For all exposures, we observed greater impairment of arterial reactivity in a resistance artery (i.e. MCA) compared with the aorta. These data could suggest the smaller arteries may be more sensitive or first to be affected, or that different mechanism(s) for impairment may be involved depending on arterial hierarchy.

Application of a novel index for understanding vascular health following pharmacological intervention in a pre-clinical model of metabolic disease.

While a thorough understanding of microvascular function in health and how it becomes compromised with progression of disease risk is critical for developing effective therapeutic interventions, our ability to accurately assess the beneficial impact of pharmacological interventions to improve outcomes is vital. Here we introduce a novel Vascular Health Index (VHI) that allows for simultaneous assessment of changes to vascular reactivity/endothelial function, vascular wall mechanics and microvessel density within cerebral and skeletal muscle vascular networks with progression of metabolic disease in obese Zucker rats (OZR); under control conditions and following pharmacological interventions of clinical relevance. Outcomes are compared to "healthy" conditions in lean Zucker rats. We detail the calculation of vascular health index, full assessments of validity, and describe progressive changes to vascular health index over the development of metabolic disease in obese Zucker rats. Further, we detail the improvement to cerebral and skeletal muscle vascular health index following chronic treatment of obese Zucker rats with anti-hypertensive (15%-52% for skeletal muscle vascular health index; 12%-48% for cerebral vascular health index; p < 0.05 for both), anti-dyslipidemic (13%-48% for skeletal muscle vascular health index; p < 0.05), anti-diabetic (12%-32% for cerebral vascular health index; p < 0.05) and anti-oxidant/inflammation (41%-64% for skeletal muscle vascular health index; 29%-42% for cerebral vascular health index; p < 0.05 for both) drugs. The results present the effectiveness of mechanistically diverse interventions to improve cerebral or skeletal muscle vascular health index in obese Zucker rats and provide insight into the superiority of some pharmacological agents despite similar effectiveness in terms of impact on intended targets. In addition, we demonstrate the utility of including a wider, more integrative approach to the study of microvasculopathy under settings of elevated disease risk and following pharmacological intervention. A major benefit of integrating vascular health index is an increased understanding of the development, timing and efficacy of interventions through greater insight into integrated microvascular function in combination with individual, higher resolution metrics.

Xanthine oxidase mediates chronic stress-induced cerebrovascular dysfunction and cognitive impairment.

Xanthine oxidase (XO) mediates vascular function. Chronic stress impairs cerebrovascular function and increases the risk of stroke and cognitive decline. Our study determined the role of XO on stress-induced cerebrovascular dysfunction and cognitive decline. We measured middle cerebral artery (MCA) function, free radical formation, and working memory in 6-month-old C57BL/6 mice who underwent 8 weeks of control conditions or unpredictable chronic mild stress (UCMS) with or without febuxostat (50 mg/L), a XO inhibitor. UCMS mice had an impaired MCA dilation to acetylcholine vs. controls (p < 0.0001), and increased total free radical formation, XOR protein levels, and hydrogen peroxide production in the liver compared to controls. UCMS increased hydrogen peroxide production in the brain and cerebrovasculature compared to controls. Working memory, using the y-maze test, was impaired (p < 0.05) in UCMS mice compared to control mice. However, blocking XO using febuxostat prevented the UCMS-induced impaired MCA response, while free radical production and hydrogen peroxide levels were similar to controls in the liver and brain of UCMS mice treated with febuxostat. Further, UCMS + Feb mice did not have a significant reduction in working memory. These data suggest that the cerebrovascular dysfunction associated with chronic stress may be driven by XO, which leads to a reduction in working memory.

Maternal electronic cigarette use during pregnancy affects long-term arterial function in offspring.

Vaping, or electronic cigarette (ecig) use, is prevalent among pregnant women, although little is known about the effects of perinatal ecig use on cardiovascular health of the progeny (even when using nicotine-free e-liquid). Maternal toxicant inhalation may adversely affect vital conduit vessel development. We tested the hypothesis that perinatal exposure to maternal vaping would lead to a dose-dependent dysfunction that would persist into later life of offspring. Pregnant Sprague-Dawley rats were exposed to either nicotine-free (ecig0) or nicotine-containing ecig aerosol (18 mg/mL, ecig18) starting on gestational day 2 and continued until pups were weaned (postnatal day 21). Pups were never directly exposed. Conduit artery function (stiffness and reactivity) and structure were assessed in 3- and 7-mo-old offspring. At 3 mo, pulse wave velocity (PWV) in the ecig0 and ecig18 offspring was significantly higher than controls in both the 20 puffs/day (6.6 ± 2.1 and 4.8 ± 1.3 vs. 3.2 ± 0.7 m/s, respectively, P < 0.05, means ± SD) and in 60 puffs/day exposure cohort (7.5 ± 2.8 and 7.5 ± 2.5 vs. 3.2 ± 0.5 m/s, respectively, P < 0.01). Wire myography revealed (range of 23%-31%) impaired aortic relaxation in all ecig exposure groups (with or without nicotine). Incubation of vessels with TEMPOL or Febuxostat reversed the aortic dysfunction, implicating the involvement of reactive oxygen species. Nearly identical changes and pattern was seen in vascular outcomes of 7-mo-old offspring. The take-home message from this preclinical study is that maternal vaping during pregnancy, with or without nicotine, leads to maladaptations in vascular (aortic) development that persist into adult life of offspring.NEW & NOTEWORTHY We observe a significant alteration in arterial structure and function in adolescent and adult offspring due to developmental exposure to toxicants resulting from perinatal maternal vaping. Taken together with previous work that described lasting dysfunction in cerebral microvasculature in offspring, these data underscore the adverse consequences of maternal exposure to electronic cigarette aerosol in conduit and resistance vessels alike, irrespective of nicotine content.

A novel vascular health index: Using data analytics and population health to facilitate mechanistic modeling of microvascular status.

The study of vascular function across conditions has been an intensive area of investigation for many years. While these efforts have revealed many factors contributing to vascular health, challenges remain for integrating results across research groups, animal models, and experimental conditions to understand integrated vascular function. As such, the insights attained in clinical/population research from linking datasets, have not been fully realized in the basic sciences, thus frustrating advanced analytics and complex modeling. To achieve comparable advances, we must address the conceptual challenge of defining/measuring integrated vascular function and the technical challenge of combining data across conditions, models, and groups. Here, we describe an approach to establish and validate a composite metric of vascular function by comparing parameters of vascular function in metabolic disease (the obese Zucker rat) to the same parameters in age-matched, "healthy" conditions, resulting in a common outcome measure which we term the vascular health index (VHI). VHI allows for the integration of datasets, thus expanding sample size and permitting advanced modeling to gain insight into the development of peripheral and cerebral vascular dysfunction. Markers of vascular reactivity, vascular wall mechanics, and microvascular network density are integrated in the VHI. We provide a detailed presentation of the development of the VHI and provide multiple measures to assess face, content, criterion, and discriminant validity of the metric. Our results demonstrate how the VHI captures multiple indices of dysfunction in the skeletal muscle and cerebral vasculature with metabolic disease and provide context for an integrated understanding of vascular health under challenged conditions.

Left Ventricular Segmental Strain Identifies Unique Myocardial Deformation Patterns After Intrinsic and Extrinsic Stressors in Mice.

We used segmental strain analysis to evaluate whether intrinsic (diet-induced obesity [DIO]) and extrinsic (unpredictable chronic mild stress [UCMS]) stressors can alter deformational patterns of the left ventricle. Six-week-old male C57BL/6J mice were randomized into the lean or obese group (n = 24/group). Mice underwent 12 wk of DIO with a high-fat diet (HFD). At 18 wk, lean and obese mice were further randomized into UCMS and non-UCMS groups (UCMS, 7 h/d, 5 d/wk, for 8 wk). Echocardiography was performed at baseline (6 wk), post-HFD (18 wk) and post-UCMS (26 wk). Machine learning was applied to the DIO and UCMS groups. There was robust predictive accuracy (area under the receiver operating characteristic curve [AUC] = 0.921) when comparing obese with lean mice, with radial strain changes in the lateral (-64%, p ≤ 0.001) and anterior free (-53%, p < 0.001) walls being most informative. The ability to predict mice that underwent UCMS, irrespective of diet, was assessed (AUC = 0.886), revealing longitudinal strain rate of the anterior midwall and radial strain of the posterior septal wall as the top features. The wall segments indicate a predilection for changes in deformation patterns to the free wall (DIO) and septal wall (UCMS), indicating disease-specific alterations to the myocardium.

The development of peripheral microvasculopathy with chronic metabolic disease in obese Zucker rats: a retrograde emergence?

The study of peripheral vasculopathy with chronic metabolic disease is challenged by divergent contributions from spatial (the level of resolution or specific tissue being studied) and temporal origins (evolution of the developing impairments in time). Over many years of studying the development of skeletal muscle vasculopathy and its functional implications, we may be at the point of presenting an integrated conceptual model that addresses these challenges within the obese Zucker rat (OZR) model. At the early stages of metabolic disease, where systemic markers of elevated cardiovascular disease risk are present, the only evidence of vascular dysfunction is at postcapillary and collecting venules, where leukocyte adhesion/rolling is elevated with impaired venular endothelial function. As metabolic disease severity and duration increases, reduced microvessel density becomes evident as well as increased variability in microvascular hematocrit. Subsequently, hemodynamic impairments to distal arteriolar networks emerge, manifesting as increasing perfusion heterogeneity and impaired arteriolar reactivity. This retrograde "wave of dysfunction" continues, creating a condition wherein deficiencies to the distal arteriolar, capillary, and venular microcirculation stabilize and impairments to proximal arteriolar reactivity, wall mechanics, and perfusion distribution evolve. This proximal arteriolar dysfunction parallels increasing failure in fatigue resistance, hyperemic responses, and O2 uptake within self-perfused skeletal muscle. Taken together, these results present a conceptual model for the retrograde development of peripheral vasculopathy with chronic metabolic disease and provide insight into the timing and targeting of interventional strategies to improve health outcomes.NEW & NOTEWORTHY Working from an established database spanning multiple scales and times, we studied progression of peripheral microvascular dysfunction in chronic metabolic disease. The data implicate the postcapillary venular endothelium as the initiating site for vasculopathy. Indicators of dysfunction, spanning network structures, hemodynamics, vascular reactivity, and perfusion progress in an insidious retrograde manner to present as functional impairments to muscle blood flow and performance much later. The silent vasculopathy progression may provide insight into clinical treatment challenges.

Short-term effects of electronic cigarettes on cerebrovascular function: A time course study.

NEW FINDINGS: What is the central question of this study? Acute exposure to electronic cigarettes (Ecigs) triggers abnormal vascular responses in systemic arteries; however, effects on cerebral vessels are poorly understood and time for recovery is not known. We hypothesized that exposure to cigarettes or Ecigs would trigger rapid (<4 h) impairment of the middle cerebral artery (MCA) but that this would resolve by 24 h. What is the main finding and its importance? Cigarettes and Ecigs caused similar degree and duration of MCA impairment. We find it takes ~72 hours after exposure for MCA function to return to normal. This suggests that Ecig use is likely to produce similar adverse vascular health outcomes to those seen with cigarette smoke. ABSTRACT: Temporal influences of electronic cigarettes (Ecigs) on blood vessels are poorly understood. In this study, we evaluated a single episode of cigarette versus Ecig exposure on middle cerebral artery (MCA) reactivity and determined how long after the exposure MCA responses took to return to normal. We hypothesized that cigarette and Ecig exposure would induce rapid (<4 h) reduction in MCA endothelial function and would resolve within 24 h. Sprague-Dawley rats (4 months old) were exposed to either air (n = 5), traditional cigarettes (20 puffs, n = 16) or Ecigs (20-puff group, n = 16; or 60-puff group, n = 12). Thereafter, the cigarette and Ecig groups were randomly assigned for postexposure vessel myography testing on day 0 (D0, 1-4 h postexposure), day 1 (D1, 24-28 h postexposure), day 2 (D2, 48-52 h postexposure) and day 3 (72-76 h postexposure). The greatest effect on endothelium-dependent dilatation was observed within 24 h of exposure (∼50% decline between D0 and D1) for both cigarette and Ecig groups, and impairment persisted with all groups for up to 3 days. Changes in endothelium-independent dilatation responses were less severe (∼27%) and shorter lived (recovering by D2) compared with endothelium-dependent dilatation responses. Vasoconstriction in response to serotonin (5-HT) was similar to endothelium-independent dilatation, with greatest impairment (∼45% for all exposure groups) at D0-D1, returning to normal by D2. These data show that exposure to cigarettes and Ecigs triggers a similar level/duration of cerebrovascular dysfunction after a single exposure. The finding that Ecig (without nicotine) and cigarette (with nicotine) exposure produce the same effects suggesting that nicotine is not likely to be triggering MCA dysfunction, and that vaping (with/without nicotine) has potential to produce the same vascular harm and/or disease as smoking.

The stability of tastant detection by mouse lingual chemosensory tissue requires Regulator of G protein Signaling-21 (RGS21).

The T1R and T2R families of G protein-coupled receptors (GPCRs) initiate tastant perception by signaling via guanine nucleotide exchange and hydrolysis performed by associated heterotrimeric G proteins (Gαßγ). Heterotrimeric G protein signal termination is sped up by Gα-directed GTPase-accelerating proteins (GAPs) known as the Regulators of G protein Signaling (RGS proteins). Of this family, RGS21 is highly expressed in lingual epithelial cells and we have shown it acting in vitro to decrease the potency of bitterants on cultured cells. However, constitutive RGS21 loss in mice reduces organismal response to GPCR-mediated tastants-opposite to expectations arising from observed in vitro activity of RGS21 as a GAP and inhibitor of T2R signaling. Here, we show reduced quinine aversion and reduced sucrose preference by mice lacking RGS21 does not result from post-ingestive effects, as taste-salient brief-access tests confirm the reduced bitterant aversion and reduced sweetener preference seen using two-bottle choice testing. Eliminating Rgs21 expression after chemosensory system development, via tamoxifen-induced Cre recombination in eight week-old mice, led to a reduction in quinine aversive behavior that advanced over time, suggesting that RGS21 functions as a negative regulator to sustain stable bitter tastant reception. Consistent with this notion, we observed downregulation of multiple T2R proteins in the lingual tissue of Rgs21-deficient mice. Reduced tastant-mediated responses exhibited by mice lacking Rgs21 expression either since birth or in adulthood has highlighted the potential requirement for a GPCR GAP to maintain the full character of tastant signaling, likely at the level of mitigating receptor downregulation.

Human and rodent red blood cells do not demonstrate xanthine oxidase activity or XO-catalyzed nitrite reduction to NO.

A number of molybdopterin enzymes, including xanthine oxidoreductase (XOR), aldehyde oxidase (AO), sulfite oxidase (SO), and mitochondrial amidoxime reducing component (mARC), have been identified as nitrate and nitrite reductases. Of these enzymes, XOR has been the most extensively studied and reported to be a substantive source of nitric oxide (NO) under inflammatory/hypoxic conditions that limit the catalytic activity of the canonical NOS pathway. It has also been postulated that XOR nitrite reductase activity extends to red blood cell (RBCs) membranes where it has been immunohistochemically identified. These findings, when combined with countervailing reports of XOR activity in RBCs, incentivized our current study to critically evaluate XOR protein abundance/enzymatic activity in/on RBCs from human, mouse, and rat sources. Using various protein concentrations of RBC homogenates for both human and rodent samples, neither XOR protein nor enzymatic activity (xanthine → uric acid) was detectable. In addition, potential loading of RBC-associated glycosaminoglycans (GAGs) by exposing RBC preparations to purified XO before washing did not solicit detectable enzymatic activity (xanthine → uric acid) or alter NO generation profiles. To ensure these observations extended to absence of XOR-mediated contributions to overall RBC-associated nitrite reduction, we examined the nitrite reductase activity of washed and lysed RBC preparations via enhanced chemiluminescence in the presence or absence of the XOR-specific inhibitor febuxostat (Uloric®). Neither addition of inhibitor nor the presence of the XOR substrate xanthine significantly altered the rates of nitrite reduction to NO by RBC preparations from either human or rodent sources confirming the absence of XO enzymatic activity. Furthermore, examination of the influence of the age (young cells vs. old cells) of human RBCs on XO activity also failed to demonstrate detectable XO protein. Combined, these data suggest: 1) that XO does not contribute to nitrite reduction in/on human and rodent erythrocytes, 2) care should be taken to validate immuno-detectable XO by demonstrating enzymatic activity, and 3) XO does not associate with human erythrocytic glycosaminoglycans or participate in nonspecific binding.

Can Myogenic Tone Protect Endothelial Function? Integrating Myogenic Activation and Dilator Reactivity for Cerebral Resistance Arteries in Metabolic Disease.

The obese Zucker rat (OZR) manifests multiple risk factors for impaired cerebrovascular function, including hypertension and insulin resistance although how they combine to produce integrated vascular function is unclear. As studies have suggested that myogenic activation (MA) severity for middle cerebral arteries (MCAs) may be proportional to hypertension severity, we hypothesized that MA will negatively correlate with dilator reactivity in OZR. MA of MCA from OZR was divided into low, medium, and high based on the slope of MA, while MCA reactivity and vascular metabolite bioavailability were assessed in all groups. Endothelium-dependent dilation of MCA in OZR was attenuated and correlated with the MA slope. Treatment of OZR MCA with TEMPOL (antioxidant) improved dilation in low or medium MA groups, but had less impact on high MA. Alternatively, treatment with gadolinium to normalize MA in OZR had reduced impact on dilator reactivity in MCA from low and medium MA groups, but improved responses in the high group. Treatment with both agents resulted in dilator responses that were comparable across all groups. These results suggest that, under conditions with stronger MA, endothelial function may receive some protection despite the environment, potentially from the ability of MCA to reduce wall tension despite increased pressure.

Role of Perivascular Adipose Tissue and Exercise on Arterial Function with Obesity.

Adipose tissue and arterial dysfunction are common in the obese state. Perivascular adipose tissue (PVAT) plays an important role in mediating arterial health, and with obesity, the PVAT dysfunction negatively affects arterial health. Exercise training exerts direct and beneficial effects on PVAT, providing an additional and novel pathway by which exercise can improve arterial health in diseased populations.

Chronic stress induced perivascular adipose tissue impairment of aortic function and the therapeutic effect of exercise.

NEW FINDINGS: What is the central question of this study? Thoracic perivascular adipose tissue (tPVAT) is known to, in part, regulate aortic function: what are the effects of unpredictable chronic mild stress (UCMS) on the tPVAT regulation of aortic function and what is the role of exercise training in alleviating the potential negative actions of UCMS on tPVAT? What is the main finding and its importance? UCMS causes tPVAT to disrupt endothelium-dependent dilatation, increases inflammatory cytokine production and diminishes tPVAT-adiponectin. Exercise training proved efficacious in preventing tPVAT-mediated disruption of aortic function. The data support a tPVAT mechanism through which chronic stress negatively impacts vascular health, which adds to our knowledge of how psychological disorders might increase the risk of cardiovascular disease. ABSTRACT: Chronic stress is a major risk for cardiovascular disease. Perivascular adipose tissue (PVAT) has been shown to regulate vascular function; however, the impact of chronic stress and the comorbidity of metabolic syndrome (MetS) on thoracic (t)PVAT is unknown. Additionally, aerobic exercise training (AET) is known to combat the pathology of MetS and chronic stress, but the role of tPVAT in these actions is also unknown. Therefore, the purpose of this study was to examine the effects of unpredictable chronic mild stress (UCMS) on the tPVAT regulation of aortic function and the preventative effect of AET. Lean (LZR) and obese (OZR) Zucker rats (16-17 weeks old) were exposed to 8 weeks of UCMS with and without treadmill exercise (AET). In LZR, UCMS impaired aortic endothelium-dependent dilatation (EDD) (assessed ex vivo by wire myography) and aortic stiffness (assessed by elastic modulus) with no change in OZR subject to UCMS. However, both LZR and OZR UCMS tPVAT impaired EDD compared to respective controls. LZR and OZR subject to UCMS had higher oxidative stress production, diminished adiponectin and impaired aortic nitric oxide levels. Divergently, UCMS induced greater inflammatory cytokine production in LZR UCMS tPVAT, but not in OZR UCMS tPVAT. AET prevented the tPVAT impairment of aortic relaxation with UCMS in LZR and OZR. Additionally, AET reduced aortic stiffness in both LZR and OZR. These beneficial effects on tPVAT regulation of the aorta are likely due to AET preservation of adiponectin, reduced oxidative stress and inflammation, and enhanced nitric oxide. UCMS impaired tPVAT-regulated aortic function in LZR, and augmented MetS-induced EDD in OZR. Conversely, AET in combination with UCMS largely preserved aortic function and the tPVAT environment, in both groups.

Longitudinal uncoupling of the heart and arteries with aging in a community-dwelling population.

Although mechanical energy transfer between the heart and arterial system, referred to as arterial-ventricular (AV) coupling, is an important determinant of cardiovascular performance, how AV coupling changes over time within and among individuals as they age has not been fully explored. We studied 129 participants (baseline age 21-96) of the Baltimore Longitudinal Study of Aging, free of clinical CVD. Participants underwent repeated multigated cardiac blood pool scans to estimate left ventricular (LV) volumes (SV, EDV, and ESV). Total systemic vascular resistance (TSVR), total arterial compliance (TAC), effective arterial elastance (Ea), and end-systolic LV elastance (Elv) were calculated using LV volumes and brachial BP measurements; calculated Ea/Elv was the measure of AV coupling. Linear mixed-effects models were used to estimate person-specific rates of change (Change) for each variable. The rate at which Ea increased over time was faster than the rate at which Elv increased, resulting in AV uncoupling (increased Ea/Elv) over time that was significantly greater in women than in men. Loss of arterial compliance was the main determinant of (Ea/Elv)Change, which was negatively associated with changes in SV and EDV but positively with changes in ESV. Progressive AV uncoupling occurred with aging and was more pronounced in women than men. While Ea change did not differ by sex, Elv increased at a slower rate in women than in men. AV uncoupling was inversely associated with EDV and SV rates of change and a directly associated with an increase in ESV rate of change. Additional studies are needed to explore the functional consequences of AV uncoupling in healthy individuals with respect to the emergence of age-associated clinical cardiovascular diseases, such as heart failure with preserved ejection fraction.

Perivascular adipose tissue mediated aortic reactivity data: Female lean and obese Zucker rats.

Perivascular adipose tissue (PVAT) is recognized as a paracrine organ that controls vascular function. One of the early data demonstrated PVAT from male Sprague-Dawley rats altered aortic vascular reactivity [1]. Subsequent studies have suggested PVAT mediated vascular reactivity is impaired in a variety of vascular beds with animal models of metabolic syndrome [2]. Findings in these experimental animals are generally reported by only male data. Here we report the new data on the effects of PVAT on the aortic reactivity of female lean zucker rats (LZR) and obese zucker rats (OZR). The data presented here is related to a recent manuscript entitled "Aortic dysfunction in metabolic syndrome mediated by perivascular adipose tissue TNFα- and NOX2-dependent pathway" [3] which demonstrated PVAT from male obese Zucker rats (OZR) impaired endothelial function of aorta which is associated with altered PVAT inflammatory signaling.

Exercise training prevents the perivascular adipose tissue-induced aortic dysfunction with metabolic syndrome.

The aim of the study was to determine the effects of exercise training on improving the thoracic perivascular adipose tissue (tPVAT) phenotype (inflammation, oxidative stress, and proteasome function) in metabolic syndrome and its subsequent actions on aortic function. METHODS: Lean and obese (model of metabolic syndrome) Zucker rats (n=8/group) underwent 8-weeks of control conditions or treadmill exercise (70% of max speed, 1 h/day, 5 days/week). At the end of the intervention, the tPVAT was removed and conditioned media was made. The cleaned aorta was attached to a force transducer to assess endothelium-dependent and independent dilation in the presence or absence of tPVAT-conditioned media. tPVAT gene expression, inflammatory /oxidative phenotype, and proteasome function were assessed. RESULTS: The main findings were that Ex induced: (1) a beige-like, anti-inflammatory tPVAT phenotype; (2) a greater abundance of •NO in tPVAT; (3) a reduction in tPVAT oxidant production; and (4) an improved tPVAT proteasome function. Regarding aortic function, endothelium-dependent dilation was greater in exercised lean and obese groups vs. controls (p < 0.05). Lean control tPVAT improved aortic relaxation, whereas obese control tPVAT decreased aortic relaxation. In contrast, the obese Ex-tPVAT increased aortic dilation, whereas the lean Ex-tPVAT did not affect aortic dilation. CONCLUSION: Overall, exercise had the most dramatic impact on the obese tPVAT reflecting a change towards an environment with less oxidant load, less inflammation and improved proteasome function. Such beneficial changes to the tPVAT micro-environment with exercise likely played a significant role in mediating the improvement in aortic function in metabolic syndrome following 8 weeks of exercise.

Educational intervention improves fruit and vegetable intake in young adults with metabolic syndrome components.

The FRUVEDomics study investigates the effect of a diet intervention focused on increasing fruit and vegetable intake on the gut microbiome and cardiovascular health of young adults with/at risk for metabolic syndrome (MetS). It was hypothesized that the recommended diet would result in metabolic and gut microbiome changes. The 9-week dietary intervention adhered to the US Department of Agriculture Dietary Guidelines for Americans and focused on increasing fruit and vegetable intake to equal half of the diet. Seventeen eligible young adults with/or at high risk of MetS consented and completed preintervention and postintervention measurements, including anthropometric, body composition, cardiovascular, complete blood lipid panel, and collection of stool sample for microbial analysis. Participants attended weekly consultations to assess food logs, food receipts, and adherence to the diet. Following intention-to-treat guidelines, all 17 individuals were included in the dietary, clinical, and anthropometric analysis. Fruit and vegetable intake increased from 1.6 to 3.4 cups of fruits and vegetables (P < .001) daily. Total fiber (P = .02) and insoluble fiber (P < .0001) also increased. Clinical laboratory changes included an increase in sodium (P = .0006) and low-density lipoprotein cholesterol (P = .04). In the fecal microbiome, Erysipelotrichaceae (phylum Firmicutes) decreased (log2 fold change: -1.78, P = .01) and Caulobacteraceae (phylum Proteobacteria) increased (log2 fold change = 1.07, P = .01). Implementing a free-living 9-week diet, with intensive education and accountability, gave young adults at high risk for/or diagnosed with MetS the knowledge, skills, and feedback to improve diet. To yield greater impact, a longer diet intervention may be needed in this population.