Multi-Scale Peripheral Vasculopathy with Metabolic Syndrome

The combination of cardiovascular and metabolic risk factors including obesity, dyslipidemia, hypertension, and insulin resistance, in combination with a prothrombotic and proinflammatory state, is a condition termed Metabolic Syndrome (METS). Twenty percent of the adult population is afflicted with METS which increases the risk of type-2 diabetes mellitus and cardiovascular disease. Further, the presence of peripheral vascular disease (PVD) is tightly coupled with METS which is a perfusion-demand mismatch of blood supply to active skeletal muscle resulting in painful claudication and a late-stage potential for amputation. The underlying contributors of METS associated micro-vasculopathies in the skeletal muscle, their impact on impaired perfusion, and the potential for reversibility remain unclear. Owing its hyperphagia to leptin signaling resistance, the obese Zucker rat (OZR) is a translationally relevant model for human METS and the associated micro-vasculopathies. The overall purpose of this thesis is to utilize a multi-scale approach, particularly intravital microscopy and isolate vessels, to garner a greater understanding of the observed OZR vasculopathies and to investigate the potential of therapeutic interventions for their reversibility. Project 1: The purpose was to identify any alterations in postcapillary and collecting venule function in the OZR compared to healthy controls. The OZR presented with impaired dilator reactivity and elevation in thromboxane A2 constrictor responses for both postcapillary and collecting venules. Project 2: The purpose was to identify the possible contributors of a disconnect for in-situ and ex-vivo vascular studies utilizing the OZR model. Using a multi-scale approach, Project 2 provides insight to this disconnect and reveals a heterogenous adrenergic response in the OZR, giving rise to new potential avenues of study. Project 3: The purpose was to determine the potential for reversibility or restoration of established PVD using the chronic ingestion of an HMG-CoA inhibitor, atorvastatin, and/or the implementation of regular exercise. Following a seven-week intervention, the intervention groups revealed vascular improvements with the combination group having the greatest capacity for reversibility (in specific indices). Significance: Therefore, this thesis further advances the understanding of METS associated PVD as well as potential modes for improvement following its establishment

Beneficial pleiotropic antidepressive effects of cardiovascular disease risk factor interventions in the metabolic syndrome

© 2018 The Authors. Background--Although the increased prevalence and severity of clinical depression and elevated cardiovascular disease risk represent 2 vexing public health issues, the growing awareness of their combined presentation compounds the challenge. The obese Zucker rat, a model of the metabolic syndrome, spontaneously develops significant depressive symptoms in parallel with the progression of the metabolic syndrome and, thus, represents a compelling model for study. The primary objective was to assess the impact on both cardiovascular outcomes, specifically vascular structure and function, and depressive symptoms in obese Zucker rats after aggressive treatment for cardiovascular disease risk factors with long-term exercise or targeted pharmacological interventions. Methods and Results--We chronically treated obese Zucker rats with clinically relevant interventions against cardiovascular disease risk factors to determine impacts on vascular outcomes and depressive symptom severity. While most of the interventions (chronic exercise, anti-hypertensive, the interventions (long-term exercise, antihypertensive, antidyslipidemia, and antidiabetic) were differentially effective at improving vascular outcomes, only those that also resulted in a significant improvement to oxidant stress, inflammation, arachidonic acid metabolism (prostacyclin versus thromboxane A2), and their associated sequelae were effective at also blunting depressive symptom severity. Using multivariable analyses, discrimination between the effectiveness of treatment groups to maintain behavioral outcomes appeared to be dependent on breaking the cycle of inflammation and oxidant stress, with the associated outcomes of improving endothelial metabolism and both cerebral and peripheral vascular structure and function. Conclusions--This initial study provides a compelling framework from which to further interrogate the links between cardiovascular disease risk factors and depressive symptoms and suggests mechanistic links and potentially effective avenues for intervention

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 perivascularadipose tissue (tPVAT) phenotype (inflammation, oxidative stress, and proteasome function) in metabolic syn-drome and its subsequent actions on aortic function.Methods:Lean and obese (model of metabolic syndrome) Zucker rats (n=8/group) underwent 8-weeks ofcontrol conditions or treadmill exercise (70% of max speed, 1 h/day, 5 days/week). At the end of the inter-vention, the tPVAT was removed and conditioned media was made. The cleaned aorta was attached to a forcetransducer 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 wereassessed.Results:The mainfindings were that Ex induced: (1) a beige-like, anti-inflammatory tPVAT phenotype; (2) agreater abundance of•NO in tPVAT; (3) a reduction in tPVAT oxidant production; and (4) an improved tPVATproteasome function. Regarding aortic function, endothelium-dependent dilation was greater in exercised leanand obese groups vs. controls (p \u3c 0.05). Lean control tPVAT improved aortic relaxation, whereas obese controltPVAT decreased aortic relaxation. In contrast, the obese Ex-tPVAT increased aortic dilation, whereas the leanEx-tPVAT did not affect aortic dilation.Conclusion:Overall, exercise had the most dramatic impact on the obese tPVAT reflecting a change towards anenvironment with less oxidant load, less inflammation and improved proteasome function. Such beneficialchanges to the tPVAT micro-environment with exercise likely played a significant role in mediating the im-provement in aortic function in metabolic syndrome following 8 weeks of exercise

Role of Chronic Stress and Exercise on Microvascular Function in Metabolic Syndrome

Purpose—The present study examined the effect of unpredictable chronic mild stress (UCMS) on peripheral microvessel function in healthy and metabolic syndrome (MetS) rodents, and whether exercise training could prevent the vascular dysfunction associated with UCMS. Methods—Lean and obese (model of MetS) Zucker rats (LZR; OZR) were exposed to 8 weeks of UCMS, exercise (Ex), UCMS+Ex, or control conditions. At the end of the intervention, gracilis arterioles (GAs) were isolated and hung in a pressurized myobath to assess endotheliumdependent (EDD) and -independent (EID) dilation. Levels of nitric oxide (NO) and reactive oxygen species (ROS) were measured through DAF-FM and DHE staining, respectively. Results—Compared to LZR controls, EDD and EID was lower (p=0.0001) in LZR-UCMS. The OZR-Ex group had a higher EDD (p=0.0001) and EID (p=0.003), compared to OZR-Controls; whereas only a difference in EDD (p=0.01) was noted between LZR-Control and LZR-Ex groups. Importantly, EDD and EID were higher in the LZR (p=0.0001; p=0.02) and OZR (p=0.0001; p=0.02) UCMS+Ex groups compared to UCMS alone. Lower NO bioavailability and higher ROS were noted in the LZR-UCMS group (p=0.0001), but not OZR-UCMS, compared to controls. Ex and UCMS-Ex groups had higher NO bioavailability (p=0.0001) compared to control and UCMS groups, but ROS levels remained high. Conclusions—The comorbidity between UCMS and MetS does not exacerbate the effects of one another on GA EDD responses, but does lead to the development of other vasculopathy adaptations, which can be partially explained by alterations in NO and ROS production. Importantly, exercise training alleviates most of the negative effects of UCMS on GA function

Protection from vascular dysfunction in female rats with chronic stress and depressive symptoms

© 2018 the American Physiological Society. The increasing prevalence and severity of clinical depression are strongly correlated with vascular disease risk, creating a comorbid condition with poor outcomes but demonstrating a sexual disparity whereby female subjects are at lower risk than male subjects for subsequent cardiovascular events. To determine the potential mechanisms responsible for this protection against stress/ depression-induced vasculopathy in female subjects, we exposed male, intact female, and ovariectomized (OVX) female lean Zucker rats to the unpredictable chronic mild stress (UCMS) model for 8 wk and determined depressive symptom severity, vascular reactivity in ex vivo aortic rings and middle cerebral arteries (MCA), and the profile of major metabolites regulating vascular tone. While all groups exhibited severe depressive behaviors from UCMS, severity was significantly greater in female rats than male or OVX female rats. In all groups, endothelium-dependent dilation was depressed in aortic rings and MCAs, although myogenic activation and vascular (MCA) stiffness were not impacted. Higher-resolution results from pharmacological and biochemical assays suggested that vasoactive metabolite profiles were better maintained in female rats with normal gonadal sex steroids than male or OVX female rats, despite increased depressive symptom severity (i.e., higher nitric oxide and prostacyclin and lower H2O2 and thromboxane A2 levels). These results suggest that female rats exhibit more severe depressive behaviors with UCMS but are partially protected from the vasculopathy that afflicts male rats and female rats lacking normal sex hormone profiles. Determining how female sex hormones afford partial vascular protection from chronic stress and depression is a necessary step for addressing the burden of these conditions on cardiovascular health. NEW & NOTEWORTHY This study used a translationally relevant model for chronic stress and elevated depressive symptoms to determine how these factors impact conduit and resistance arteriolar function in otherwise healthy rats. While chronic stress leads to an impaired vascular reactivity associated with elevated oxidant stress, inflammation, and reduced metabolite levels, we demonstrated partial protection from vascular dysfunction in female rats with normal sex hormone profiles compared with male or ovariectomized female rats

Protection from chronic stress- and depressive symptom-induced vascular endothelial dysfunction in female rats is abolished by preexisting metabolic disease

© 2018 the American Physiological Society. While it is known that chronic stress and clinical depression are powerful predictors of poor cardiovascular outcomes, recent clinical evidence has identified correlations between the development of metabolic disease and depressive symptoms, creating a combined condition of severely elevated cardiovascular disease risk. In this study, we used the obese Zucker rat (OZRs) and the unpredictable chronic mild stress (UCMS) model to determine the impact of preexisting metabolic disease on the relationship between chronic stress/depressive symptoms and vascular function. Additionally, we determined the impact of metabolic syndrome on sex-based protection from chronic stress/depressive effects on vascular function in female lean Zucker rats (LZRs). In general, vasodilator reactivity was attenuated under control conditions in OZRs compared with LZRs. Although still impaired, conduit arterial and resistance arteriolar dilator reactivity under control conditions in female OZRs was superior to that in male or ovariectomized (OVX) female OZRs, largely because of better maintenance of vascular nitric oxide and prostacyclin levels. However, imposition of metabolic syndrome in combination with UCMS in OZRs further impaired dilator reactivity in both vessel subtypes to a similarly severe extent and abolished any protective effect in female rats compared with male or OVX female rats. The loss of vascular protection in female OZRs with UCMS was reflected in vasodilator metabolite levels, which closely matched those in male and OVX female OZRs subjected to UCMS. These results suggest that presentation of metabolic disease in combination with depressive symptoms can overwhelm the vasoprotection identified in female rats and, thereby, may reflect a severe impairment to normal endothelial function. NEW & NOTEWORTHY This study addresses the protection from chronic stress- and depression-induced vascular dysfunction identified in female compared with male or ovariectomized female rats. We determined the impact of preexisting metabolic disease, a frequent comorbidity of clinical depression in humans, on that vascular protection. With preexisting metabolic syndrome, female rats lost all protection from chronic stress/depressive symptoms and became phenotypically similar to male and ovariectomized female rats, with comparably poor vasoactive dilator metabolite profiles