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

The study of peripheral vasculopathy with chronic metabolic disease is challenged by divergent contributions from spatial (the level of resolution or specific tissue being studied) and temporal origins (evolution of the developing impairments in time). Over many years of studying the development of skeletal muscle vasculopathy and its functional implications, we may be at the point of presenting an integrated conceptual model that addresses these challenges within the obese Zucker rat (OZR) model. At the early stages of metabolic disease, where systemic markers of elevated cardiovascular disease risk are present, the only evidence of vascular dysfunction is at postcapillary and collecting venules, where leukocyte adhesion/rolling is elevated with impaired venular endothelial function.

Feasibility of Bioengineered Tracheal and Bronchial Reconstruction Using Stented Aortic Matrices.

Importance: Airway transplantation could be an option for patients with proximal lung tumor or with end-stage tracheobronchial disease. New methods for airway transplantation remain highly controversial.

Objective: To establish the feasibility of airway bioengineering using a technique based on the implantation of stented aortic matrices.

Increased peripheral vascular disease risk progressively constrains perfusion adaptability in the skeletal muscle microcirculation.

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.

An Unpredictable Chronic Mild Stress Protocol for Instigating Depressive Symptoms, Behavioral Changes and Negative Health Outcomes in Rodents.

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.

Metabolic syndrome impairs reactivity and wall mechanics of cerebral resistance arteries in obese Zucker rats.

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.

Cerebral Cortical Microvascular Rarefaction in Metabolic Syndrome is Dependent on Insulin Resistance and Loss of Nitric Oxide Bioavailability.

Objective: Chronic presentation of the MS is associated with an increased likelihood for stroke and poor stroke outcomes following occlusive cerebrovascular events. However, the physiological mechanisms contributing to compromised outcomes remain unclear, and the degree of cerebral cortical MVD may represent a central determinant of stroke outcomes.

Methods: This study used the OZR model of MS and clinically relevant, chronic interventions to determine the impact on cerebral cortical microvascular rarefaction via immunohistochemistry with a parallel determination of cerebrovascular function to identify putative mechanistic contributors.

Protective effect of sex on chronic stress- and depressive behavior-induced vascular dysfunction in BALB/cJ mice.

The presence of chronic, unresolvable stresses leads to negative health outcomes, including development of clinical depression/depressive disorders, with outcome severity being correlated with depressive symptom severity. One of the major outcomes associated with chronic stress and depression is the development of cardiovascular disease (CVD) and an elevated CVD risk profile. However, in epidemiological research, sex disparities are evident, with premenopausal women suffering from depressive symptoms more acutely than men, but also demonstrating a relative protection from the onset of CVD.

Aspirin resistance with genetic dyslipidemia: contribution of vascular thromboxane generation.

One clinical intervention against the negative outcomes associated with atherothrombotic vascular disease (AVD) is low-dose, chronic aspirin therapy. However, epidemiological studies suggest that recurrence of adverse vascular events with aspirin therapy is growing and associated with therapy duration. The contributors to this outcome are unclear and include poor patient compliance and aspirin-resistant platelet thromboxane A(2) (TxA(2)) production.

Depressive behavior and vascular dysfunction: a link between clinical depression and vascular disease?

As chronic stress and depression have become recognized as significant risk factors for peripheral vascular disease in patients with no prior history of vasculopathy, we interrogated this relationship utilizing an established mouse model of chronic stress/depressive symptoms from behavioral research. Male mice were exposed to 8 wk of unpredictable chronic mild stress (UCMS; e.g.

Differential impact of familial hypercholesterolemia and combined hyperlipidemia on vascular wall and network remodeling in mice.

Genetic familial hypercholesterolemia (FH) and combined hyperlipidemia (FCH) are characterized by elevated plasma low-density lipoprotein (LDL) (FH) and LDL/triglycerides (FCH), with mouse models represented by LDL receptor (LDLR) and apolipoprotein E (ApoE) gene deletion mice, respectively. Given the impact of FH and FCH on health outcomes, we determined the impact of FH/FCH on vascular structure in LDLR and ApoE mice. LDLR, ApoE and control mice were utilized at 12-13 and 22-23 weeks when gracilis arteries were studied for wall mechanics and gastrocnemius muscles were harvested for microvessel density measurements.

Increased arachidonic acid-induced thromboxane generation impairs skeletal muscle arteriolar dilation with genetic dyslipidemia.

Objective: The aim of this study was to determine if arachidonic acid (AA)-induced skeletal muscle arteriolar dilation is altered with hypercholesterolemia in ApoE and low-density lipoprotein receptor (LDLR) gene deletion mice fed a normal diet. This study also determined contributors to altered AA-induced dilation between dyslipidemic mice and controls, C57/Bl/6J (C57).

Methods: Gracilis muscle arterioles were isolated, with mechanical responses assessed following a challenge with AA under control conditions and after elements of AA metabolism pathways were inhibited.

Supplemental oxygen reduces intimal hyperplasia after intraarterial stenting in the rabbit.

Hypothesis: Supplemental oxygen can reduce intimal hyperplasia (IH) after stent deployment in a rabbit model.

Background: Endovascular stent placement is technically feasible, but long-term durability in vessels outside the aortoiliac system is compromised with postinterventional IH, which causes restenosis and failure of the arterial conduit.

Methods: Groups (n = 4 to 6) of female New Zealand white rabbits underwent placement of a 3-mm intraaortic stent with laparotomy and were placed in either normoxic (21% inspired oxygen concentration) or supplemental-oxygen (40% inspired oxygen concentration) environments for 0, 7, 14, and 28 days.

Expansion rates and outcomes for the 3.0-cm to the 3.9-cm infrarenal abdominal aortic aneurysm.

Objective: This study was performed for the determination of the expansion rates and outcomes and for recommendations for the surveillance of the 3.0-cm to 3.9-cm abdominal aortic aneurysm (AAA).