Perivascular mast cells promote neointimal elastin deposit and suppress chronic vein graft restensosis in hyperlipidaemic mice : mast cells and vein graft remodelling

Aims: Mast cells are versatile innate immune cells and are reported to promote vascular inflammation and neointimal lesion formation, thereby contributing to the development of vascular stenosis and atherosclerosis. However, it is not clear whether mast cells also regulate vascular matrix remodelling in established neointima. This study addressed the hypothesis that perivascular mast cells regulate neointimal matrix remodelling using a mouse vein graft model. Methods: The impact of mast cells on neointimal remodelling was investigated using mast cell-deficient animals in both normolipidaemic (KitW-sh/W-sh) and hyperlipidaemic (apoE-/-KitW-sh/W-sh) conditions. The effect of perivascular mast cells on vascular matrix remodelling, including collagen and elastin deposition, was investigated using a local mast cell reconstitution method that selectively repopulated mast cells around the carotid artery (where the vein graft was inserted) in KitW-sh/W-sh mice. Results: In normolipidaemic vein grafts (KitW-sh/W-sh vs. the wild type control C57BL/6J), collagen synthesis was not affected by mast cell deficiency at 4 weeks. In contrast, neointimal elastin was reduced by 6.5-fold in mast cell-deficient KitW-sh/W-sh mice, which was prevented by perivascular mast cell reconstitution. Mast cell deficiency induced a similar reduction in neointimal elastin in hyperlipidaemic mice (apoE-/-KitW-sh/W-sh vs. apoE-/-), with a significant increase in cell proliferation and neointimal area at 4 week. Conclusion: Mast cells appear to promote elastin deposition in vein grafts and this may lead to further suppression of cell proliferation and neointimal thickening under hyperlipidaemic conditions

Perivascular mast cells promote neointimal elastin deposition and suppress chronic vein graft restenosis in hyperlipidaemic mice.

Aims: Mast cells are versatile innate immune cells and are reported to promote vascular inflammation and neointimal lesion formation, thereby contributing to the development of vascular stenosis and atherosclerosis. However, it is not clear whether mast cells also regulate vascular matrix remodelling in established neointima. This study addressed the hypothesis that perivascular mast cells regulate neointimal matrix remodelling using a mouse vein graft model. Methods: The impact of mast cells on neointimal remodelling was investigated using mast cell-deficient animals in both normolipidaemic (KitW-sh/W-sh) and hyperlipidaemic (apoE-/-KitW-sh/W-sh) conditions. The effect of perivascular mast cells on vascular matrix remodelling, including collagen and elastin deposition, was investigated using a local mast cell reconstitution method that selectively repopulated mast cells around the carotid artery (where the vein graft was inserted) in KitW-sh/W-sh mice. Results: In normolipidaemic vein grafts (KitW-sh/W-sh vs. the wild type control C57BL/6J), collagen synthesis was not affected by mast cell deficiency at 4 weeks. In contrast, neointimal elastin was reduced by 6.5-fold in mast cell-deficient KitW-sh/W-sh mice, which was prevented by perivascular mast cell reconstitution. Mast cell deficiency induced a similar reduction in neointimal elastin in hyperlipidaemic mice (apoE-/-KitW-sh/W-sh vs. apoE-/-), with a significant increase in cell proliferation and neointimal area at 4 week. Conclusion: Mast cells appear to promote elastin deposition in vein grafts and this may lead to further suppression of cell proliferation and neointimal thickening under hyperlipidaemic conditions

Androgens and coronary artery disease

This chapter reviews data that examine the relationship between androgens and coronary artery disease (CAD) in men. Androgens can exert both beneficial and deleterious actions on a myriad of factors implicated in the pathogenic mechanisms of atherosclerosis and CAD. Androgen/androgen receptor (AR) can modulate arterial disease and vascular function via genomic (AR) or non-genomic mechanisms in animal models and in vitro experimental studies. The diversity and complexity of the actions of testosterone (and its metabolites E2 and DHT) and DHEA on the vasculature reflect the multiple cellular targets in the vessel wall, differences between species, gender, concomitant disease and, most importantly, level/dosage of testosterone exposure. At present, it is not possible to determine the net effect of androgens on CAD pathogenesis and clinical outcomes. While observational clinical studies showed a consistent association between low testosterone and CAD (risk factors, events and mortality), and some experimental studies may suggest positive effects of androgens on CAD risk factors, body composition and individual vascular mechanisms, it is hazardous to suggest that manipulation of the androgenic milieu will result in clinical benefits in a complex multifactorial condition such as CAD. This ongoing uncertainty also underlines recent concerns regarding the possibility of adverse cardiovascular side effects in androgen treatment of endocrine and non-endocrine conditions, hampering efforts to exploit the potential therapeutic benefits of testosterone for men in the treatment of osteoporosis, sarcopaenia, chronic debilitating disease and obesity-related hypoandrogenism in the ageing male population. Large-scale prospective randomised placebo-controlled trials of sufficient size and duration are urgently needed to assess not only the benefits in terms of meaningful clinical benefits and patient-important outcomes but also to document the risks of serious adverse events in testosterone treatment. In the meantime, for patients with established pathological hypogonadism, there are no substantive data to suggest that physiological testosterone therapy is associated with increased cardiovascular risk and their management should not deviate from current recommended practice. For complete coverage of this and related topics, please visit www.endotext.org

Direct relationship between levels of TNF-α expression and endothelial dysfunction in reperfusion injury

We previously found that myocardial ischemia/ reperfusion (I/R) initiates expression of tumor necrosis factor-α (TNF) leading to coronary endothelial dysfunction. However, it is not clear whether there is a direct relationship between levels of TNF expression and endothelial dysfunction in reperfusion injury. We studied levels of TNF expression by using different transgenic animals expressing varying amounts of TNF in I/R. We crossed TNF overexpression (TNF++/++) with TNF knockout (TNF-/-) mice; thus we have a heterozygote population of mice with the expression of TNF "in between" the TNF-/- and TNF++/++ mice. Mouse hearts were subjected to 30 min of global ischemia followed by 90 min of reperfusion and their vasoactivity before and after I/R was examined in wild type (WT), TNF-/-, TNF++/++ and TNF heterozygote (TNF -/++, cross between TNF-/- and TNF++/++) mice. In heterozygote TNF-/++ mice with intermediate cardiac-specific expression of TNF, acetyl-choline-induced or flow-induced endothelial-dependent vasodilation following I/R was between TNF++/++ and TNF-/- following I/R. Neutralizing antibodies to TNF administered immediately before the onset of reperfusion-preserved endothelial-dependent dilation following I/R in WT, TNF-/++ and TNF++/++ mice. In WT, TNF -/++ and TNF++/++ mice, I/R-induced endothelial dysfunction was progressively lessened by administration of free-radical scavenger TEMPOL immediately before initiating reperfusion. During I/R, production of superoxide (O2-) was greatest in TNF ++/++ mice as compared to WT, TNF-/++ and TNF -/- mice. Following I/R, arginase mRNA expression was elevated in the WT, substantially elevated in the TNF-/++ and TNF ++/++mice and not affected in the TNF-/- mice. These results suggest that the level of TNF expression determines arginase expression in endothelial cells during myocardial I/R, which is one of the mechanisms by which TNF compromises coronary endothelial function in reperfusion injury

Perivascular mast cells regulate vein graft neointimal formation and remodeling

Objective. Emerging evidence suggests an important role for mast cells in vein graft failure. This study addressed the hypothesis that perivascular mast cells regulate in situ vascular inflammatory and proliferative responses and subsequent vein graft neointimal lesion formation, using an optimized local mast cell reconstitution method. Methods and Results. Neointimal hyperplasia was induced by insertion of a vein graft into the right carotid artery in wild type and mast cell deficient KitW−sh/W−sh mice. In some experiments, mast cells were reconstituted systemically (tail vein injection of bone marrow-derived mast cells) or locally (directly into the right neck area) prior to vein grafting. Vein graft neointimal lesion formation was significantly (P < 0.05) reduced in KitW−sh/W−sh mice. Mast cell deficiency reduced the number of proliferating cells, and inhibited L-selectin, CCL2, M-CSF and MIP-3α expression in the vein grafts. Local but not systemic mast cell reconstitution restored a perivascular mast cell population that subsequently promoted neointimal formation in mast cell deficient mice. Conclusion. Our data demonstrate that perivascular mast cells play a key role in promoting neointima formation by inducing local acute inflammatory and proliferative responses. These results suggest that ex vivo intraoperative targeting of mast cells may have therapeutic potential for the prevention of pathological vein graft remodeling

Role of TNF-α in vascular dysfunction

Healthy vascular function is primarily regulated by several factors including EDRF (endothelium-dependent relaxing factor), EDCF (endothelium-dependent contracting factor) and EDHF (endothelium-dependent hyperpolarizing factor). Vascular dysfunction or injury induced by aging, smoking, inflammation, trauma, hyperlipidaemia and hyperglycaemia are among a myriad of risk factors that may contribute to the pathogenesis of many cardiovascular diseases, such as hypertension, diabetes and atherosclerosis. However, the exact mechanisms underlying the impaired vascular activity remain unresolved and there is no current scientific consensus. Accumulating evidence suggests that the inflammatory cytokine TNF (tumour necrosis factor)-α plays a pivotal role in the disruption of macrovascular and microvascular circulation both in vivo and in vitro. AGEs (advanced glycation end-products)/RAGE (receptor for AGEs), LOX-1 [lectin-like oxidized low-density lipoprotein receptor-1) and NF-κB (nuclear factor κB) signalling play key roles in TNF-α expression through an increase in circulating and/or local vascular TNF-α production. The increase in TNF-α expression induces the production of ROS (reactive oxygen species), resulting in endothelial dysfunction in many pathophysiological conditions. Lipid metabolism, dietary supplements and physical activity affect TNF-α expression. The interaction between TNF-α and stem cells is also important in terms of vascular repair or regeneration. Careful scrutiny of these factors may help elucidate the mechanisms that induce vascular dysfunction. The focus of the present review is to summarize recent evidence showing the role of TNF-α in vascular dysfunction in cardiovascular disease. We believe these findings may prompt new directions for targeting inflammation in future therapies

Characterisation of an atherosclerotic micro-calcification model using ApoE-/- mice and PET/CT

Intraplaque calcification is a prominent feature of advanced atherosclerotic plaque development. Current clinical evidence suggests that the size of calcium deposit may confer different effects on plaque stability [1], [2], [3]. Macro-calcified deposits (CT detected) are thought to confer plaque stability whereas micro-calcification ([18F]NaF PET detected) are thought to be a feature of high-risk ‘vulnerable’ plaques which are prone to rupture. Following on from the emerging role of micro-calcification in high risk plaques within the clinic [4], there is now an urgent need for preclinical atherosclerotic models with this feature to gain mechanistic insights and assess the impact of calcification-targeted therapies. Using a combination of invasive and ex vivo methods, ApoE−/− mice placed on an atherogenic diet have been shown to develop intraplaque calcification [5]. Additionally, [18F]NaF PET/CT has been used to assess the impact of exercise on calcification in ApoE−/− mice on a western diet [6]. In this study, we set out to determine if [18F]NaF PET/CT could be used to non-invasively detect and quantify micro-calficiation in the ApoE−/− high cholesterol diet (HCD) mouse model, and examine the temporal nature of this process

The transition from incoherent to coherent random laser in defect waveguide based on organic/inorganic hybrid laser dye

This paper systematically demonstrated a variety of experimental phenomena of random lasers (RLs) of N,N′-di-(3-(isobutyl polyhedral oligomeric silsesquioxanes)propyl) perylene diimide (DPP) organic/inorganic hybrid laser dye, which is composed of perylene diimide (PDI) as gain media and polyhedral oligomeric silsesquioxanes (POSS) as scattering media at a mole ratio of 1:2. In this work, we observe the transition from incoherent RL in the DPP-doped solutions and polymer membrane systems using dip-coating method to coherent RL in the polymer membrane system with defect waveguide using semi-polymerization (SP) coating method. Meanwhile, we found that the hybrid dye-DPP has a long lasing lifetime compared with the traditional laser dyes, which indicates that the POSS group can suppress the photo-bleaching effect to extend the working life of laser dyes

Dietary Docosahexaenoic Acid Reduces Oscillatory Wall Shear Stress, Atherosclerosis, and Hypertension, Most Likely Mediated via an IL‐1–Mediated Mechanism

Background: Hypertension is a complex condition and a common cardiovascular risk factor. Dietary docosahexaenoic acid (DHA) modulates atherosclerosis and hypertension, possibly via an inflammatory mechanism. IL‐1 (interleukin 1) has an established role in atherosclerosis and inflammation, although whether IL‐1 inhibition modulates blood pressure is unclear. Methods and Results: Male apoE−/− (apolipoprotein E–null) mice were fed either a high fat diet or a high fat diet plus DHA (300 mg/kg per day) for 12 weeks. Blood pressure and cardiac function were assessed, and effects of DHA on wall shear stress and atherosclerosis were determined. DHA supplementation improved left ventricular function, reduced wall shear stress and oscillatory shear at ostia in the descending aorta, and significantly lowered blood pressure compared with controls (119.5±7 versus 159.7±3 mm Hg, P<0.001, n=4 per group). Analysis of atheroma following DHA feeding in mice demonstrated a 4‐fold reduction in lesion burden in distal aortas and in brachiocephalic arteries (P<0.001, n=12 per group). In addition, DHA treatment selectively decreased plaque endothelial IL‐1β (P<0.01). Conclusions: Our findings revealed that raised blood pressure can be reduced by inhibiting IL‐1 indirectly by administration of DHA in the diet through a mechanism that involves a reduction in wall shear stress and local expression of the proinflammatory cytokine IL‐1β