Previously we showed that neuropeptide Y (NPY), a sympathetic vasoconstrictor neurotransmitter, stimulates endothelial cell migration, proliferation, and differentiation in vitro. Here, we report on NPY’s actions, receptors, and mediators in ischemic angiogenesis. In rats, hindlimb ischemia stimulates sympathetic NPY release (attenuated by lumbar sympathectomy) and upregulates NPY-Y2 (Y2) receptor and a peptidase forming Y2/Y5-selective agonist. Exogenous NPY at physiological concentrations also induces Y5 receptor, stimulates neovascularization, and restores ischemic muscle blood flow and performance. NPY-mediated ischemic angiogenesis is not prevented by a selective Y1 receptor antagonist but is reduced in Y2–/– mice. Nonischemic muscle vascularity is also lower in Y2–/– mice, whereas it is increased in NPY-overexpressing rats compared with their WT controls. Ex vivo, NPY-induced aortic sprouting is markedly reduced in Y2–/– aortas and spontaneous sprouting is severely impaired in NPY–/– mice. NPY-mediated aortic sprouting, but not cell migration/proliferation, is blocked by an antifetal liver kinase 1 antibody and abolished in mice null for eNOS. Thus, NPY mediates neurogenic ischemic angiogenesis at physiological concentrations by activating Y2/Y5 receptors and eNOS, in part due to release of VEGF. NPY’s effectiveness in revascularization and restoring function of ischemic tissue suggests its therapeutic potential in ischemic conditions

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Protective effects of essential fatty acid deficiency (EFAD) on autoimmunity were shown in rodents. Our goal was to investigate the mechanisms of EFAD effects on autoimmune diabetes in nonobese diabetic (NOD) mice. Weanling female mice were randomized between a control diet group and an EFAD diet group, and the development of diabetes and immune response was determined over a 6-month period. The cumulative incidence of diabetes was significantly reduced in the EFAD group (20 vs 68.75% in the control group; p < 0.01), without affecting the insulitis process. Splenocyte reactivity to phytohemagglutinin and anti-CD3 antibody was significantly increased in EFAD-fed mice (p < 0.01). The EFAD group also exhibited a dramatic increase in baseline (29-fold) and antigen-presenting cell (APC)-stimulated (10-fold) T cell responses in syngeneic mixed leukocyte reaction. These responses were associated with a marked increase in splenocyte interleukin-4 (IL-4) production, a reduction in interferon-? production, and a down-regulation of CD45RB isoform expression. Macrophages in the EFAD group exerted a reduced suppressive effect on concanavalin A-induced splenocyte proliferation and were found to release increased amounts of tumor necrosis factor-a and IL-1 and reduced amounts of prostaglandin E,. These results clearly demonstrate that EFAD prevents diabetes in NOD mice. The data suggest an enhanced activity of Th2-like cells, as well as an effect on APC activity linked to alteration in eicosanoid metabolism.

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A 47-year-old black woman with no prior medical problems presented to the emergency department after a syncopal event associated with palpitations while walking. The patient noticed new onset of palpitations while walking that lasted about an hour. She subsequently had a syncopal episode. She denied dizziness, lightheadedness, dehydration, or seizure-like activity. Medications included antihistamines and oral contraceptives. On admission she was afebrile, heart rate 84 bpm, blood pressure 121/73 mm Hg, respiratory rate 18 breaths per minute, and her oxygen saturation was 97% on room air. The physical examination was normal except for a small (1 cm) head laceration.A noncontrast computed tomography of the head was negative for any acute intracranial findings. The chest radiograph showed no acute cardiopulmonary disease. The electrocardiogram showed normal sinus rhythm at a ventricular rate of 69 bpm, no evidence of ST segment changes, and an isolated T wave inversion in V2 (Figure 1).She was admitted with high suspicion for cardiac syncope given her symptoms of palpitations before the event. Myocardial infarction was ruled out. A pro-B-type natriuretic peptide was normal and thyroid-stimulating hormone test was normal. A D-dimer level was not checked. Telemetry was only significant for episodes of sinus tachycardia. A resting transthoracic echocardiogram was technically difficult but showed normal left ventricular (LV) size and function, ejection fraction 50%, and grossly normal right ventricular (RV) size and function (Figure 2; Movies I and II in the Data Supplement). There was not enough tricuspid regurgitation on the resting echocardiogram for estimation of pulmonary artery systolic pressure at rest.The clinical team ordered a stress echocardiogram which was performed for evaluation of ischemia and arrhythmia. The test was terminated at 3 minutes and 53 seconds, after the patient exhibited symptoms of dyspnea and fatigue. The electrocardigram was positive for exercise-induced myocardial ischemia (>2 mm ST segment depression in the inferior and lateral leads) at maximal stress of 103% maximum predicted heart rate and 5 metabolic equivalents (Figure 3). There was blunted blood pressure response to exercise from 110/68 mm Hg at baseline to 118/62 mm Hg at peak stress. After stress echocardiographic imaging, using perflutren contrast for improved endocardial border visualization demonstrated normal augmentation of LV function. However, there was significant dilation of the RV, with severe RV dysfunction and flattening of the interventricular septum, suggestive of RV pressure and volume overload (Figure 4; Movies I and II in the Data Supplement). There was an insufficient degree of tricuspid regurgitation to allow for estimation of RV systolic pressures. This information suggested an abnormality in the pulmonary vascular physiology, likely because of increased pulmonary vascular resistance and inadequate contractile reserve of the RV. In our clinical scenario, these findings were considered suspicious for an acute...