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One of the growing challenges to public health and clinical outcomes is the emergence of cognitive impairments, particularly depressive symptom severity, because of chronic elevations in metabolic disease and cerebrovascular disease risk. To more clearly delineate these relationships and to assess the potential for sexual dimorphism, we used lean (LZR) and obese Zucker rats (OZR) of increasing age to determine relationships between internal carotid artery (ICA) hemodynamics, cerebral vasculopathies, and the emergence of depressive symptoms. Male OZR exhibited progressive elevations in perfusion pressure within the ICA, which were paralleled by endothelial dysfunction, increased cerebral arterial myogenic activation, and reduced cerebral cortex microvessel density. In contrast, female OZR exhibited a greater degree of ICA hypertension than male OZR but maintained normal endothelial function, myogenic activation, and microvessel density to an older age range than did males. Although both male and female OZR exhibited significant and progressive elevations in depressive symptom severity, these were significantly worse in females. Finally, plasma cortisol concentration was elevated higher and at a younger age in female OZR as compared with males, and this difference was maintained to final animal usage at ∼17 wk of age. These results suggest that an increased severity of blood pressure waves may penetrate the cerebral circulation more deeply in female OZR than in males, which may predispose the females to a more severe emergence of depressive symptoms with chronic metabolic disease, whereas males may be more predisposed to more direct cerebral vasculopathies (e.g., stroke, transient ischemic attack). NEW & NOTEWORTHY We provide novel insight that the superior maintenance of cerebrovascular endothelial function in female versus male rats with chronic metabolic disease buffers myogenic activation of cerebral resistance arteries/arterioles despite worsening hypertension. As hypertension development is earlier and more severe in females, potentially due to an elevated stress response, the blunted myogenic activation allows greater arterial pressure wave penetrance into the cerebral microcirculation and is associated with accelerated emergence/severity of depressive symptoms in obese female rats.

Introduction: A full understanding of the integration of the mechanisms of vascular tone regulation requires an interrogation of the temporal behavior of arterioles across vasoactive challenges. Building on previous work, the purpose of the present study was to start to interrogate the temporal nature of arteriolar tone regulation with physiological stimuli., Methods: We determined the response rate of ex vivo proximal and in situ distal resistance arterioles when challenged by one-, two-, and three-parameter combinations of five major physiological stimuli (norepinephrine, intravascular pressure, oxygen, adenosine [metabolism], and intralumenal flow). Predictive machine learning models determined which factors were most influential in controlling the rate of arteriolar responses., Results: Results indicate that vascular response rate is dependent on the intensity of the stimulus used and can be severely hindered by altered environments, caused by application of secondary or tertiary stimuli. Advanced analytics suggest that adrenergic influences were dominant in predicting proximal arteriolar response rate compared to metabolic influences in distal arterioles., Conclusion: These data suggest that the vascular response rate to physiologic stimuli can be strongly influenced by the local environment. Translating how these effects impact vascular networks is imperative for understanding how the microcirculation appropriately perfuses tissue across conditions., (© 2024 S. Karger AG, Basel.)

Cancer, a multifactorial disease characterized by uncontrolled cellular proliferation, remains a global health challenge with significant morbidity and mortality. Genomic and molecular aberrations, coupled with environmental factors, contribute to its heterogeneity and complexity. Chemotherapeutic agents like doxorubicin (Dox) have shown efficacy against various cancers but are hindered by dose-dependent cytotoxicity, particularly on vital organs like the heart and brain. Autophagy, a cellular process involved in self-degradation and recycling, emerges as a promising therapeutic target in cancer therapy and neurodegenerative diseases. Dysregulation of autophagy contributes to cancer progression and drug resistance, while its modulation holds the potential to enhance treatment outcomes and mitigate adverse effects. Additionally, emerging evidence suggests a potential link between autophagy, DNA damage, and caretaker breast cancer genes BRCA1/2, highlighting the interplay between DNA repair mechanisms and cellular homeostasis. This review explores the intricate relationship between cancer, Dox-induced cytotoxicity, autophagy modulation, and the potential implications of autophagy in DNA damage repair pathways, particularly in the context of BRCA1/2 mutations.

Under different pathophysiological conditions, endothelial cells lose endothelial phenotype and gain mesenchymal cell-like phenotype via a process known as endothelial-to-mesenchymal transition (EndMT). At the molecular level, endothelial cells lose the expression of endothelial cell-specific markers such as CD31/platelet-endothelial cell adhesion molecule, von Willebrand factor, and vascular-endothelial cadherin and gain the expression of mesenchymal cell markers such as α-smooth muscle actin, N-cadherin, vimentin, fibroblast specific protein-1, and collagens. EndMT is induced by numerous different pathways triggered and modulated by multiple different and often redundant mechanisms in a context-dependent manner depending on the pathophysiological status of the cell. EndMT plays an essential role in embryonic development, particularly in atrioventricular valve development; however, EndMT is also implicated in the pathogenesis of several genetically determined and acquired diseases, including malignant, cardiovascular, inflammatory, and fibrotic disorders. Among cardiovascular diseases, aberrant EndMT is reported in atherosclerosis, pulmonary hypertension, valvular disease, fibroelastosis, and cardiac fibrosis. Accordingly, understanding the mechanisms behind the cause and/or effect of EndMT to eventually target EndMT appears to be a promising strategy for treating aberrant EndMT-associated diseases. However, this approach is limited by a lack of precise functional and molecular pathways, causes and/or effects, and a lack of robust animal models and human data about EndMT in different diseases. Here, we review different mechanisms in EndMT and the role of EndMT in various cardiovascular diseases.

Although existing literature supports associations between cerebrovascular dysfunction and the emergence of depression and depressive symptoms, relatively little is known about underlying mechanistic pathways that may explain potential relationships. As such, an integrated understanding of these relationships in preclinical models could provide insight into the nature of the relationship, basic mechanistic linkages, and areas in which additional investment should be targeted. This scoping review was conducted in MEDLINE, EMBASE, and Scopus to outline the relationship between depressive symptoms and cerebrovascular dysfunction in preclinical animal models with an additional focus on the areas above. From 3,438 articles initially identified, 15 studies met the inclusion criteria and were included in the review. All studies reported a positive association between the severity of markers for cerebrovascular dysfunction and that for depressive symptoms in rodent models and this spanned all models for either pathology. Specific mechanistic links between the two such as chronic inflammation, elevated vascular oxidant stress, and altered serotonergic signaling were highlighted. Notably, almost all studies addressed outcomes in male animals, with a near complete lack of data from females, and there was little consistency in terms of how cerebrovascular dysfunction was assessed. Across nearly all studies was a lack of clarity for any "cause and effect" relationship between depressive symptoms and cerebrovascular dysfunction. At this time, it is reasonable to conclude that a correlative relationship clearly exists between the two, and future investigation will be required to parse out more specific aspects of this relationship. NEW & NOTEWORTHY This scoping review presents a structured evaluation of all relevant existing literature linking cerebral vasculopathy to depressive symptom emergence in preclinical models. Results support a definite connection between vascular dysfunction and depressive symptoms, highlighting the importance of chronic elevations in inflammation and oxidant stress, and impaired serotonergic signaling. The review also identified significant knowledge gaps addressing male versus female differences and limited clear mechanistic links between cerebral vasculopathy and depressive symptoms.

Blood flow regulation within the microvasculature reflects a complex interaction of regulatory mechanisms and varies spatially and temporally according to conditions such as metabolism, growth, injury, and disease. Understanding the role of microvascular flow distributions across conditions is of interest to investigators spanning multiple disciplines; however, data collection within networks can be labor-intensive and challenging due to limited resolution. To overcome these experimental challenges, computational network models that can accurately simulate vascular behavior are highly beneficial. Constrained constructive optimization (CCO) is a commonly used algorithm for vascular simulation, particularly well known for its adaptability toward vascular modeling across tissues. The present work demonstrates an implementation of CCO aimed to simulate a branching arteriolar microvasculature in healthy skeletal muscle, validated against literature including comprehensive rat gluteus maximus vasculature datasets, and reviews a list of user-specified adjustable model parameters to understand how their variability affects the simulated networks. Network geometric properties, including mean element diameters, lengths, and numbers of bifurcations per order, Horton's law ratios, and fractal dimension, demonstrate good validation once model parameters are adjusted to experimental data. This model successfully demonstrates hemodynamic properties such as Murray's law and the network Fahraeus effect. Application of centrifugal and Strahler ordering schemes results in divergent descriptions of identical simulated networks. This work introduces a novel CCO-based model focused on generating branching skeletal muscle microvascular arteriolar networks based on adjustable model parameters, thus making it a valuable tool for investigations into skeletal muscle microvascular structure and tissue perfusion. NEW & NOTEWORTHY The present work introduces a CCO-based algorithm for generating branching arteriolar networks, with adjustable model parameters to enable modeling in varying skeletal muscle tissues. The geometric and hemodynamic parameters of the generated networks have been comprehensively validated using experimental data collected previously in-house and from literature. This is one of few validated CCO-based models to specialize in skeletal muscle microvasculature and acts as a beneficial tool for investigating the microvasculature for hypothesis testing and validation.

Endothelial autophagy plays an important role in the regulation of endothelial function. The inhibition of endothelial autophagy is associated with the reduced expression of protein disulfide isomerase 4 ( PDIA-4 ); however, its role in endothelial cells is not known. Here, we report that endothelial cell-specific loss of PDIA-4 leads to impaired autophagic flux accompanied by loss of endothelial function and apoptosis. Endothelial cell-specific loss of PDIA-4 also induced marked changes in endothelial cell architecture, accompanied by the loss of endothelial markers and the gain of mesenchymal markers consistent with endothelial-to-mesenchymal transition (EndMT). The loss of PDIA-4 activated TGFβ-signaling, and inhibition of TGFβ-signaling suppressed EndMT in PDIA-4 -silenced endothelial cells in vitro. Our findings help elucidate the role of PDIA-4 in endothelial autophagy and endothelial function and provide a potential target to modulate endothelial function and/or limit autophagy and EndMT in (patho-)physiological conditions.

Introduction: Acquisition of a deeper understanding of microvascular function across physiological and pathological conditions can be complicated by poor accessibility of the vascular networks and the necessary sophistication or intrusiveness of the equipment needed to acquire meaningful data. Laser Doppler fluximetry (LDF) provides a mechanism wherein investigators can readily acquire large amounts of data with minor inconvenience for the subject. However, beyond fairly basic analyses of erythrocyte perfusion (fluximetry) data within the cutaneous microcirculation (i.e., perfusion at rest and following imposed challenges), a deeper understanding of microvascular perfusion requires a more sophisticated approach that can be challenging for many investigators., Methods: This manuscript provides investigators with clear guidance for data acquisition from human subjects for full analysis of fluximetry data, including levels of perfusion, single- and multiscale Lempel-Ziv complexity (LZC) and sample entropy (SampEn), and wavelet-based analyses for the major physiological components of the signal. Representative data and responses are presented from a recruited cohort of healthy volunteers, and computer codes for full data analysis (MATLAB) are provided to facilitate efforts by interested investigators., Conclusion: It is anticipated that these materials can reduce the challenge to investigators integrating these approaches into their research programs and facilitate translational research in cardiovascular science., (© 2024 S. Karger AG, Basel.)

Background: Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide. Arteriolar tone regulation plays a critical role in maintaining appropriate organ blood flow and perfusion distribution, which is vital for both vascular and overall health., Summary: This scoping review aimed to explore the interplay between five major regulators of arteriolar tone: metabolism (adenosine), adrenergic control (norepinephrine), myogenic activation (intravascular pressure), perivascular oxygen tension, and intraluminal flow rates. Specifically, the aim was to address how arteriolar reactivity changes in the presence of other vasoactive stimuli and by what mechanisms. The review focused on animal studies that investigated the impact of combining two or more of these stimuli on arteriolar diameter. Overall, 848 articles were identified through MEDLINE and EMBASE database searches, and 38 studies were included in the final review., Key Messages: The results indicate that arteriolar reactivity is influenced by multiple factors, including competitive processes, structural limitations, and indirect interactions among stimuli. Additionally, the review identified a lack of research involving female animal models and limited insight into the interaction of molecular signaling pathways, which represent gaps in the literature., (© 2023 S. Karger AG, Basel.)

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 A 2 (TxA 2 ). 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 TxA 2 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 TxA 2 production. Anti-TxA 2 interventions prevasculopathy blunted rarefaction and depressive symptoms, while biosimulation indicated that cerebrovascular rarefaction increased hypoxia within capillary networks as a potential contributing mechanism.

Circulating fatty acid-binding protein 3 (FABP3) is an effective biomarker of myocardial injury and peripheral artery disease (PAD). The endothelium, which forms the inner most layer of every blood vessel, is exposed to higher levels of FABP3 in PAD or following myocardial injury, but the pathophysiological role of endothelial FABP3, the effect of FABP3 exposure on endothelial cells, and related mechanisms are unknown. Here, we aimed to evaluate the pathophysiological role of endothelial FABP3 and related mechanisms in vitro. Our molecular and functional in vitro analyses show that (1) FABP3 is basally expressed in endothelial cells; (2) inflammatory stress in the form of lipopolysaccharide (LPS) upregulated endothelial FABP3 expression; (3) loss of endogenous FABP3 protected endothelial cells against LPS-induced endothelial dysfunction; however, exogenous FABP3 exposure exacerbated LPS-induced inflammation; (4) loss of endogenous FABP3 protected against LPS-induced endothelial dysfunction by promoting cell survival and anti-inflammatory and pro-angiogenic signaling pathways. Together, these findings suggest that gain-of endothelial FABP3 exacerbates, whereas loss-of endothelial FABP3 inhibits LPS-induced endothelial dysfunction by promoting cell survival and anti-inflammatory and pro-angiogenic signaling. We propose that an increased circulating FABP3 in myocardial injury or PAD patients may be detrimental to endothelial function, and therefore, therapies aimed at inhibiting FABP3 may improve endothelial function in diseased states., Competing Interests: Conflict of interest The authors declare no conflict of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Menon, Halvorson, Alimorad, Frisbee, Lizotte, Ward, Goldman, Chantler and Frisbee.)

Introduction: Physiological system complexity represents an imposing challenge to gaining insight into how arteriolar behavior emerges. Further, mechanistic complexity in arteriolar tone regulation requires that a systematic determination of how these processes interact to alter vascular diameter be undertaken., Methods: The present study evaluated the reactivity of ex vivo proximal and in situ distal resistance arterioles in skeletal muscle with challenges across the full range of multiple physiologically relevant stimuli and determined the stability of responses over progressive alterations to each other parameter. The five parameters chosen for examination were (1) metabolism (adenosine concentration), (2) adrenergic activation (norepinephrine concentration), (3) myogenic activation (intravascular pressure), (4) oxygen (superfusate PO2), and (5) wall shear rate (altered intraluminal flow). Vasomotor tone of both arteriole groups following challenge with individual parameters was determined; subsequently, responses were determined following all two- and three-parameter combinations to gain deeper insight into how stimuli integrate to change arteriolar tone. A hierarchical ranking of stimulus significance for establishing arteriolar tone was performed using mathematical and statistical analyses in conjunction with machine learning methods., Results: Results were consistent across methods and indicated that metabolic and adrenergic influences were most robust and stable across all conditions. While the other parameters individually impact arteriolar tone, their impact can be readily overridden by the two dominant contributors., Conclusion: These data suggest that mechanisms regulating arteriolar tone are strongly affected by acute changes to the local environment and that ongoing investigation into how microvessels integrate stimuli regulating tone will provide a more thorough understanding of arteriolar behavior emergence across physiological and pathological states., (© 2023 S. Karger AG, Basel.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Menon, Halvorson, Alimorad, Frisbee, Lizotte, Ward, Goldman, Chantler and Frisbee.)

Background: Although there is scientific literature supporting an association between depression and preeclampsia (PE), little is known about the underlying mechanistic pathways that may explain these observed associations. Thus, this study aimed to outline the relationship between depression and PE, and to highlight the underlying cardiovascular and metabolic risk factors that are common to both., Methods: A scoping review of the literature was conducted in Medline, Scopus, and Web of Science., Results: From 706 articles initially identified, 23 articles met the inclusion criteria and were included in this review. Although some studies reported a positive association between PE and postpartum depressive symptoms, challenges comparing different methodologies, measurement instruments and when measurements were administered, and patient populations do not permit a decisive conclusion. In addition, very few studies addressed potential underlying mechanisms that may be contributing to observed associations; thus, a secondary search was conducted to identify cardiovascular and metabolic risk factors that are common to both depression and PE., Conclusion: The cardiovascular and metabolic risk factors ( i.e., increased inflammation and oxidative stress and decreased vascular and endothelial function) common to both depression and PE suggest that these factors may contribute as underlying mechanisms in both conditions. These similarities underscore the importance to better understand these mechanisms so preventative and therapeutic strategies could be developed to improve maternal health., Competing Interests: All the authors are members of the University of Western Ontario and have no competing interests to declare., (© Mei Yuan et al., 2022; Published by Mary Ann Liebert, Inc.)

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 O 2 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.

Background: Despite well-established efficacy for patients with a cardiovascular diagnosis or event, exercise-based cardiac rehabilitation program participation and completion has remained alarmingly low due to both system-level barriers and patient-level factors. Patient mental health, particularly depression, is now recognized as significantly associated with reduced enrollment, participation, attendance, and completion of a cardiac rehabilitation program. More recently, anxiety sensitivity has emerged as an independent construct, related to but distinct from both depression and anxiety. Anxiety sensitivity has been reported to be adversely associated with participation in exercise and, thus, may be important for patients in cardiac rehabilitation. Accordingly, the objective of this study was to conduct a scoping review to summarize the evidence for associations between anxiety sensitivity and cardiovascular disease risk factors, exercise, and clinical outcomes in cardiac rehabilitation., Methods: A formal scoping review, following PRISMA-ScR guidelines, was undertaken. Searches of MEDLINE, Web of Science, CINAHL, PSYCINFO, and Scopus databases were conducted, supplemented by hand searches; studies published through December of 2020 were included. The initial screening was based on titles and abstracts and the second stage of screening was based on full text examination., Results: The final search results included 28 studies. Studies reported statistically significant associations between anxiety sensitivity and exercise, cardiovascular disease, and participation in cardiac rehabilitation. Many studies, however, were conducted in non-clinical, community-based populations; there were few studies conducted in cardiovascular disease and cardiac rehabilitation clinical patient populations. Additionally, significant gaps remain in our understanding of the sex-based differences in the complex relationships between anxiety sensitivity, exercise and cardiac rehabilitation., Conclusion: More research is needed to understand specific associations between anxiety sensitivity and clinical outcomes among clinical cardiovascular disease patients and participants in cardiac rehabilitation programs. Treatment of anxiety sensitivity to optimize clinical outcomes in cardiac rehabilitation programs should be investigated in future studies., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors. Published by Elsevier B.V.)

Metabolic syndrome (MetS) is a complex pathological state consisting of metabolic risk factors such as hypertension, insulin resistance, and obesity. The interconnectivity of cellular pathways within various biological systems suggests that each individual component of MetS may share common pathological sources. Additionally, MetS is closely associated with vasculopathy, including a reduction in microvessel density (MVD) (rarefaction) and elevated risk for various cardiovascular diseases. Microvascular impairments may contribute to perfusion-demand mismatch, where local metabolic needs are insufficiently met due to the lack of nutrient and oxygen supply, thus creating pathological positive-feedback loops and furthering the progression of disease. Sexual dimorphism is evident in these underlying cellular mechanisms, which places males and females at different levels of risk for cardiovascular disease and acute ischemic events. Estrogen exhibits protective effects on the endothelium of pre-menopausal women, while androgens may be antagonistic to cardiovascular health. This review examines MetS and its influences on MVD, as well as sex differences relating to the components of MetS and cardiovascular risk profiles. Finally, translational relevance and interventions are discussed in the context of these sex-based differences., (© 2021 S. Karger AG, Basel.)

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., (© 2021 The Authors. Experimental Physiology © 2021 The Physiological Society.)

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., (© 2021 S. Karger AG, Basel.)

New Findings: What is the topic of this review? Altered perfusion distribution at skeletal muscle arteriolar bifurcations and how this is modified by development of chronic metabolic disease. What advances does it highlight? The outcome created is a distribution of erythrocytes in the distal microcirculation that is characterized by increased spatial heterogeneity and reduced flexibility such that mass transport/exchange within the network is impaired, with limited ability to respond to imposed challenges. This advances our understanding of how altered vascular structure and function with metabolic disease impairs perfusion to skeletal muscle at a level of resolution that would not be identified through bulk flow responses., Abstract: This review is based on the presentation 'Shifted vascular optimization: the emergence of a new arteriolar behaviour with chronic metabolic disease', given at the Symposium 'Understanding Complex Behaviours in the Microcirculation: from Blood Flow to Oxygenation' during the Annual Meeting of the Physiological Society at the Aberdeen Exhibition and Conference Centre in Aberdeen, UK in July 2019. The past years of dedicated investigation on linkages between vascular (dys)function under conditions of elevated cardiovascular disease risk and tissue/organ performance have produced results and insights that frequently suffer from limited correlation and causation. Reaching out from this challenge, it was proposed that this may reflect a 'level of resolution' argument and that altered haemodynamic behaviour in vascular networks could be a stronger predictor of functional outcomes than higher resolution measures. Using this approach, we have determined that an attractor that describes the spatial and temporal shift in perfusion distribution at successive arteriolar bifurcations within the skeletal muscle is a strong predictor of functional outcomes within animals and provides novel insight into fundamental mechanistic contributors to altered patterns of intra-muscular perfusion. This article focuses on the applicability and utility of the attractor in models of cardiovascular and metabolic disease risk of increasing severity. We will also discuss the utility of the attractor in terms of understanding the effectiveness of aggressive interventions for reversing established vasculopathy and perfusion impairments., (© 2020 The Authors. Experimental Physiology © 2020 The Physiological Society.)

Type 2 diabetes (T2D) is a growing health concern with nearly 400 million affected worldwide as of 2014. T2D presents with hyperglycemia and insulin resistance resulting in increased risk for blindness, renal failure, nerve damage, and premature death. Skeletal muscle is a major site for insulin resistance and is responsible for up to 80% of glucose uptake during euglycemic hyperglycemic clamps. Glucose uptake in skeletal muscle is driven by mitochondrial oxidative phosphorylation and for this reason mitochondrial dysfunction has been implicated in T2D. In this review we integrate mitochondrial function with physiologic function to present a broader understanding of mitochondrial functional status in T2D utilizing studies from both human and rodent models. Quantification of mitochondrial function is explained both in vitro and in vivo highlighting the use of proper controls and the complications imposed by obesity and sedentary lifestyle. This review suggests that skeletal muscle mitochondria are not necessarily dysfunctional but limited oxygen supply to working muscle creates this misperception. Finally, we propose changes in experimental design to address this question unequivocally. If mitochondrial function is not impaired it suggests that therapeutic interventions and drug development must move away from the organelle and toward the cardiovascular system.

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., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Type 2 diabetes (T2D) presents with hyperglycemia and insulin resistance, affecting over 30 million people in the United States alone. Previous work has hypothesized that mitochondria are dysfunctional in T2D and results in both reduced ATP production and glucose disposal. However, a direct link between mitochondrial function and T2D has not been determined. In the current study, the Goto-Kakizaki (GK) rat model of T2D was used to quantify mitochondrial function in vitro and in vivo over a broad range of contraction-induced metabolic workloads. During high-frequency sciatic nerve stimulation, hindlimb muscle contractions at 2- and 4-Hz intensities, the GK rat failed to maintain similar bioenergetic steady states to Wistar control (WC) rats measured by phosphorus magnetic resonance spectroscopy, despite similar force production. Differences were not due to changes in mitochondrial content in red (RG) or white gastrocnemius (WG) muscles (cytochrome c oxidase, RG: 22.2 ± 1.6 vs. 23.3 ± 1.7 U/g wet wt; WG: 10.8 ± 1.1 vs. 12.1 ± 0.9 U/g wet wt; GK vs. WC, respectively). Mitochondria isolated from muscles of GK and WC rats also showed no difference in mitochondrial ATP production capacity in vitro, measured by high-resolution respirometry. At lower intensities (0.25-1 Hz) there were no detectable differences between GK and WC rats in sustained energy balance. There were similar phosphocreatine concentrations during steady-state contraction and postcontractile recovery (τ = 72 ± 6 s GK versus 71 ± 2 s WC). Taken together, these results suggest that deficiencies in skeletal muscle energetics seen at higher intensities are not due to mitochondrial dysfunction in the GK rat.

Type 2 diabetes mellitus (T2DM) is a prevalent pathology associated with elevated cerebrovascular disease risk. We determined wall mechanics and vascular reactivity in ex vivo middle cerebral arteries (MCA) from male Goto-Kakizaki rats (GK; ~17 wk old) versus control Wistar Kyoto rats (WKY) to test the hypothesis that the diabetic environment in GK, in the absence of obesity and other comorbidities, leads to endothelial dysfunction and impaired vascular tone regulation. Dilation of MCA following challenge with acetylcholine and hypoxia was blunted in MCA from GK versus WKY, due to lower nitric oxide bioavailability and altered arachidonic acid metabolism, whereas myogenic activation and constrictor responses to serotonin were unchanged. MCA wall distensibility and cross-sectional area were not different between GK and WKY, suggesting that wall mechanics were unchanged at this age, supported by the determination that MCA dilation to sodium nitroprusside was also intact. With the use of ex vivo aortic rings as a bioassay, altered vascular reactivity determined in MCA was paralleled by relaxation responses in artery segments from GK, whereas measurements of vasoactive metabolite production indicated a loss of nitric oxide and prostacyclin bioavailability and an increased thromboxane A 2 production with both methacholine challenge and hypoxia. These results suggest that endothelium-dependent dilator reactivity of MCA in GK is impaired with T2DM, and that this impairment is associated with the genesis of a prooxidant/pro-inflammatory condition with diabetes mellitus. The restriction of vascular impairments to endothelial function only, at this age and development, provide insight into the severity of multimorbid conditions of which T2DM is only one constituent.

One of the clearly established health outcomes associated with chronic metabolic diseases (eg, type II diabetes mellitus) is that the ability of skeletal muscle to maintain contractile performance during periods of elevated metabolic demand is compromised as compared to the fatigue-resistance of muscle under normal, healthy conditions. While there has been extensive effort dedicated to determining the major factors that contribute to the compromised performance of skeletal muscle with chronic metabolic disease, the extent to which this poor outcome reflects a dysfunctional state of the microcirculation, where the delivery and distribution of metabolic substrates can be impaired, versus derangements to normal metabolic processes and mitochondrial function, versus a combination of the two, represents an area of considerable unknown. The purpose of this manuscript is to present some of the current concepts for dysfunction to both the microcirculation of skeletal muscle as well as to mitochondrial metabolism under these conditions, such that these diverse issues can be merged into an integrated framework for future investigation. Based on an interpretation of the current literature, it may be hypothesized that the primary site of dysfunction with earlier stages of metabolic disease may lie at the level of the vasculature, rather than at the level of the mitochondria., (© 2018 John Wiley & Sons Ltd.)

Despite extensive investigation into the impact of metabolic disease on vascular function and, by extension, tissue perfusion and organ function, interpreting results for specific risk factors can be complicated by the additional risks present in most models. To specifically determine the impact of type 2 diabetes without obesity on skeletal muscle microvascular structure/function and on active hyperemia with elevated metabolic demand, we used 17-wk-old Goto-Kakizaki (GK) rats to study microvascular function at multiple levels of resolution. Gracilis muscle arterioles demonstrated blunted dilation to acetylcholine (both ex vivo proximal and in situ distal arterioles) and elevated shear (distal arterioles only). All other alterations to reactivity appeared to reflect compromised endothelial function associated with increased thromboxane (Tx)A 2 production and oxidant stress/inflammation rather than alterations to vascular smooth muscle function. Structural changes to the microcirculation of GK rats were confined to reduced microvessel density of ~12%, with no evidence for altered vascular wall mechanics. Active hyperemia with either field stimulation of in situ cremaster muscle or electrical stimulation via the sciatic nerve for in situ gastrocnemius muscle was blunted in GK rats, primarily because of blunted functional dilation of skeletal muscle arterioles. The blunted active hyperemia was associated with impaired oxygen uptake (V̇o 2 ) across the muscle and accelerated muscle fatigue. Acute interventions to reduce oxidant stress (TEMPOL) and TxA 2 action (SQ-29548) or production (dazmegrel) improved muscle perfusion, V̇o 2 , and muscle performance. These results suggest that type 2 diabetes mellitus in GK rats impairs skeletal muscle arteriolar function apparently early in the progression of the disease and potentially via an increased reactive oxygen species/inflammation-induced TxA 2 production/action on network function as a major contributing mechanism. NEW & NOTEWORTHY The impact of type 2 diabetes mellitus on vascular structure/function remains an area lacking clarity. Using diabetic Goto-Kakizaki rats before the development of other risk factors, we determined alterations to vascular structure/function and skeletal muscle active hyperemia. Type 2 diabetes mellitus reduced arteriolar endothelium-dependent dilation associated with increased thromboxane A 2 generation. Although modest microvascular rarefaction was evident, there were no other alterations to vascular structure/function. Skeletal muscle active hyperemia was blunted, although it improved after antioxidant or anti-thromboxane A 2 treatment.

It has long been known that chronic metabolic disease is associated with a parallel increase in the risk for developing peripheral vascular disease. Although more clinically relevant, our understanding about reversing established vasculopathy is limited compared with our understanding of the mechanisms and development of impaired vascular structure/function under these conditions. Using the 13-wk-old obese Zucker rat (OZR) model of metabolic syndrome, where microvascular dysfunction is sufficiently established to contribute to impaired skeletal muscle function, we imposed a 7-wk intervention of chronic atorvastatin treatment, chronic treadmill exercise, or both. By 20 wk of age, untreated OZRs manifested a diverse vasculopathy that was a central contributor to poor muscle performance, perfusion, and impaired O 2 exchange. Atorvastatin or exercise, with the combination being most effective, improved skeletal muscle vascular metabolite profiles (i.e., nitric oxide, PGI 2 , and thromboxane A 2 bioavailability), reactivity, and perfusion distribution at both individual bifurcations and within the entire microvascular network versus responses in untreated OZRs. However, improvements to microvascular structure (i.e., wall mechanics and microvascular density) were less robust. The combination of the above improvements to vascular function with interventions resulted in an improved muscle performance and O 2 transport and exchange versus untreated OZRs, especially at moderate metabolic rates (3-Hz twitch contraction). These results suggest that specific interventions can improve specific indexes of function from established vasculopathy, but either this process was incomplete after 7-wk duration or measures of vascular structure are either resistant to reversal or require better-targeted interventions. NEW & NOTEWORTHY We used atorvastatin and/or chronic exercise to reverse established microvasculopathy in skeletal muscle of rats with metabolic syndrome. With established vasculopathy, atorvastatin and exercise had moderate abilities to reverse dysfunction, and the combined application of both was more effective at restoring function. However, increased vascular wall stiffness and reduced microvessel density were more resistant to reversal. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/reversal-of-microvascular-dysfunction/ .

This study used an anaesthetized rat model to directly observe changes in diameter of the vessels supplying the sciatic nerve in response to acetylcholine (10 -4 M), a muscarinic receptor agonist, and atropine (10 -5 M), a muscarinic receptor antagonist. Topical application of acetylcholine resulted in increases in vessel diameter (baseline: 22.0 ± 2.5 μm, acetylcholine: 28.8 ± 3.3 μm), while topical application of atropine resulted in a decrease in diameter (baseline: 26.6 ± 3.2 μm, atropine: 15.5 ± 3.6 μm) of the epineurial vessels. Mean arterial pressure was not affected by either acetylcholine (baseline: 103.8 ± 1.8 mm Hg, acetylcholine: 102.8 ± 3.2 mm Hg) or atropine (baseline: 104.0 ± 1.9 mm Hg, atropine: 105.2 ± 2.2 mm Hg). These data suggest that muscarinic-receptor-mediated responses can affect the diameter of the epineurial vessels at the sciatic nerve. In addition, muscarinic-receptor-mediated responses appear to contribute to baseline diameter of epineurial vessels at the sciatic nerve.

Prediabetes is associated with impaired contraction-evoked dilation of skeletal muscle arterioles, which may be due to increased sympathetic activity accompanying this early stage of diabetes disease. Herein, we sought to determine whether blunted contraction-evoked vasodilation resulted from enhanced sympathetic neuropeptide Y1 receptor (Y1R) and alpha-1 adrenergic receptor (α1R) activation. Using intravital video microscopy, second-, third-, and fourth-order (2A, 3A, and 4A) arteriolar diameters were measured before and following electrical field stimulation of the gluteus maximus muscle (GM) in prediabetic (PD, Pound Mouse) and control (CTRL, c57bl6, CTRL) mice. Baseline diameter was similar between groups; however, single tetanic contraction (100 Hz; 400 and 800 msec) and sustained rhythmic contraction (2 and 8 Hz, 30 sec) evoked rapid onset vasodilation and steady-state vasodilatory responses that were blunted by 50% or greater in PD versus CTRL. Following Y1R and α1R blockade with sympathetic antagonists BIBP3226 and prazosin, contraction-evoked arteriolar dilation in PD was restored to levels observed in CTRL. Furthermore, arteriolar vasoconstrictor responses to NPY (10 -13 -10 -8  mol/L) and PE (10 -9 -10 -5  mol/L) were greater in PD versus CTRL at higher concentrations, especially at 3A and 4A. These findings suggest that contraction-evoked vasodilation in PD is blunted by Y1R and α1R receptor activation throughout skeletal muscle arteriolar networks., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

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 and OZR) were exposed to 8 wk of UCMS, exercise (Ex), UCMS + Ex, or control conditions. At the end of the intervention, gracilis arterioles (GA) were isolated and hung in a pressurized myobath to assess endothelium-dependent (EDD) and endothelium-independent (EID) dilation. Levels of nitric oxide (NO) and reactive oxygen species (ROS) were measured through 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate and dihydroethidium staining, respectively., Results: Compared with LZR controls, EDD and EID were lower (P = 0.0001) in LZR-UCMS. The OZR-Ex group had a higher EDD (P = 0.0001) and EID (P = 0.003) compared with OZR controls, whereas only a difference in EDD (P = 0.01) was noted between the 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 with UCMS alone. Lower NO bioavailability and higher ROS were noted in the LZR-UCMS group (P = 0.0001), but not OZR-UCMS, compared with controls. The Ex and UCMS-Ex groups had higher NO bioavailability (P = 0.0001) compared with the 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.

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 H 2 O 2 and thromboxane A 2 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.

New Findings: What is the central question of this study? How does chronic stress impact cerebrovascular function and does metabolic syndrome accelerate the cerebrovascular adaptations to stress? What role does exercise training have in preventing cerebrovascular changes to stress and metabolic syndrome? What is the main finding and its importance? Stressful conditions lead to pathological adaptations of the cerebrovasculature via an oxidative nitric oxide pathway, and the presence of metabolic syndrome produces a greater susceptibility to stress-induced cerebrovascular dysfunction. The results also provide insight into the mechanisms that may contribute to the influence of stress and the role of exercise in preventing the negative actions of stress on cerebrovascular function and structure., Abstract: Chronic unresolvable stress leads to the development of depression and cardiovascular disease. There is a high prevalence of depression with the metabolic syndrome (MetS), but to what extent the MetS concurrent with psychological stress affects cerebrovascular function is unknown. We investigated the differential effect of MetS on cerebrovascular structure/function in rats (16-17 weeks old) following 8 weeks of unpredictable chronic mild stress (UCMS) and whether exercise training could limit any cerebrovascular dysfunction. In healthy lean Zucker rats (LZR), UCMS decreased (28%, P < 0.05) ex vivo middle cerebral artery (MCA) endothelium-dependent dilatation (EDD), but changes in MCA remodelling and stiffness were not evident, though cerebral microvessel density (MVD) decreased (30%, P < 0.05). The presence of UCMS and MetS (obese Zucker rats; OZR) decreased MCA EDD (35%, P < 0.05) and dilatation to sodium nitroprusside (20%, P < 0.05), while MCA stiffness increased and cerebral MVD decreased (31%, P < 0.05), which were linked to reduced nitric oxide and increased oxidative levels. Aerobic exercise prevented UCMS impairments in MCA function and MVD in LZR, and partly restored MCA function, stiffness and MVD in OZR. Our data suggest that the benefits of exercise with UCMS were due to a reduction in oxidative stress and increased production of nitric oxide in the cerebral vessels. In conclusion, UCMS significantly impaired MCA structure and function, but the effects of UCMS were more substantial in OZR vs. LZR. Importantly, aerobic exercise when combined with UCMS prevented the MCA dysfunction through subtle shifts in nitric oxide and oxidative stress in the cerebral microvasculature., (© 2018 The Authors. Experimental Physiology © 2018 The 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.

New Findings: What is the central question of this study? Tumour necrosis factor-α (TNFα) has been shown to impair vascular function, but the impact of thoracic aorta perivascular adipose tissue (tPVAT)-derived TNFα on tPVAT and aortic function in metabolic syndrome is unknown. What is the main finding and its importance? Release of TNFα by tPVAT causes production of reactive oxygen species in tPVAT through activation of an NADPH-oxidase 2 (NOX2)-dependent pathway, activates production of aortic reactive oxygen species and mediates aortic stiffness, potentially through matrix metalloproteinase 9 activity. Neutralization of TNFα and/or inhibition of NOX2 blocks the tPVAT-induced impairment of aortic function. These data partly implicate tPVAT NOX2 and TNFα in mediating the vascular pathology of metabolic syndrome., Abstract: Perivascular adipose tissue (PVAT) is recognized for its vasoactive effects, but it is unclear how metabolic syndrome impacts thoracic aorta (t)PVAT and the subsequent effect on functional and structural aortic stiffness. Thoracic aorta and tPVAT were removed from 16- to 17-week-old lean (LZR, n = 16) and obese Zucker rats (OZR, n = 16). The OZR presented with aortic endothelial dysfunction, assessed by wire myography, and increased aortic stiffness, assessed by elastic modulus. The OZR tPVAT exudate further exacerbated the endothelial dysfunction, reducing nitric oxide and endothelium-dependent relaxation (P < 0.05). Additionally, OZR tPVAT exudate had increased MMP9 activity (P < 0.05) and further increased the elastic modulus of the aorta after 72 h of co-culture (P < 0.05). We found that the observed aortic dysfunction caused by OZR tPVAT was mediated through increased production and release of tumour necrosis factor-α (TNFα; P < 0.01), which was dependent on tPVAT NADPH-oxidase 2 (NOX2) activity. The OZR tPVAT release of reactive oxygen species and subsequent aortic dysfunction were inhibited by TNFα neutralization and/or inhibition of NOX2. Additionally, we found that OZR tPVAT had reduced activity of the active sites of the 20S proteasome (P < 0.05) and reduced superoxide dismutase activity (P < 0.01). In conclusion, metabolic syndrome causes tPVAT dysfunction through an interplay between TNFα and NOX2 that leads to tPVAT-mediated aortic stiffness by activation of aortic reactive oxygen species and increased MMP9 activity., (© 2018 The Authors. Experimental Physiology © 2018 The Physiological Society.)

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 A 2 ), 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., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

New Findings: What is the central question of this study? Does a stroke event influence aortic endothelial function; and what is the role of peripheral circulating leucocytes in stroke on the vascular reactivity of the aorta? What is the main finding and its importance? In vitro co-culture experiments demonstrated that aortic endothelium-dependent relaxation was impaired when rat aortic rings were co-cultured with leucocytes stimulated with serum from stroke patients. Impaired vascular reactivity was not observed in aortic rings without leucocytes stimulated with serum from stroke patients or age-matched control patients with or without leucocytes. These data suggest that leucocyte-dependent altered aortic endothelium-dependent relaxation with stroke and the systemic consequences of stroke on vascular inflammation may occur in the aorta. Post-stroke inflammation has been linked to poor stroke outcomes. The vascular endothelium senses and responds to circulating factors, in particular inflammatory cytokines. Although stroke-associated local cerebrovascular dysfunction is well reported, the effects of a stroke on conduit artery function are not fully understood. We tested the hypothesis that serum from stroke patients triggers leucocyte-dependent aortic endothelial dysfunction that is associated with elevated concentrations of cytokines. Total leucocytes were isolated from healthy individuals, and the cells were incubated in serum from control subjects or stroke patients for 6 h. The quantity of cytokines in media was determined using an immunoassay. Vascular reactivity was determined by the rat aortic rings that were co-cultured with or without leucocytes and stimulated with serum samples from control subjects or stroke patients. Endothelium-dependent dilatation was significantly impaired in aortic rings co-cultured with leucocytes plus serum from stroke patients (50 ± 30 versus 85 ± 13%, P < 0.05) versus serum from control subjects. In contrast, no difference was observed in aortic function stimulated with serum from control subjects or stroke patients without total leucocytes. Likewise, total leucocyte-derived cytokine concentrations were significantly increased in a time-dependent manner on stimulation with serum from stroke patients (P < 0.05). These observations support the concept that the increased response of leucocytes drives the development of stroke-associated vascular endothelial dysfunction. As such, pharmacologically targeting the source of inflammatory cytokines might alleviate stroke-associated peripheral vascular dysfunction., (© 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.)

Objective: A growing body of evidence indicates that impaired microvascular perfusion plays a pathological role in a number of diseases. This manuscript aims to better define which aspects of microvascular perfusion are important, what mass transport processes (eg, insulin action, tissue oxygenation) may be impacted, and what therapies might reverse these pathologies., Methods: We derive a theory of microvascular perfusion and solute flux drawing from established relationships in mass transport and anatomy. We then apply this theory to predict relationships between microvascular perfusion parameters and microvascular solute flux., Results: For convection-limited exchange processes (eg, pulmonary oxygen uptake), our model predicts that bulk blood flow is of primary importance. For diffusion-limited exchange processes (eg, insulin action), our model predicts that perfused capillary density is of primary importance. For convection/diffusion co-limited exchange processes (eg, tissue oxygenation), our model predicts that various microvascular perfusion parameters interact in a complex, context-specific manner. We further show that our model can predict established mass transport defects in disease (eg, insulin resistance in diabetes)., Conclusions: The contributions of microvascular perfusion parameters to tissue-level solute flux can be described using a minimal mathematical model. Our results hold promise for informing therapeutic interventions targeting microvascular perfusion., (© 2017 John Wiley & Sons Ltd.)

Key Points: With the development of the metabolic syndrome, both post-capillary and collecting venular dilator reactivity within the skeletal muscle of obese Zucker rats (OZR) is impaired. The impaired dilator reactivity in OZR reflects a loss in venular nitric oxide and PGI 2 bioavailability, associated with the chronic elevation in oxidant stress. Additionally, with the impaired dilator responses, a modest increase in adrenergic constriction combined with an elevated thromboxane A 2 production may contribute to impaired functional dilator and hyperaemic responses at the venular level. For the shift in skeletal muscle venular function with development of the metabolic syndrome, issues such as aggregate microvascular perfusion resistance, mass transport and exchange within with capillary networks, and fluid handling across the microcirculation are compelling avenues for future investigation., Abstract: While research into vascular outcomes of the metabolic syndrome has focused on arterial/arteriolar and capillary levels, investigation into venular function and how this impacts responses has received little attention. Using the in situ cremaster muscle of obese Zucker rats (OZR; with lean Zucker rats (LZR) as controls), we determined indices of venular function. At ∼17 weeks of age, skeletal muscle post-capillary venular density was reduced by ∼20% in LZR vs. OZR, although there was no evidence of remodelling of the venular wall. Venular tone at ∼25 μm (post-capillary) and ∼75 μm (collecting) diameter was elevated in OZR vs. LZR. Venular dilatation to acetylcholine was blunted in OZR vs. LZR due to increased oxidant stress-based loss of nitric oxide bioavailability (post-capillary) and increased α 1 - (and α 2 -) mediated constrictor tone (collecting). Venular constrictor responses in OZR were comparable to LZR for most stimuli, although constriction to α 1 -adrenoreceptor stimulation was elevated. In response to field stimulation of the cremaster muscle (0.5, 1, 3 Hz), venular dilator and hyperaemic responses to lower frequencies were blunted in OZR, but responses at 3 Hz were similar between strains. Venous production of TxA 2 was higher in OZR than LZR and significantly higher than PGI 2 production in either following arachidonic acid challenge. These results suggest that multi-faceted alterations to skeletal muscle venular function in OZR may contribute to alterations in upstream capillary pressure profiles and the transcapillary exchange of solutes and water under conditions of metabolic syndrome., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

Two of the primary risk factors for the progressive evolution of cardiovascular disease are obesity and impaired glycemic control-including both insulin resistance and overt type 2 diabetes mellitus, leading to increased research emphasis on these conditions, their mechanistic bases, and their health outcomes. This Special Topics Issue of the journal Microcirculation summarizes a symposium at the recent Joint Meeting of the American Physiological Society and the Physiological Society, held in Dublin, Ireland, on July 30, 2016. This symposium, "Adaptive outcomes of microvascular networks to obesity and type 2 diabetes mellitus/insulin resistance," presented four lectures, each of which addressed the larger issue from a different perspective., (© 2016 John Wiley & Sons Ltd.)

Purpose: Although studies suggest elevated adrenergic activity paralleling metabolic syndrome in OZRs, the moderate hypertension and modest impact on organ perfusion question the multi-scale validity of these data., Methods: To understand how adrenergic function contributes to vascular reactivity in OZR, we utilized a multi-scale approach to investigate pressure responses, skeletal muscle blood flow, and vascular reactivity following adrenergic challenge., Results: For OZR, adrenergic challenge resulted in increased pressor responses vs LZRs, mediated via α 1 receptors, with minimal contribution by either ROS or NO bioavailability. In situ gastrocnemius muscle of OZR exhibited blunted functional hyperemia, partially restored with α 1 inhibition, although improved muscle performance and VO 2 required combined treatment with TEMPOL. Within OZR in situ cremaster muscle, proximal arterioles exhibited a more heterogeneous constriction to adrenergic challenge, biased toward hyperresponsiveness, vs LZR. This increasingly heterogeneous pattern was mirrored in ex vivo arterioles, mediated via α 1 receptors, with roles for ROS and NO bioavailability evident in hyperresponsive vessels only., Conclusions: These results support the central role of the α 1 adrenoreceptor for augmented pressor responses and elevations in vascular resistance, but identify an increased heterogeneity of constrictor reactivity in OZR that is presently of unclear purpose., (© 2016 John Wiley & Sons Ltd.)

Metabolic syndrome (MS) in obese Zucker rats (OZR) is associated with impaired skeletal muscle performance and blunted hyperemia. Studies suggest that reduced O 2 diffusion capacity is required to explain compromised muscle performance and that heterogeneous microvascular perfusion distribution is critical. We modeled tissue oxygenation during muscle contraction in control and OZR skeletal muscle using physiologically realistic relationships. Using a network model of Krogh cylinders with increasing perfusion asymmetry and increased plasma skimming, we predict increased perfusion heterogeneity and decreased muscle oxygenation in OZR, with partial recovery following therapy. Notably, increasing O 2 delivery had less impact on VO 2 than equivalent decreases in O 2 delivery, providing a mechanism for previous empirical work associating perfusion heterogeneity and impaired O 2 extraction. We demonstrate that increased skeletal muscle perfusion asymmetry is a defining characteristic of MS and must be considered to effectively model and understand blood-tissue O 2 exchange in this model of human disease.

This review summarizes material presented in "Adaptive Outcomes of Microvascular Networks to Obesity and Type II Diabetes/Insulin Resistance" on July 30, 2016, at the Joint Meeting of the American Physiological Society and the Physiological Society, in Dublin, Ireland. We discuss the poor predictive power of traditional markers of vascular dysfunction for functional outcomes of muscle fatigue-resistance and active hyperemia within the setting of elevated peripheral vascular disease risk. Using the obese Zucker rat model of the metabolic syndrome, we describe how blood flow distribution at arteriolar bifurcations (γ) is altered with PVD risk reflecting increased spatial heterogeneity of distribution within networks. The ability of the microvasculature to compensate for increased heterogeneity is attenuated in OZR, creating a condition wherein the inability to match perfusion to local demand is entrenched and made more difficult to overcome. This appears to be an incremental process, as multiple models of increased PVD risk manifest incremental shifts to the spatial and temporal behavior of γ. These data suggest that γ, a superior predictor of functional outcomes for skeletal muscle, may represent a broadly applicable concept that can inform us about system behavior, with health and increased disease/disease risk, and with imposition of therapeutic regimens., (© 2016 John Wiley & Sons Ltd.)

A major challenge facing public health is the increased incidence and prevalence of the metabolic syndrome, a clinical condition characterized by excess adiposity, impaired glycaemic control, dyslipidaemia and moderate hypertension. The greatest concern for this syndrome is the profound increase in risk for development of peripheral vascular disease (PVD) in afflicted persons. However, ongoing studies suggest that reductions in bulk blood flow to skeletal muscle may not be the primary contributor to the premature muscle fatigue that is a hallmark of PVD. Compelling evidence has been provided suggesting that an increasingly spatially heterogeneous and temporally stable distribution of blood flow at successive arteriolar bifurcations in metabolic syndrome creates an environment where a large number of the pre-capillary arterioles have low perfusion, low haematocrit, and are increasingly confined to this state, with limited ability to adapt perfusion in response to a challenged environment. Single pharmacological interventions are unable to significantly restore function owing to a divergence in their spatial effectiveness, although combined therapeutic approaches to correct adrenergic dysfunction, elevated oxidant stress and increased thromboxane A2 improve perfusion-based outcomes. Integrated, multi-target therapeutic interventions designed to restore healthy network function and flexibility may provide for superior outcomes in subjects with metabolic syndrome-associated PVD., (© 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.)

To determine the impact of progressive elevations in peripheral vascular disease (PVD) risk on microvascular function, we utilized eight rat models spanning "healthy" to "high PVD risk" and used a multiscale approach to interrogate microvascular function and outcomes: healthy: Sprague-Dawley rats (SDR) and lean Zucker rats (LZR); mild risk: SDR on high-salt diet (HSD) and SDR on high-fructose diet (HFD); moderate risk: reduced renal mass-hypertensive rats (RRM) and spontaneously hypertensive rats (SHR); high risk: obese Zucker rats (OZR) and Dahl salt-sensitive rats (DSS). Vascular reactivity and biochemical analyses demonstrated that even mild elevations in PVD risk severely attenuated nitric oxide (NO) bioavailability and caused progressive shifts in arachidonic acid metabolism, increasing thromboxane A2 levels. With the introduction of hypertension, arteriolar myogenic activation and adrenergic constriction were increased. However, while functional hyperemia and fatigue resistance of in situ skeletal muscle were not impacted with mild or moderate PVD risk, blood oxygen handling suggested an increasingly heterogeneous perfusion within resting and contracting skeletal muscle. Analysis of in situ networks demonstrated an increasingly stable and heterogeneous distribution of perfusion at arteriolar bifurcations with elevated PVD risk, a phenomenon that was manifested first in the distal microcirculation and evolved proximally with increasing risk. The increased perfusion distribution heterogeneity and loss of flexibility throughout the microvascular network, the result of the combined effects on NO bioavailability, arachidonic acid metabolism, myogenic activation, and adrenergic constriction, may represent the most accurate predictor of the skeletal muscle microvasculopathy and poor health outcomes associated with chronic elevations in PVD risk., (Copyright © 2016 the American Physiological Society.)

Chronic, unresolved stress is a major risk factor for the development of clinical depression. While many preclinical models of stress-induced depression have been reported, the unpredictable chronic mild stress (UCMS) protocol is an established translationally-relevant model for inducing behavioral symptoms commonly associated with clinical depression, such as anhedonia, altered grooming behavior, and learned helplessness in rodents. The UCMS protocol also induces physiological (e.g., hypercortisolemia, hypertension) and neurological (e.g., anhedonia, learned helplessness) changes that are clinically associated with depression. Importantly, UCMS-induced depressive symptoms can be ameliorated through chronic, but not acute, treatment with common SSRIs. As such, the UCMS protocol offers many advantages over acute stress protocols or protocols that utilize more extreme stressors. Our protocol involves randomized, daily exposures to 7 distinct stressors: damp bedding, removal of bedding, cage tilt, alteration of light/dark cycles, social stresses, shallow water bath, and predator sounds/smells. By subjecting rodents 3-4 hr daily to these mild stressors for 8 weeks, we demonstrate both significant behavioral changes and poor health outcomes to the cardiovascular system. This approach allows for in-depth interrogation of the neurological, behavioral, and physiological alterations associated with chronic stress-induced depression, as well as for testing of new potential therapeutic agents or intervention strategies.

The metabolic syndrome (MetS) is highly prevalent in the North American population and is associated with increased risk for development of cerebrovascular disease. This study determined the structural and functional changes in the middle cerebral arteries (MCA) during the progression of MetS and the effects of chronic pharmacological interventions on mitigating vascular alterations in obese Zucker rats (OZR), a translationally relevant model of MetS. The reactivity and wall mechanics of ex vivo pressurized MCA from lean Zucker rats (LZR) and OZR were determined at 7-8, 12-13, and 16-17 wk of age under control conditions and following chronic treatment with pharmacological agents targeting specific systemic pathologies. With increasing age, control OZR demonstrated reduced nitric oxide bioavailability, impaired dilator (acetylcholine) reactivity, elevated myogenic properties, structural narrowing, and wall stiffening compared with LZR. Antihypertensive therapy (e.g., captopril or hydralazine) starting at 7-8 wk of age blunted the progression of arterial stiffening compared with OZR controls, while treatments that reduced inflammation and oxidative stress (e.g., atorvastatin, rosiglitazone, and captopril) improved NO bioavailability and vascular reactivity compared with OZR controls and had mixed effects on structural remodeling. These data identify specific functional and structural cerebral adaptations that limit cerebrovascular blood flow in MetS patients, contributing to increased risk of cognitive decline, cerebral hypoperfusion, and ischemic stroke; however, these pathological adaptations could potentially be blunted if treated early in the progression of MetS., (Copyright © 2015 the American Physiological Society.)