http://repub.eur.nl/res/aut/6314/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/39364/ 2013-04-01T00:00:00Z Aims: Wall shear stress differentially regulates the arginase pathway in carotid arteries perfused ex vivo. Specific patterns of wall shear stress can locally determine atherosclerotic plaque size and composition in vivo. The present work investigates the effects of arginase inhibition on shear stress induced plaque composition. Methods and results: Carotid arteries of apolipoprotein E deficient mice were exposed to high (HSS), low (LSS) and oscillatory (OSS) shear stress conditions by the placement of a local shear stress modifier device for 9 weeks with or without the administration of the arginase inhibitor N-ω-Hydroxy-nor-L-arginine (nor-Noha) (10 mg/kg, i.p., 5 days/week). Carotid arginase activity was measured by colorimetric determination of urea. Atherosclerotic plaque size and composition, arginase expression and cellular localization were assessed by immunohistochemistry. Arginase activity was significantly increased in both LSS and OSS regions as compared to HSS. In the lesions, arginase II isoform co-localized preferentially with EC. Inhibition of arginase by nor-Noha decreased arginase activity and reduced plaque size in both LSS and OSS regions. Arginase inhibition affected mainly the composition of plaques developed in LSS regions by decreasing the total vascular ROS, the number of macrophages, apoptosis rate, lipid and collagen contents. Conclusions: Arginase activity is modulated by patterns of wall shear stress in vivo. Chronic inhibition of vascular arginase decreased the size of atherosclerotic lesions in both OSS and LSS regions, whereas changes on plaque composition were more pronounced in plaques induced by LSS. We identified wall shear stress as a key biomechanical regulator of arginase during plaque formation and stability. http://repub.eur.nl/res/pub/30551/ 2011-11-23T00:00:00Z Atherosclerosis is a chronic and often progressive disease of the wall of the arterial vasculature. The term atherosclerosis is derived from the Greek words “athero” meaning gruel or paste and “skleros” meaning stiff or hard. Atherosclerosis is considered a major clinical problem, which underlies most ischemic events of both the heart as well as the brain. It is the result of the Western lifestyle and can start very early in life even in persons without a strong genetic disposition like untreated familial hypercholesteremia. From the second decade onwards, the disease progresses more rapidly. The clinical silence of atherosclerosis is often broken between the 3rd and 5th decade, when patients present with ischemic complaints of e.g. heart and brain. Despite the continuing decrease in cardiovascular disease (CVD) associated death over the last decade, it still is one of the main causes of death in The Netherlands, accounting for 30,7% of total deaths in 2007. As a result, the socio-economic consequences remain huge. It has been estimated that in the European Union annual CVD-associated costs are €169 billion, of which €105 billion are costs directly related to healthcare. Historically, atherosclerosis was simply considered as an accumulation of lipids in the vascular wall. In the late 90’s, Russell Ross proposed a major revision of this theory, and these days the perspective of atherosclerosis as a complicated lipid-driven inflammatory disease is widely accepted. Lipid metabolism and inflammation mutually influence each other yielding the complete spectrum of atherosclerotic disease progression. This is reflected in the correlation between future cardiovascular events and the combined values of cholesterol, as indicator of lipid status, and CRP, as indicator of systemic inflammatory activity. Since CRP levels reflect systemic inflammatory activity, this notion underscores the role of immunity in human atherosclerosis. http://repub.eur.nl/res/pub/34537/ 2011-01-01T00:00:00Z Interest in the use of contrast-enhanced MRI to enable in vivo specific characterization of atherosclerotic plaques is increasing. In this study the intrinsic ability of three differently sized gadolinium-based contrast agents to permeate different mouse plaque phenotypes was evaluated with MRI. A tapered cast was implanted around the right carotid artery of apoE-/-mice to induce two different plaque phenotypes: a thin cap fibroatheroma (TCFA) and a non-TCFA lesion. Both plaques were allowed to develop over 6 and 9 weeks, leading to an intermediate and advanced lesion, respectively. Signal enhancement in the carotid artery wall, following intravenous injection of Gd-HP-DO3A as well as paramagnetic micelles and liposomes was evaluated. In vivo T1-weighted MRI plaque enhancement characteristics were complemented by fluorescence microscopy and correlated to lesion phenotype. The two smallest contrast agents, i.e. Gd-HP-DO3A and micelles, were found to enhance contrast in T1-weighted MR images of all investigated plaque phenotypes. Maximum contrast enhancement ranged between 53 and 70% at 6min after injection of Gd-HP-DO3A with highest enhancement and longest retention in the non-TCFA lesion. Twenty-four hours after injection of micelles maximum contrast enhancement ranged between 24 and 35% in all plaque phenotypes. Administration of the larger liposomes did not cause significant contrast enhancement in the atherosclerotic plaques. Confocal fluorescence microscopy confirmed the MRI-based differences in plaque permeation between micelles and liposomes. Plaque permeation of contrast agents was strongly dependent on size. Our results implicate that, when equipped with targeting ligands, liposomes are most suitable for the imaging of plaque-associated endothelial markers due to low background enhancement, whereas micelles, which accumulate extravascularly on a long timescale, are suited for imaging of less abundant markers inside plaques. Low molecular weight compounds may be employed for target-specific imaging of highly abundant extravascular plaque-associated targets. http://repub.eur.nl/res/pub/28634/ 2010-10-11T00:00:00Z Background: Alterations of wall shear stress can predispose the endothelium to the development of atherosclerotic plaques. We evaluated the modulation of arginase by wall shear stress. Material and methods: We perfused isolated carotid arterial segments to either unidirectional high mean shear stress (HSS) or low mean and oscillating shear stress (OSS) for 3 days. Vascular function was analyzed by diameter measurement, arginase expression and localization by western blot and immunohistochemistry, respectively. These effects were also evaluated in right carotid artery of apolipoprotein E (apoE-/-) deficient mice, fed with high cholesterol diet, which was exposed to HSS, LSS and OSS flow conditions by the placement of a shear stress modifier for 9 weeks. ApoE-/- mice received either the arginase inhibitor nor-Noha (20mg/kg, 5 days/week) or placebo for 9 weeks. Plaque size and I/M ratio were determined by histology. Results: Our data from ex vivo perfusion showed that exposure of carotid segments to both low and oscillatory flow conditions significantly increase arginase II protein expression and activity as compared to high shear stress athero-protective flow condition. Long-term treatment with nor-Noha effectively decreased arginase activity at LSS and OSS regions, which in turn was accompanied by a decreased I/M ratio and the size of atherosclerotic lesion. In the lesion, inhibition of arginase decreased the number of CD68 positive cells at LSS and OSS zones. Exposure of carotid artery to OSS induced a more pronounced activation of arginase as compared to HSS. Conclusions: Arginase is modulated by patterns of wall shear stress. Long-term treatment of apoE- /- mice with arginase inhibitor decreased carotid I/M ratio and atherosclerotic lesion at LSS and OSS regions. Therefore, inhibition of arginase by nor-Noha may emerge as a distinct way to target atherosclerosis disease. http://repub.eur.nl/res/pub/30000/ 2008-12-01T00:00:00Z http://repub.eur.nl/res/pub/35054/ 2007-12-01T00:00:00Z Wall shear stress (WSS), the frictional force between blood and endothelium, is an important determinant of vascular function. It is generally assumed that WSS remains constant at a reference value of 15 dyn/cm2. In a study of small rodents, we realized that this assumption could not be valid. This review presents an overview of recent studies in large and small animals where shear stress was measured, derived from velocity measurements or otherwise, in large vessels. The data show that large variations exist within a single species (human: variation of 2-16 N/m2). Moreover, when we compared different species at the same location within the arterial tree, an inverse relationship between animal size and wall shear stress was noted. When we related WSS to diameter, a unique relationship was derived for all species studied. This relationship could not be described by the well-known r3law of Murray, but by the r2law introduced by Zamir et al. in 1972. In summary, by comparing data from the literature, we have shown that: (i) the assumption of a physiological WSS level of ∼15 dyn/cm2for all straight vessels in the arterial tree is incorrect; (ii) WSS is not constant throughout the vascular tree; (iii) WSS varies between species; (iv) WSS is inversely related to the vessel diameter. These data support an "r2law" rather than Murray's r3law for the larger vessels in the arterial tree. http://repub.eur.nl/res/pub/36379/ 2007-10-01T00:00:00Z PURPOSE OF REVIEW: This review describes evidence that shear stress acts through modulation of inflammation and by that process affects atherogenesis and plaque composition. RECENT FINDINGS: In low shear stress regions antiatherogenic transcription factors are downregulated and pro-atherogenic transcription factors are upregulated. Consequently, inflammatory cells may home low shear stress regions more easily to the plaques because of increased expression of adhesion factors, a decreased rolling speed and an increased expression of chemokines, thereby changing the composition of the plaques into a more vulnerable phenotype. In contrast, in advanced plaque development vascular lumen decreases and shear stress increases, especially upstream of the plaques. The predominant upstream location of lipids induces a prevalent upstream location of inflammatory cells leading to localized plaque rupture. SUMMARY: Shear stress has been shown to play a role in plaque induction, plaque progression and plaque rupture. The mechanism for plaque induction seems to differ from the role of shear stress for plaque rupture, whereby the former mechanism is induced by low shear stress and the latter by high shear stress. http://repub.eur.nl/res/pub/35539/ 2007-03-01T00:00:00Z We previously found that low shear stress (LSS) induces atherosclerotic plaques in mice with increased lipid and matrix metalloproteinase content and decreased vascular smooth muscle and collagen content. Here, we evaluated the role of chemokines in this process, using an extravascular device inducing regions of LSS, high shear stress, and oscillatory shear stress (OSS) in the carotid artery. One week of shear stress alterations induced expression of IFN-γ-inducible protein-10 (IP-10) exclusively in the LSS region, whereas monocyte chemoattractant protein-1 (MCP-1) and the mouse homolog of growth-regulated oncogene α (GRO-α) were equally upregulated in both LSS and OSS regions. After 3 weeks, GRO-α and IP-10 were specifically upregulated in LSS regions. After 9 weeks, lesions with thinner fibrous caps and larger necrotic cores were found in the LSS region compared with the OSS region. Equal levels of MCP-1 expression were observed in both regions, while expression of fractalkine was found in the LSS region only. Blockage of fractalkine inhibited plaque growth and resulted in striking differences in plaque composition in the LSS region. We conclude that LSS or OSS triggers expression of chemokines involved in atherogenesis. Fractalkine upregulation is critically important for the composition of LSS-induced atherosclerotic lesions. http://repub.eur.nl/res/pub/35615/ 2007-02-01T00:00:00Z BACKGROUND - Atherosclerosis is considered an inflammatory disease. Recent studies provided evidence for a predominant upstream location of plaque inflammation. The present study introduces a novel technique that evaluates the underlying mechanism of this spatial organization. METHODS AND RESULTS - In hypercholesterolemic rabbits, atherosclerosis of the infrarenal aorta was induced by a combination of endothelial denudation and a high-cholesterol diet (2% cholesterol for 2 months). At the time of death, aortic vessel segments were dissected and reconstructed with a new technique that preserved the original intravascular ultrasound-derived lumen geometry. This enabled us to study the spatial relation of histological markers like macrophages, smooth muscle cells, lipids, gelatinolytic activity, and oxidized low-density lipoprotein. Results showed a predominant upstream localization of macrophages and gelatinase activity. Colocalization studies indicated that gelatinase activity was associated with macrophages and smooth muscle cells. Further analysis revealed that this was caused by subsets of smooth muscle cells and macrophages, which were associated with oxidized low-density lipoprotein accumulation. CONCLUSIONS - Upstream localization of a vulnerable plaque phenotype is probably due to an accumulation of oxidized low-density lipoprotein, which activates/induces subsets of smooth muscle cells and macrophages to gelatinase production. http://repub.eur.nl/res/pub/4732/ 2003-01-01T00:00:00Z Introduction Atherosclerosis belongs to the chronic diseases with the highest mortality in the Western world. While the disease has traditionally been explained by risk factors like high cholesterol and hypertension, evidence is now accumulating for a role of the immune system in the progression of atherosclerosis. This article will explore the role of innate and adaptive immunity in atherosclerosis only. It does not aim at describing all facets of the immune system. In order to facilitate the reading of the article the pathophysiology of the immune system in atherosclerosis is preceded by the relevant physiology.