Search

Vasa vasorum are blood microvessels which penetrate the adventitia and outer layers of the media of large blood vessels, supplying them with nutrients and oxygen. A growing body of evidence suggests that vasa vasorum play a central role in the pathogenesis of atherosclerosis. In this review, we will make a case for the role of microvascular dysfunction in the initiation of disease. When seen through this lens, new therapeutic opportunities for prevention can be envisioned. In particular, we discuss how targeting the cellular metabolism and epigenetic machinery of vasa vasorum neovessels could be harnessed to render vasa vasorum endothelial cells less sensitive to atherogenic stimuli., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Platelet P2Y 12 is an important adenosine diphosphate (ADP) receptor that is involved in agonist-induced platelet aggregation and is a valuable target for the development of anti-platelet drugs. Here we characterise the effects of thio analogues of uridine triphosphate (UTP) on ADP-induced platelet aggregation. Using human platelet-rich plasma, we demonstrate that UTP inhibits P2Y 12 but not P2Y₁ receptors and antagonises 10 µM ADP-induced platelet aggregation in a concentration-dependent manner with an IC 50 value of ~250 °µM. An eight-fold higher platelet inhibitory activity was observed with a 2-thio analogue of UTP (2 S -UTP), with an IC 50 of 30 µM. The 4-thio analogue (4 S -UTP) with an IC 50 of 7.5 µM was 33-fold more effective. A three-fold decrease in inhibitory activity, however, was observed by introducing an isobutyl group at the 4 S - position. A complete loss of inhibition was observed with thio-modification of the γ phosphate of the sugar moiety, which yields an enzymatically stable analogue. The interaction of UTP analogues with P2Y 12 receptor was verified by P2Y 12 receptor binding and cyclic AMP (cAMP) assays. These novel data demonstrate for the first time that 2- and 4-thio analogues of UTP are potent P2Y 12 receptor antagonists that may be useful for therapeutic intervention.

In this meeting report, particularly addressing the topic of protection of the cardiovascular system from ischemia/reperfusion injury, highlights are presented that relate to conditioning strategies of the heart with respect to molecular mechanisms and outcome in patients' cohorts, the influence of co-morbidities and medications, as well as the contribution of innate immune reactions in cardioprotection. Moreover, developmental or systems biology approaches bear great potential in systematically uncovering unexpected components involved in ischemia-reperfusion injury or heart regeneration. Based on the characterization of particular platelet integrins, mitochondrial redox-linked proteins, or lipid-diol compounds in cardiovascular diseases, their targeting by newly developed theranostics and technologies opens new avenues for diagnosis and therapy of myocardial infarction to improve the patients' outcome., Competing Interests: HEB is a shareholder of CellAegis Inc.

Background: Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists or GnRH antagonists is the mainstay of treatment for metastatic prostate cancer (mCaP). However, ADT is associated with serious cardiovascular events. Only a few studies that directly compare the cardiovascular risk of LHRH agonists versus GnRH antagonists have been published., Objectives: This review aims to compare the cardiovascular risk of LHRH agonists versus GnRH antagonists based on the literature., Methods: A literature search that considered full publications and abstracts published before December 10, 2014 was performed. Due to their high evidence quality, only meta-analyses and pooled studies were included in this review., Results: Four studies were included. These investigated the cardiovascular risk of patients receiving an ADT with LHRH agonists and/or GnRH antagonists. However, only one of these directly compared the cardiovascular risk of ADT with LHRH agonists versus GnRH antagonists. This meta-analysis showed a significant reduction in cardiovascular risk for patients receiving a GnRH antagonist compared to those patients receiving a LHRH agonist (HR: 0.597; 95 % CI: 0.380-0.938; P = 0.0253). Subgroup analyses showed that, in particular, patients with pre-existing cardiovascular diseases who were treated with a GnRH antagonist have a significantly lower risk of experiencing a cardiovascular event when compared with patients receiving a GnRH agonist (HR: 0.44; 95 % CI: 0.26-0.74; P = 0.002)., Conclusion: In conclusion, GnRH antagonists are associated with a lower risk of cardiovascular events, compared with LHRH agonists, when administered as ADT in CaP patients, and particularly in patients with a history of cardiovascular disease. Thus, patients with a history of cardiovascular disease may benefit from ADT with a GnRH antagonist.

Background: Platelets express two ADP receptors namely P2Y1 and P2Y12 that regulate ADP and other agonists-induced platelet aggregation. P2Y1 receptor activation causes platelet shape change while P2Y12 receptor activation induces platelet aggregation. Previously, anti-aggregatory effects of ATP on ADP-induced and pro-aggregatory effects on epinephrine-induced platelet aggregation have been reported. However, the effects of other nucleoside triphosphates on platelet aggregation have never been described. The aim of the present study was to characterise the effects of nucleoside triphosphates (ATP, UTP, GTP, and CTP) on agonist-induced platelet aggregation., Methods: The experiments were performed on platelet rich plasma freshly isolated from blood donated by healthy human volunteers., Results: All the nucleoside triphosphates tested inhibited ADP- and collagen-induced platelet aggregation in a concentration-dependent manner with a rank order of potency, 2MeSATP >ATP ≥ α,β,methyleneATP>UTP >>CTP ≥ GTP. The IC50 values against ADP (10 μM)-induced platelet aggregation were 0.039 ± 0.013, 18 ± 7, 25 ± 6, 32 ± 9, 360 ± 130, and 400 ± 160 μM, respectively. Low concentrations of ATP induced platelet shape change which was due to contaminating ADP. However, higher concentrations antagonised ADP and MRS2365-induced platelet shape change. The ATP analogue α,β,methyleneATP and CTP but not UTP and GTP also antagonised ADP-induced platelet shape change. Similarly, low ATP concentrations potentiated epinephrine-induced platelet aggregation that was abolished by P2Y1 antagonist MRS2500 suggesting P2Y1 receptor activation due to contaminating ADP. Higher ATP concentrations, α,β,methyleneATP, UTP, CTP, and GTP antagonised epinephrine-induced platelet aggregation., Conclusion: Thus, the data demonstrate nucleoside triphosphates in general act as P2Y12 receptor antagonists and antagonise ADP-, collagen-, and epinephrine-induced platelet aggregation., (© 2013.)

HMG-CoA-Reductase inhibitors, also known as statins, are currently the most powerful cholesterol-lowering drugs available on the market. Clinical trials and experimental evidence suggest that statins have anti-atherosclerotic effects. These are in part consequence of lipid lowering but also result from pleiotropic actions of the drugs. In this article, the anti-atherosclerotic actions of statins will be reviewed., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Various virus infections cause dysfunctional hemostasis and in some instances lead to the development of viral hemorrhagic fever syndrome. How do diverse viruses induce the expression of tissue factor on vascular cells? We hypothesize that a direct stimulation of pattern recognition receptors (PRR) by viral nucleic acids may be the key. Double-stranded RNA (dsRNA) is produced by many viruses and is recognized by various PRR, including Toll-like receptor-3 (TLR3). We have investigated whether poly I:C, a model for viral dsRNA, can influence cellular hemostasis. Poly I:C could up-regulate tissue factor and down-regulate thrombomodulin expression on endothelial cells but not on monocytes. The response to poly I:C was diminished upon small interfering RNA (siRNA)-mediated inhibition of TLR3, but not other PRR. In vivo, application of poly I:C induced similar changes in the aortic endothelium of mice as determined by enface microscopy. D-dimer, a circulating marker for enhanced coagulation and fibrinolysis, and tissue fibrin deposition was elevated. All the hemostasis-related responses to poly I:C, but not cytokine secretion, were blunted in TLR3(-/-) mice. Hence, the activation of TLR3 can induce the procoagulant state in the endothelium, and this could be relevant for understanding the mechanisms of viral stimulation of hemostasis.

Background: Atherosclerosis and inflammation/angiogenesis are strongly associated including growth of vasa vasorum (VV) and plaque neovascularization, but a causative role for neovascularization has still not been established. Hence, we investigated the effect of 3-deazaadenosine (c(3)Ado), an anti-inflammatory and anti-proliferative drug, on plaque progression and VV neovascularization in apoE(-/-)/LDL(-/-) double knockout mice., Methods: The arterial trees from apoE(-/-)/LDL(-/-) mice with, or without c(3)Ado at the age of 16 weeks (n=10), 18 weeks (n=8) and 20 weeks (n=7) were infused in situ with Microfil, and the aortas harvested and scanned with micro-CT (12mum cubic voxel). We characterized plaque volume and VV luminal volume along the descending aorta using Analyze 6.0 software. Cellular effects of c(3)Ado on human endothelial and vascular smooth muscle cells were investigated in cell cultures and on nylon cDNA expression arrays., Results: Lesions spatially connected to VV increased from 16 to 20 weeks significantly (p<0.001). The volume of atherosclerotic lesions was significantly reduced in animals treated with c(3)Ado (p<0.01). This was accompanied by a significant decrease of vasa vasorum neovascularization along the descending aorta (p<0.01). Using nylon cDNA expression arrays, we identified the regulation of anti-proliferative, anti-inflammatory genes in human smooth muscle cells which might be involved in the anti-angiogenic effects of c(3)Ado. Moreover, c(3)Ado dose-dependently prevented the proliferation and migration of human coronary artery endothelial cells in vitro., Conclusion: The smaller lesion volume in animals treated with c(3)Ado was closely associated with a reduced VV neovascularization, suggesting a direct relationship between lesion growth and VV development.

Objectives: To determine if hemorrhage into an arterial wall can be detected in CT images by virtue of the iron content., Materials and Methods: Aortas from male apoE(-/-)/LDL(-/-) mice (n = 31) were infused in situ with contrast agent, for micro-CT scanning and histology. Roentgen-opacities within the aortic walls were identified by histology and micro-x-ray fluorescence to be iron or calcium. Dual-energy scanning was performed at 2 energy levels using synchrotron-based micro-CT [(2 microm)(3) voxels, 16 and 20 keV] and 64-slice CT (0.4 x 0.4 x 0.6 mm voxels, 80 and 120 kVp)., Results: Opacities were identified as hemorrhage-related clusters of multiple punctate deposits, containing both Fe (0.48 x 10(-12) g/voxel) and Ca (3.18 x 10(-2) g/voxel), or as isolated confluent accumulations of exclusively calcium. Subtraction of the dual-energy CT scans discriminated iron from calcium deposits., Conclusion: Detection and quantification of iron deposits in hemorrhaged atherosclerotic lesions is feasible by dual-energy CT imaging.

Objective: We hypothesized that apolipoprotein E (apoE)(-/-)/low-density lipoprotein (LDL)(-/-) double knockout mice might develop vasa vasorum (VV) in association with advanced lesion formation., Methods and Results: Aortas from apoE(-/-)/LDL(-/-) mice aged 16, 18, 20, or 80 weeks were infused in situ with Microfil, harvested, and scanned with micro-computed tomography (CT). We characterized plaque volume and CT "density" as well as VV luminal volume along the aorta using Analyze 6.0 software. Results were complemented by a detailed histological plaque classification according to American Heart Association guidelines. From 16 to 80 weeks, plaque volume and VV opacified lumen volume increased with age (P<0.001). The 3-dimensional micro-CT images of arterial and venous VV trees allowed perfusion territories to be delineated. The spatial location and magnitude of VV density and adventitial inflammation were strongly correlated in advanced atherosclerotic lesions (r=0.91) and identified as an independent correlate to advanced lesions. At age 80 weeks, VV luminal volume was increased 20-fold compared with animals at age 16 weeks (P<0.001). Micro-CT showed that adventitial VV communicate with intraplaque microvessels., Conclusions: Our results show that apoE(-/-)/LDL(-/-) double knockout mice develop VV and advanced atheromas along the aorta. Lesion volume was closely associated with amount of neovascularization in advanced atheromas.

Objective: Animal models of restenosis have been a cornerstone of testing potential therapies and have improved the understanding of the underlying mechanisms. The aim of this study was to provide an in-depth comparison of the progression of restenotic lesion formation after arterial injury in apolipoprotein E -/- and C57BL/6 control mice., Methods: In this study, we investigated the difference in lesion formation of apolipoprotein E -/- and C57BL/6 controls on a high-cholesterol, high-fat diet after arterial injury. One week prior to arterial injury of the left femoral artery, mice were started on a high-cholesterol, high-fat diet. Diets were continued after arterial injury until euthanization. At five consecutive time points (2, 5, 10, 15, and 21 days), the intimal hyperplasia in the injured arteries was analyzed., Results: In the C57BL/6 control mice, a continuously increasing lesion formation, consisting primarily of alpha-smooth muscle actin-positive cells, was observed. Lesion formation in apolipoprotein E -/- mice was significantly more pronounced, resulting in complete occlusion of the arteries in four out of five vessels after 21 days. Lesions in apolipoprotein E -/- mice consisted predominantly of lipid-loaded foam cells and alpha-smooth muscle actin-positive cells. Further histological evaluation demonstrated cholesterol crystals in the lesions and neovascularizsation in cases of occlusion., Conclusions: Thus, apoE -/- mice on a high-cholesterol, high-fat diet provide a more valid model for the characterization of the development of restenotic lesions after mechanical irritation such as angioplasty than C57BL/6 mice.