256层CT对颈动脉粥样硬化斑块成分及性质的分析

目的　探讨256层螺旋CT 血管造影（CT angiography,CTA）评价颈动脉粥样硬化斑块的价值。 方法　 对234例拟诊颈动脉硬化狭窄的患者行头颈部CTA检查, 根据颈动脉有无斑块分为病变组和正常对照组,通过CT值分析斑块成分和性质。 结果　病变组266支动脉,其中脂肪斑块组51支、纤维斑块组26支、钙化斑块组67支、混合斑块组122支;正常组163支。脂肪斑块组脑梗死出现率明显大于纤维斑块组和钙化斑块组（P＜0.01）;脂肪合并钙化斑块组脑梗死出现率明显大于纤维合并钙化斑块组（P＜0.01）;含脂肪斑块组溃疡出现率大于含纤维斑块组（P＜0.05）。 结论　256层螺旋CT能够分析颈动脉斑块的成分、性质,初步评价颈动脉斑块的稳定性。     

Fluorescence spectroscopic and histochemical analysis using hematoporphyrin as a microenvironmental probe for atherosclerotic change in the human aorta.

Hematoporphyrin (HP) was used as a microenvironmental fluorescent probe to investigate the development of human atherosclerotic plaques. We compared the site of HP accumulation with changes in the HP fluorescence spectrum in atheromatous plaques and in a liposome control model, using a confocal laser scanning microscope equipped with a photonic multi-channel analyzer linked to a fluorescence spectrometer. Wavelength shifts of the two peaks of HP fluorescence (F1, 620 nm; and F2, 640-690 nm) were monitored, and the integrated F2/F1 ratio was calculated as a measure of HP fluorescence. The F1 peak is characteristic of a predominantly aqueous site. The ratio reflects selective changes in the distribution and overcrowding of HP molecules in the limited space of the artificial membrane model. Compared with a normal artery, the atherosclerotic lesions showed an increase in the area of HP fluorescence, increased fluorescence intensity, a red shift of the HP fluorescence spectrum, and an increased F2/F1 ratio. The F2/F1 ratio of the membranous structures was markedly greater in the cores of the fibrous plaques than in the other plaques. The F1 peak showed increased intensity in the atheromatous plaque core, whereas in hydrophilic fibrous regions, such as the cap of the plaque, the intensity of the F1 peak was lower than in the core region. HP aggregation was observed in damaged cells and in water surrounded by lipid in the atheromatous core. Using HP as a probe allowed us to determine not only the ionization or polarity of each region in the atherosclerotic plaques but also to detect the separation and fusion of the lipid bilayer or micelle lipids, as well as damage to the cellular membranes and cholesterol enrichment. These findings suggest that HP is useful for detecting clinically important changes in atherosclerotic lesions, to lipid-rich, unstable, and vulnerable plaques, which are closely associated with cardiovascular events.     

冠状动脉粥样硬化斑块内血管新生与斑块稳定的关系

目的　比较稳定斑块和不稳定斑块内新生血管形态学分布和数量上的差异 ,探讨新生血管与斑块稳定的关系。方法　从死亡前有急性冠脉综合征发生的 5 2例尸检冠状动脉标本中选取晚期动脉粥样硬化病变的组织块共 92 2块 ,以脂质核心面积是否大于斑块面积的 4 0 %为标准将其分为不稳定斑块组 (15 3块 )和稳定斑块组 (76 9块 ) ,比较两组斑块内新生血管的检出率。由两组随机选取各 4 0个组织块进行第八因子相关抗原抗体的免疫组织化学染色 ,观察阳性物质在斑块内的分布特点并通过计算机图像分析系统进行量化分析。结果　不稳定斑块组新生血管检出率 (80 4 % )显著高于稳定斑块组 (6 6 6 % ,P <0 0 1)。新生血管主要分布在斑块的肩部和基底部 ,纤维帽相对较少 ;不稳定斑块组各部位的新生血管最大密度 [肩部 :(2 2 16± 19 96 )个 /mm2 ,基底部 :(2 1 6 8± 2 0 4 4 )个 /mm2 ,纤维帽 :(3 80± 5 32 )个 /mm2 ]均显著大于稳定斑块组的相应部位 [肩部 :(10 0 4± 11 5 2 )个 /mm2 ;基底部 :(9 6 8± 11 5 2 )个 /mm2 ;纤维帽 :(1 4 8± 2 2 8)个 /mm2 ,P <0 0 5 ]。结论　不稳定斑块组较稳定斑块组新生血管检出率和密度均显著增高 ,提示新生血管与斑块的不稳定性密切相关。除目前较为公认的脂质核心大小     

Age-related changes in plaque composition: a study in patients suffering from carotid artery stenosis.

OBJECTIVE: The extent of atherosclerotic plaque burden and the incidence of atherosclerosis-related cardiovascular events accelerate with increasing age. The composition of the plaque is associated with plaque thrombosis and acute coronary occlusion. Surprisingly, however, the relation between advancing age and atherosclerotic plaque composition is still unclear. In the present study, we investigated the association between plaque characteristics and advancing age in a population of patients with haemodynamically significant carotid artery stenosis. METHODS: Patients (N=383), ages 39-89 years, underwent carotid endarterectomy (CEA). Morphometric analysis was performed on the dissected atherosclerotic plaques to study the prevalence of fibrous and atheromatous plaques. Picro sirius red, haematoxylin eosin, alfa actin and CD68 stainings were performed to investigate the extent of collagen, calcification, smooth muscle cells and macrophages in carotid plaques, respectively. The presence of metalloproteinases-2 and -9 was assessed by ELISA. RESULTS: With aging, a decrease in fibrous plaques and an increase in atheromatous plaques were observed. This was accompanied by an age-associated decrease in smooth muscle cell content in carotid plaques. Macrophage content slightly increased with age. In addition, total matrix metalloprotease (MMP)-2 was negatively and MMP-9 positively related with age. Differences in plaque phenotype were most prominent for the youngest age quartile compared with older age quartiles. CONCLUSIONS: With increasing age, the morphology of atherosclerotic plaques from patients with carotid artery stenosis changes. Plaques become more atheromatous and contain less smooth muscle cells with increasing age. Local inflammation and MMP-9 levels slightly increased with age in plaques obtained from patients suffering from haemodynamically significant advanced atherosclerotic lesions.     

人体冠状动脉粥样硬化斑块中氧化低密度脂蛋白和新生血管与斑块稳定性的关系

目的探讨氧化低密度脂蛋白(oxLDL)在人体冠脉稳定斑块和不稳定斑块内的分布、与血管新生之间的关系及其在不稳定斑块形成过程中的可能作用。方法选取经临床和病理解剖检查确诊的急性冠脉综合征(ACS)病例进行免疫组织化学SABC法染色并通过计算机图像分析系统进行量化分析。结果(1)不稳定斑块组内各部位oxLDL的聚集程度均明显高于稳定斑块组。oxLDL主要分布于斑块的肩部,纤维帽及基底部相对较少。oxLDL阳性面积比(‰)分别为肩部:不稳定斑块组20.43±3.12,稳定斑块组17.65±4.22;基底部:不稳定斑块组5.65±1.65,稳定斑块组3.22±1.02;纤维帽:不稳定斑块组4.77±2.03,稳定斑块组2.80±0.22。oxLDL是脂质核心的主要组成部分。(2)斑块肩部Ⅷ因子与oxLDL的阳性面积比呈明显正相关(r=0.8247,P=0.000)。结论不稳定斑块组较稳定斑块组oxLDL的聚集量高,尤其是肩部oxLDL的分布明显高于稳定组,提示斑块内oxLDL含量的多少及分布区域是影响斑块稳定性的重要因素。oxLDL通过促进炎细胞经新生血管在斑块局部聚集而影响斑块的稳定性。     

Raman spectroscopy study of atherosclerosis in human carotid artery

Fourier-transform (FT)-Raman spectroscopy has been used for identification and evaluation of human artherosclerotic lesions, providing biochemical information on arteries. In this work, fragments of human carotid arteries postmortem were analyzed using a FT-Raman spectrometer operating at an excitation wavelength of 1064 nm, power of 200 mW, and spectral resolution of 4 cm(-1). A total of 75 carotid fragments were spectroscopically scanned and FT-Raman results were compared with histopathology. Discriminant analysis using Mahalanobis distance was applied over principal components scores for tissue classification into three categories: nonatherosclerotic, atherosclerotic plaque without calcification and with calcification. Nonatherosclerotic artery, atherosclerotic plaque, and calcified plaque exhibit spectral signatures related to biochemicals presented in each tissue type, such as bands of collagen and elastin (proteins), cholesterol and its esters, and calcium hydroxyapatite and carbonate apatite, respectively. Spectra of nonatherosclerotic artery were then classified into two groups: normal and discrete diffuse thickening of the intima layer (first group) and moderate and intense diffuse thickening of the intima layer (second group). FT-Raman could identify and classify the tissues found in the atherosclerotic process in human carotid in vitro and had the ability to identify alterations to the diffuse thickening of the intima layer and classify it depending on the intensity of the thickening.     

Role of smooth-muscle cells in the formation of the atherosclerotic plaque

The role of smooth muscle cells in the formation of atherosclerotic plaques was studied by the fluorescent antibody method on autopsy material with the aid of antiserum against smooth-muscle actomyosin. The principal forms of atherosclerotic lesion (lipid stain, fibrous plaque, atheromatous plaque) were investigated in the aorta, the brain vessels, and the coronary arteries. Smooth-muscle cells were found in the intima along with atherosclerotic foci, in the lipid stain and fibrous tissue of the plaque, but not in the atheromatous masses. Proliferation and migration of smooth-muscle cells are regarded as an essential factor in the morphogenesis of atherosclerosis.Presented by Academician of the Academy of Medical Sciences of the USSR A. P. Avtsyn.Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 79, No. 6, pp. 110–113, June, 1975.     

Structure of aortic lipid spots in two ethnic groups of the Yakutsk population]

Histometric study of aortic lipid spots (LS) in males of both ethnic groups who died of incidental causes at the age of 20-39 showed a decrease of the lipid-containing smooth muscle cells number (SMC), an increase of the foam cell (FC) number and extracellular lipids, retraction of the non-lipid zone surface in LS in proportion with their thickening. LS on the aorta with fibrous plaques in both Yakuts and Russians are characterized by the accumulation of FC, extracellular lipids and by their trend to the thickening as compared to LS in the aorta without fibrous plaques. Thick aortic LS in Russians with a predominant accumulation of FC in the superficial and intermediate layers are the most probable precursors of the atherosclerotic plaque.     

Multimodal spectroscopy detects features of vulnerable atherosclerotic plaque

Early detection and treatment of rupture-prone vulnerable atherosclerotic plaques is critical to reducing patient mortality associated with cardiovascular disease. The combination of reflectance, fluorescence, and Raman spectroscopy-termed multimodal spectroscopy (MMS)-provides detailed biochemical information about tissue and can detect vulnerable plaque features: thin fibrous cap (TFC), necrotic core (NC), superficial foam cells (SFC), and thrombus. Ex vivo MMS spectra are collected from 12 patients that underwent carotid endarterectomy or femoral bypass surgery. Data are collected by means of a unitary MMS optical fiber probe and a portable clinical instrument. Blinded histopathological analysis is used to assess the vulnerability of each spectrally evaluated artery lesion. Modeling of the ex vivo MMS spectra produce objective parameters that correlate with the presence of vulnerable plaque features: TFC with fluorescence parameters indicative of collagen presence; NC∕SFC with a combination of diffuse reflectance β-carotene∕ceroid absorption and the Raman spectral signature of lipids; and thrombus with its Raman signature. Using these parameters, suspected vulnerable plaques can be detected with a sensitivity of 96% and specificity of 72%. These encouraging results warrant the continued development of MMS as a catheter-based clinical diagnostic technique for early detection of vulnerable plaques.     

Non-invasive MRI of mouse models of atherosclerosis

Early detection and characterization of atherosclerotic lesions susceptible to sudden rupture and thrombosis may decrease morbidity and mortality. Plaque development has been extensively studied using MRI in animal models of rapidly progressing atherosclerosis. These transgenic mice develop atherosclerotic plaques in the aortic root by 10 weeks of age and throughout the vasculature thereafter. Transplantation of lesion-containing segments of the thoracic aorta into wild-type mice results in nearly total reversal of atherosclerosis, making it possible to study both progression and regression of plaques in this model. MRI permits the non-invasive accurate assessment of atherosclerotic plaque burden and the differentiation between the lipid and fibrous content of individual plaques, thus providing a non-invasive approach to serially monitor the evolution of individual plaques in the mouse models. Emergence of novel contrast agents that target a diverse set of molecules within the plaque are now helping to elucidate the changes at the cellular and molecular levels during plaque progression and regression.     

Clonal characteristics of fibrous plaques and fatty streaks from human aortas.

Using isoenzymes of glucose-6-phosphate dehydrogenase (G-6-PD) as cellular markers, a study was made of atherosclerotic fibrous plaques and fatty streaks in aortas of black women heterozygous for G-6-PD. Of 29 fibrous plaques, 26 (89.7%) contained only one isoenzyme (17, A; 9, B), the other three containing both A and B. Of 28 fatty streaks, five (17.8%) contained only one isoenzyme (2, A; 3, B), the remaining 23 containing both A and B. Normal uninvolved aorta contained both A and B isoenzymes in 99 of 101 samples. These results confirm the monoclonal character of atherosclerotic fibrous plaques; this strands in contrast to the fatty streaks which most commonly contain the two isoenzymes. The studies on the fatty streaks are inconclusive at this stage in determining whether the streak is the forerunner of the fibrous plaque.     

Characteristics of the plaque under a coronary thrombus

Summary Young men dying suddenly and autopsied by the coroner sometimes have coronary thrombosis at a relatively early stage of arteriosclerosis. The plaques under such thrombi often have a complex of features, a) rupture, b) hemorrhage, c) medial destruction, d) nodular collections of foam cells, e) calcification, f) cellular infiltrates of the fibrous cap, fibrous base and adventitia, and g) a newly described kind of phagocytic activity at the boundary between the necrotic core and the fibrous base of the plaque. Commonplace innocuous plaques in most middle and old aged subjects without heart disease also often have some of these features. What structural characteristics might distinguish rare thrombogenic from commonplace innocuous plaques? Twenty-one thrombotic plaques from 18 cases of sudden coronary heart disease (CHD) death were histologically compared with 129 nonthrombotic plaques from these same 18 cases, 85 plaques from 23 cases of CHD death due to arteriosclerotic occlusion, and 94 plaques from 22 cases having no CHD. Plaques with thrombosis all had necrotic cores; plaques for comparison with these were therefore chosen all to have necrotic cores. Rupture and hemorrhage were found in 90% of thrombotic plaques, with mixing of plaque gruel and blood in the thrombus. Medial destruction, foam cells and calcification (features c, d, and e) were commonplace in all types of plaques. Small-cell infiltrates and atherophagocytosis (features f or g) were found in 72–94% of the 21 thrombotic plaques, but only in 18–24% of the 94 not CHD plaques. The necrotic core, characterized by crystalline cholesterol, appears to incite cellular responses in some plaques but not others; those responses distinguish thrombogenesis. The findings imply that thrombogenicity and its accompanying plaque cellularity are incited not by cholesterol, but by some trace or minor component of the plaque gruel of the necrotic core. The possibility of testing these hypotheses by practical methods has been shown to be feasible.     

稳定性,不稳定性心绞痛及急性心肌梗死病人冠状动脉病变的？…

比较稳定型心绞痛、不稳定型心绞痛及急性心肌梗死病人冠状动病变的组织学差异,以阐明其发生的病理学机制。方法选天临床诊明确的ＳＡ、ＵＡ及ＡＭＩ病人死后的尸检收脏标本,对其冠状动脉取材并做组织学及免疫组织化学观察。     

Human aortic fibrolipid lesions. Progenitor lesions for fibrous plaques, exhibiting early formation of the cholesterol-rich core.

The early development of the lipid-rich core and other features of atherosclerotic fibrous plaques has been elucidated by examining discrete, small regions of raised intima in human aorta, which often bear a resemblance to both fatty streaks and fibrous plaques. Approximately one-fourth of small raised lesions (less than 16 sq mm of surface area) contained little or no stainable lipid, while three-fourths had a characteristic appearance, which included a superficial layer of foam cells, a core of noncrystalline and/or crystalline lipid, and a developed or developing collagenous cap. Total intimal volumes of the lipid-containing lesions, termed "fibrolipid lesions," ranged from 3 to 43 microliters, with the majority less than 16 microliters. Core lipid in the smallest lesions was located in the musculoelastic layer of the intima. In larger lesions the core extended luminally into the elastic hyperplastic layer, and cholesterol crystals were found more frequently. Total cholesterol concentration in fibrolipid lesions was similar to that in fatty streaks; however, the ratio of unesterified to total cholesterol was relatively high, similar to that found in fibrous plaques. It is concluded that 1) the formation of a lipid-rich core and cholesterol crystallization are early events in the development of many raised lesions; 2) the consistent association between the superficial layer of foam cells and the deep-lying lipid-rich core raises the possibility of an influence, possibly indirect, of foam-cell lipid metabolism on core formation; and 3) the fibrolipid lesion may represent one stage in a potential transitional morphologic sequence between fatty streak and fibrous plaque.     

The involvement of matrix glycoproteins in vascular calcification and fibrosis: an immunohistochemical study.

Calcification and fibrointimal proliferation are associated with advanced complicated atherosclerosis in large arteries but may also occur in smaller vessels, resulting in ischaemic tissue necrosis. This study investigates whether the mechanisms of calcification and intimal fibrosis are similar in vessels of different sizes. The localization of osteopontin (OPN), matrix Gla protein (MGP), thrombospondin-1 (TSP-1), and cartilage oligomeric matrix protein (COMP) was investigated in three types of human vascular lesions: atherosclerosis, chronic vascular rejection (CVR) in renal allografts, and calcific uraemic arteriolopathy (calciphylaxis). These lesions were chosen as they affect different sized blood vessels and they exhibit a fibroproliferative intimal reaction, with or without calcification, resulting in luminal obliteration and ischaemic complications. OPN, MGP, TSP-1, and COMP were not detected in normal blood vessels. However, OPN and MGP were expressed at sites of calcification within atherosclerotic lesions and in microvessels in calciphylaxis, suggesting that calcification in different sized vessels may occur by a common mechanism. These proteins were not detected in areas of fibrointimal proliferation. In contrast, TSP-1 was localized primarily within the fibrous tissue of atherosclerotic lesions and was also expressed in the expanded fibrous intima of arteries showing CVR. COMP was localized primarily within the fibrous tissue under the lipid core of the majority of advanced atherosclerotic lesions. TSP-1 and COMP were also detected in areas of microcalcification in atherosclerotic lesions and TSP-1 was detected adjacent to areas of calcification in calciphylaxis. However, neither TSP-1 nor COMP was localized to calcific foci within these lesions. The localization of OPN, MGP, TSP-1, and COMP to pathological, but not normal arterial intima supports a pathogenetic role for these proteins in the development of vascular fibrosis and calcification. Modulation of their production and activity may offer a novel approach to the therapy of a number of vascular diseases.     

Lipids in cells of atherosclerotic and uninvolved human aorta. III. Lipid distribution in intimal sublayers

The distribution, content, and composition of tissue and cellular lipids in intimal layers of unaffected and atherosclerotic human aorta were studied. Aortic tissue was divided into medial and intimal layers; the intimal layer was further separated into elastic-hyperplastic and musculo-elastic sublayers. Cells were isolated from both intimal layers by enzyme digestion. The lipids extracted from whole tissue and cells were separated by TLC and analyzed by scanning densitometry. The highest content of phospholipids (PhL), triglycerides (TG), cholesterol (C), and cholesteryl esters (CE) was detected in the elastic-hyperplastic layer of atherosclerotic plaque. However, taking into account that the elastic-hyperplastic layer of intima in lesioned areas was thickened, the lipid content per volume unit of both sublayers in fatty streaks and in plaques was equal. In the media underlying an atherosclerotic plaque, an increase in CE rather than in other lipid classes occurred. In the intima, an overall increase in PhL, TG, C, and CE content was found to display a constant ratio between these lipid classes, similar to that of low density lipoproteins (LDL). Cells isolated from atherosclerotic lesions had a higher lipid content than cells from areas of unaffected intima. However, the increase in the content of different lipid classes was not proportional, compared with tissue lipids. The content of PhL was the same, while an increase in TG, C, and CE was observed. The major contribution to excess cellular lipid accumulation in cells from atherosclerotic lesions was made by CE.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pathological mechanisms of erythrocyte-induced vulnerability of atherosclerotic plaques

Erythrocytes are considered a new culprit contributing to atherosclerosis. Plaques with intraplaque hemorrhage are prone to new plaque hemorrhage, which may not only stimulate the progression of atherosclerosis but also promote the transition from a stable to an unstable lesion. However, the role of erythrocytes in inducing the vulnerability of plaque with intraplaque hemorrhage and the possible mechanism involved are not well understood. Recently, increased cholesterol level from erythrocytes was reported to expand the lipid core of plaque. As well, heme, iron and phospholipids derived from erythrocytes trigger peroxidization in vitro, which is strongly associated with the progression of atherosclerosis. We speculate that erythrocytes trapped in plaque may induce vulnerability of atherosclerotic plaques not only by accumulating lipids but also by promoting peroxidization within plaques, thereby expanding the lipid core, increasing the infiltration of inflammatory cells and attenuating the fibrous cap of plaques. This proposition may provide clues into the development of novel treatments to increase the stability of atherosclerotic plaques.     

Intra-plaque production of platelet-activating factor correlates with neoangiogenesis in human carotid atherosclerotic lesions

Platelet-activating factor (PAF) is a phospholipid mediator synthesized by activated inflammatory and endothelial cells. Recently PAF has been shown to contribute to neoangiogenesis in several experimental models. Here we evaluated the presence of PAF and its potential role in neovascularization within human atherosclerotic plaques. The amount of PAF extracted from 18 carotid plaques (266.65+/-40.07 pg/100 mg dry tissue; mean +/- SE) was significantly higher than that extracted from 18 normal arterial specimens (6 from carotid artery and 12 from aorta) (4.72+/-2.31 pg/100 mg dry tissue; mean +/- SE). The levels of PAF significantly correlated with the infiltration of CD68-positive monocytes and the extent of neovascularization, detected as von Willebrand Factor-positive cells. The amount of PAF also correlated with the area occupied by TNF-alpha-expressing cells. The absence of enhanced level of PAF in the circulation of atherosclerotic patients suggests a local production of this mediator within the plaque. The lipid extracts of atherosclerotic plaques containing high levels of PAF-bioactivity, but not those of control arteries, were angiogenic in a murine Matrigel model. WEB 2170, a specific PAF receptor antagonist, significantly prevented angiogenesis induced by the lipid extracts of atherosclerotic plaques. Our results indicate a local production of PAF within the atherosclerotic plaques and suggest that it may contribute to intra-plaque neoangiogenesis.     

Inelasticity of Human Carotid Atherosclerotic Plaque

Little mechanical test data exists regarding the inelastic behavior of atherosclerotic plaques. As a result finite element (FE) models of stenting procedures commonly use hyperelastic material models to describe the soft tissue response thus limiting the accuracy of the model to the expansion stage of stent implantation and leave them unable to predict the lumen gain. In this study, cyclic mechanical tests were performed to characterize the inelastic behavior of fresh human carotid atherosclerotic plaque tissue due to radial compressive loading. Plaques were classified clinically as either mixed (M), calcified (Ca), or echolucent (E). An approximately linear increase in the plastic deformation was observed with increases in the peak applied strain for all plaque types. While calcified plaques generally appeared stiffest, it was observed that the clinical classification of plaques had no significant effect on the magnitude of permanent deformation on unloading. The test data was characterized using a constitutive model that accounts for both permanent deformation and stress softening to describe the compressive plaque behavior on unloading. Material constants are reported for individual plaques as well as mean values for each plaque classification. This data can be considered as a first step in characterizing the inelastic behavior of atherosclerotic plaques and could be used in combination with future mechanical data to improve the predictive capabilities of FE models of angioplasty and stenting procedures particularly in relation to lumen gain.     

Genetic loss of Gas6 induces plaque stability in experimental atherosclerosis

The growth arrest-specific gene 6 (Gas6) plays a role in pro-atherogenic processes such as endothelial and leukocyte activation, smooth muscle cell migration and thrombosis, but its role in atherosclerosis remains uninvestigated. Here, we report that Gas6 is expressed in all stages of human and mouse atherosclerosis, in plaque endothelial cells, smooth muscle cells and macrophages. Gas6 expression is most abundant in lesions containing high amounts of macrophages, ie thin fibrous cap atheroma and ruptured plaque. Genetic loss of Gas6 does not affect the number and size of initial and advanced plaques in ApoE(-/-) mice, but alters its plaque composition. Compared to Gas6(+/+): ApoE(-/-) mice, initial and advanced plaques of Gas6(-/-): ApoE(-/-) mice contained more smooth muscle cells and more collagen and developed smaller lipid cores, while the expression of TGFbeta was increased. In addition, fewer macrophages were found in advanced plaques of Gas6(-/-): ApoE(-/-) mice. Hence, loss of Gas6 promotes the formation of more stable atherosclerotic lesions by increasing plaque fibrosis and by attenuating plaque inflammation. These findings identify a role for Gas6 in plaque composition and stability.