Adhesion molecules and atherogenesis.

Atherosclerosis is an inflammatory disease of the vessel wall characterized by monocyte infiltration in response to pro-atherogenic factors such as oxidized lipids. Recently, the role of specific adhesion molecules in this process has been explored. The endothelium overlying atherosclerotic lesions expresses P-selectin and the shoulder regions express vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), which is also expressed on endothelium in regions not prone to plaque development. Serum levels of soluble P-selectin, ICAM-1 and VCAM-1 are elevated in patients with angina pectoris or peripheral atherosclerotic disease. Reconstituted in vitro systems using monocytes on cytokine-activated endothelial cells under shear flow suggested the involvement of P-selectin, L-selectin, VCAM-1, its ligand, VLA-4 integrin and CD18 integrins. Studies of monocyte adhesion in isolated perfused carotid arteries harvested from atherosclerotic (apoE-/-) mice show a predominant involvement of P-selectin and its ligand P-selectin glycoprotein-1 (PSGL-1) in rolling and of VLA-4 and VCAM-1 in firm adhesion. Consistent with these findings, apoE-/- mice that are also deficient for P-selectin show significantly reduced atherosclerotic lesion sizes and are almost completely protected from neointimal growth after vascular injury. Milder effects are also seen in the low-density lipoprotein (LDL) receptor deficient (LDLR-/-) mouse. In a high cholesterol/cholate model, a role of ICAM-1 and CD18 integrins was also shown, but this awaits confirmation in more physiologic models. Transient blockade of the VLA-4/VCAM-1 adhesion pathway by antibodies or peptides in apoE-/- or LDLR-/- mice reduced monocyte and lipid accumulation in lesions. These data suggest that P-selectin, PSGL-1, VLA-4 and VCAM-1 are the most important adhesion molecules involved in monocyte recruitment to atherosclerotic lesions.     

抗炎药物对溃疡性结肠炎患者肠黏膜组织NF-κB的活化和细胞黏附分子表达的影响

探讨抗炎药物柳氮磺胺吡啶 (SASP)和糖皮质激素对溃疡性结肠炎 (Ulcerative colitis,UC)患者肠黏膜活检组织细胞间黏附分子 (Intercellular adhesion molecule- 1,ICAM- 1)与血管细胞黏附分子 (Vascular cell adhes-ion molecule- 1,VCAM- 1) m RNA和蛋白表达的影响 ,以及黏附分子 m RNA的表达与 NF- κB活化的关系。2 7例来自四川大学华西医院的 U C患者 (符合 1993年太原会议溃疡性结肠炎诊断标准 )被纳入本研究。其中 15例使用过药物 (SASP或 SASP 糖皮质激素 )治疗 ,12例未用过任何与 U C治疗相关的药物 ,9例同期结肠癌患者 (取其癌旁正常组织 )被作为对照。采用逆转录聚合酶链反应 (RT- PCR)检测 ICAM- 1与 VCAM- 1m RNA的表达 ;酶联免疫吸附试验 (EL ISA)测定 ICAM- 1与 VCAM- 1蛋白水平。凝胶电泳迁移率改变分析 (EMSA)检测 NF-κB DNA结合活性。结果显示 :与对照组相比 ,UC患者肠黏膜活检组织 ICAM- 1与 VCAM- 1m RNA和蛋白表达以及 NF-κBDNA结合活性明显升高 (P<0 .0 5 ) ;糖皮质激素和 SASP明显抑制 U C患者 NF-κB DNA结合活性 ,降低 ICAM- 1与 VCAM- 1m RNA和蛋白的表达 (P<0 .0 5 ) ;ICAM- 1和 VCAM- 1基因激活与 NF-κB DNA结合活性呈显著正相关 (ICAM- 1:r=0 .86 5 2 ,P<0 .0 5 ;VCAM-     

In vivo microscopy of murine islets of Langerhans: increased adhesion of transferred lymphocytes to islets depends on macrophage-derived cytokines in a model of organ-specific insulitis

Environmental factors contribute to the pathogenesis of type 1 diabetes (insulin-dependent diabetes mellitus). Multiple low doses of streptozotocin (MLDS) induce hyperglycaemia and insulitis in mice. Previously we demonstrated that adhesion of lymphocytes to endothelium of islets is only increased when donor animals were diabetic and recipient mice had received 5 mg/kg streptozotocin (STZ). Therefore we used streptozotocin to evaluate the immunological relevance of such an irritation of islets. Lymphocytes, separated from diabetic mice (MLDS), were fluorescently labelled and injected to recipient mice that had received 5 mg/kg STZ. With in vivo microscopy we measured lymphocyte flow and adherence in islets. Expression of vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) in the pancreas was assessed using immunohistochemistry. Very late antigen-4 (VLA-4) and leucocyte function-associated antigen-1 (LFA-1) expression on transferred lymphocytes was measured with flow cytometry. Pretreatment of recipients with antibodies to cytokines or silica reduced lymphocyte adherence to islet endothelium from 2.04% (goat immunoglobulin G; IgG) or 1.82% (rat IgG) to 0.47, 0.58, 0.39 or 0. 19% for monoclonal antibody (mAb) interferon-gamma (IFN-gamma), polyclonal antibody (pAb) tumour necrosis factor-alpha (TNF-alpha), pAb interleukin (IL)-1alpha or silica, respectively. Reduced adhesion was associated with a decreased expression of VCAM-1 and ICAM-1 in islets of treated recipients compared with mice treated with 5 mg/kg STZ alone. In conclusion, pretreatment of recipients with 5 mg/kg STZ leads to an increased expression of adhesion molecules in the islets and lymphocyte adhesion to islet endothelium in vivo, demonstrating an immune response of the islets. Prevention of increased expression of ICAM-1 or VCAM-1 and reduction of lymphocyte adhesion in islets by silica or antibody indicate an involvement of macrophages and macrophage derived cytokines in the generation of this immune response.     

The distribution of adhesion molecules in human atherosclerosis

Chronic inflammatory cells are a recognized component of atherosclerotic plaques at all stages of development. As adhesion molecules play a fundamental role in inflammatory processes, we have carried out an immunohistochemical investigation of the distribution of endothelial leucocyte adhesion molecule-1 (ELAM-1)*, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in human atherosclerotic lesions. Autopsy specimens from abdominal aorta and coronary arteries were obtained from 21 cases within 24 h of death. ELAM-1 and ICAM-1 were consistently expressed by the entire intimal endothelium of normal coronary arteries and also by the intimal endothelium overlying aortic fatty streaks. Both coronary artery and aortic lesions showed strong staining for ICAM-1 on and around macrophages. VCAM-1 was not detected on intimal endothelial cells, but strong staining of adventitial lymphoid aggregates for this molecule was seen. This work suggests a role for ELAM-1 and ICAM-1 in mononuclear cell recruitment during atherogenesis.     

终末糖基化产物对培养的人脐静脉内皮细胞粘附分子表达的影响

目的：探讨终末糖基化产物在糖尿病动脉粥样硬化（AS）形成中的作用机理。 方法： 分离正常人脐静脉内皮细胞（HUVECs），将终末糖基化终产物（AGE）修饰的人血清白蛋白（AGE-HSA）、人血清白蛋白（HSA）与HUVECs在体外共同培养，并用荧光单克隆抗体染色，流式细胞仪定量检测细胞间粘附分子-1（ICAM-1）、血管细胞粘附分子-1（VCAM-1）的表达。 结果： 正常人HUVEC表达ICAM-1和VCAM-1。AGE-HSA能以时间和剂量依赖的方式上调ICAM-1、VCAM-1的表达（P<0.05），而HSA对HUVECs上述粘附分子的表达均无影响。 结论： AGE能上调HUVECs粘附分子的表达，从而促进AS时单核/巨噬细胞的浸润。     

Endothelial and smooth muscle cells express leukocyte adhesion molecules heterogeneously during acute rejection of rabbit cardiac allografts.

Interactions of leukocytes with vascular wall cells figure prominently in acute rejection and development of vascular occlusive disease after cardiac transplantation. To investigate the time course and distribution among different types of vessels of expression of endothelial leukocyte adhesion molecules, issues difficult to address in humans, we studied heterotopic transplants of Dutch-Belted rabbit hearts into New Zealand white recipients without immunosuppression (average time to graft failure 8.2 +/- 0.4 days). We found constitutive expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) by coronary arterial endothelium in normal rabbits, whereas myocardial capillaries and the endocardial lining cells showed little or no expression of VCAM-1. VCAM-1 expression increased within 1 day after transplantation on the endothelium of the transplanted aorta and endocardium and on myocardial microvascular endothelial cells. ICAM-1 expression increased remarkably on all endothelia studied from 2 to 8 days after transplantation. Adhesion molecule expression on coronary artery endothelial cells also increased during severe allograft rejection (from a histological score of 1.7 +/- 0.6 pretransplant to 4.8 +/- 0.2 8 days after transplant for VCAM-1 and from 0.9 +/- 0.6 to 4.4 +/- 0.3 for ICAM-1, n = 43 arteries in 5 animals, mean +/- SD). In addition, coronary artery and aortic smooth muscle cells also showed induction of VCAM-1 and ICAM-1 8 days after transplant. We conclude that endothelial activation in a transplanted organ can occur rapidly and varies among microvascular, endocardial, and coronary artery endothelial cells, a point germane to the interpretation of endomyocardial biopsies. Augmented expression of adhesion molecules precedes temporally leukocyte accumulation in vessels. In addition, our finding of activation of coronary artery smooth muscle cells during acute rejection suggests that such episodes may contribute to the development of accelerated coronary arteriosclerosis.     

IL-1 and TNF independent pathways mediate ICAM-1/VCAM-1 up-regulation in ischemia reperfusion injury

In vitro studies have suggested that targeting interleukin (IL)-1 and tumor necrosis factor (TNF) can be used to regulate intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and potentially treat kidney inflammation. We therefore evaluated ICAM-1 and VCAM-1 regulation in knockout (KO) mice deficient in both IL-1 receptor 1 (R1) and TNF-R1 during renal ischemia reperfusion injury. ICAM-1 and VCAM-1 mRNA expression was measured with specific murine probes and Northern blotting (n =4/group). Protein expression was measured using immunohistochemistry. Serum creatinine (SCr), tubular histology, and neutrophil infiltration into postischemic kidneys were also quantified. ICAM-1 and VCAM-1 mRNA expression increased in both wild-type (WT) and KO mice at 2, 6, and 24 h. Protein expression of ICAM-1 and VCAM-1 was also increased at 24 h postischemia. SCr levels and tubular necrosis scores were comparable in WT and KO mice at 24 and 48 h. Neutrophil migration in KO mice was decreased at 24 h but comparable to WT at 48 h. These data demonstrate that IL-1 and TNF are not essential for postischemic increases in ICAM-1 and VCAM-1.     

Expression of ICAM-1, VCAM-1, E-selectin and TNF-alpha on the endothelium of femoral and iliac arteries in thromboangiitis obliterans

Immunohistochemical light and electron microscopical analysis of surgical biopsies obtained from femoral and iliac arteries of patients with thromboangiitis obliterans (TAO) were performed to investigate the presence of tumour necrosis factor-alpha (TNF-alpha) and expression of the endothelial cell adhesion molecules intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. Expression of ICAM-1, VCAM-1 and E-selectin was increased on endothelium and some inflammatory cells in the thickened intima in all TAO patients. Ultrastructural immunohistochemistry revealed contacts between mononuclear blood cells and ICAM-1-, and E-selectin-positive endothelial cells. These endothelial cells showed morphological signs of activation. The present data indicate that endothelial cells are activated in TAO and that vascular lesions are associated with TNF-alpha secretion by tissue-infiltrating inflammatory cells, ICAM-1-, VCAM-1- and E-selectin expression on endothelial cells and leukocyte adhesion via their ligands. The preferential expression of inducible adhesion molecules in microvessels and mononuclear inflammatory cells suggests that angiogenesis contributes to the persistence of the inflammatory process in TAO.     

蜂胶水提物对血管内皮细胞黏附分子表达的影响

目的:采用TNF-α诱导体外培养的人脐静脉内皮细胞(HUCECs)活化,观察蜂胶水提物(WEP)对血管内皮细胞黏附分子表达的影响,从而探讨蜂胶抗动脉粥样硬化的作用及其机制。方法:用50μg/L TNF-α诱导体外培养HUVECs损伤,用50 mg/L、100 mg/L、200 mg/L WEP分别进行干预6 h、12 h、24 h,利用流式细胞仪检测HUVEC表面ICAM-1和VCAM-1表达。结果:与对照组比较,模型组ICAM-1和VCAM-1荧光强度明显升高(P0.01)。与模型组比较,100 mg/L WEP组和200 mg/L WEP组ICAM-1和VCAM-1荧光强度明显降低(P0.01)。不同浓度WEP组ICAM-1和VCAM-1荧光强度随WEP浓度的增加下调。析因分析结果显示,用200 mg/L WEP和氟伐他汀钠(FS)联合预处理组与单一药物预处理组比较,ICAM-1和VCAM-1活性明显降低(P0.01)。结论:WEP能够减少ICAM-1和VCAM-1的表达,且在一定的范围内,有随WEP浓度升高和作用时间延长效应增强的趋势。WEP与FS联合用药,对抑制ICAM-1和VCAM-1表达有协同作用。     

High expression of human 15-lipoxygenase induces NF-kappaB-mediated expression of vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and T-cell adhesion on human endothelial cells

Expression of 15-lipoxygenase (15-LO) is induced over 100-fold in early fatty streak lesions. 15-LO activity leads to the production of specific lipid hydroperoxides, which can have major effects on the expression of proinflammatory genes involved in atherogenesis. We have used retrovirus-mediated gene transfer to achieve stable high expression of 15-LO in human endothelial ECV304 cells. These cells were used to study the effects of 15-LO on the expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), activation of nuclear factor kappa B (NF-kappaB), and T-cell adhesion on endothelial cells. NF-kappaB activation was greatly potentiated by increased 15-LO activity in the stably transduced cells, and both VCAM-1 and ICAM-1 were significantly induced in these cells in response to tumor necrosis factor-alpha (TNF-alpha) and phorbol 12-myristate 13-acetate (PMA) stimulation, as studied by flow cytometry. The induction of ICAM-1 was sensitive to antioxidants in a dose-dependent manner. The adherence of Jurkat T cells on the 15-LO-expressing endothelial cells was markedly induced after PMA stimulation. These results indicate that 15-LO activity may be involved in the early pathogenesis of atherosclerosis by inducing VCAM-1 and ICAM-1 expression and by increasing T-cell adhesion on the endothelium.     

Endothelial cell-derived foam cells fail to express adhesion molecules (ICAM-1 and VCAM-1) for monocytes

The purpose of this study was to assess the expression of cell adhesion molecules ICAM-1 (intercellular adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule-1) in endothelial cell-derived foam cells. Hamster aortic endothelial cells (HAEC) in culture were exposed to hypercholesterolemic or normal homologous serum for 24 h. At the end of the incubation period, HAEC exposed to hypercholesterolemic serum exhibited numerous lipid droplets and had a general aspect of foam cells. When examined for the expression of ICAM-1 and VCAM-1 (by indirect immunofluorescence) normal HAEC expressed constitutively (to low level) on their surface these adhesion molecules; however HAEC-derived foam cells failed to display any labeling. To further assess these results, HAEC were first incubated with normal or hypercholesterolemic sera (as above) and then exposed to freshly isolated normal hamster blood monocytes. These experiments showed that monocytes adhered in small number to normal cells and failed to adhere to the surface of HAEC-derived foam cells. Together these data indicate that endothelial cell-derived foam cells: a) do not express ICAM-1 and VCAM-1 on their surface; b) have low or no adhesion properties for monocytes and c) may represent an appropriate experimental model to study the cellular alterations that take place in the advanced stages of atherosclerosis.     

Endothelium dysfunction markers in patients with diabetic retinopathy

Diabetes mellitus leads to endothelium dysfunction and an accelerated progression of atherosclerosis. Vascular complications of diabetes mellitus can affect not only large and medium arteries resulting in coronary heart disease and peripheral arteries diseases, but also small vessels leading to retinopathy and nephropathy. Intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), E-selectin and von Willebrand factor (vWF) are considered as markers of endothelium dysfunction. The aim of our study was to evaluate plasma levels of ICAM-1, VCAM-1, E-selectin and vWF in patients with type 2 diabetes mellitus receiving insulin therapy and who had diabetic non-proliferative retinopathy, proliferative retinopathy, or did not develop diabetic retinopathy. There were no statistically significant differences between studied groups in any of evaluated endothelium dysfunction markers. There was no statistically significant correlation between measured parameters and a period of diabetic history. None of the studied markers presented a significant correlation with a period of insulin treatment.     

Biological function of CD40 on human endothelial cells: costimulation with CD40 ligand and interleukin-4 selectively induces expression of vascular cell adhesion molecule-1 and P-selectin resulting in preferential adhesion of lymphocytes

The expression of adhesion molecules on vascular endothelial cells determines the pattern of migration and extravasation of leucocytes in inflammation and immunity. Here we show that costimulation with CD40 ligand (CD40L) and interleukin (IL)-4 (or IL-13) gives rise to a unique pattern of adhesion molecule expression by human umbilical vein endothelial cells (HUVEC). CD40 ligation alone enhanced expression of vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1) and E-selectin whereas IL-4 and IL-13 increased expression of VCAM-1 and P-selectin but not ICAM-1 or E-selectin. When IL-4 and CD40L were combined there was an additional increase of both VCAM-1 and P-selectin, but ICAM-1 and E-selectin were both inhibited. The combined effects of IL-4 and CD40L signalling were not the result of altered response kinetics, enhanced sensitivity of the endothelium, or increased expression of CD40 or the IL-4 receptor. The rise in VCAM-1 expression induced by combined IL-4 and CD40L stimulation was slower and more sustained than with tumour necrosis factor-alpha (TNF-alpha) and occurred only on a subset (75-80%) of the endothelial cell population compared to 100% with TNF-alpha. Costimulation with IL-4 and CD40L increased adhesion of T cells and B cells above levels obtained with either signal alone, but decreased adhesion of neutrophils. Furthermore, CD40 and IL-4 synergistically increased IL-6 but decreased IL-8 production by HUVEC. These results show that interactions between IL-4 and CD40 on endothelial cells give rise to specific patterns of adhesion molecule expression and cytokine production that may have important implications for lymphocyte and neutrophil migration and function at sites of inflammation.     

Correlation between enhanced vascular permeability, up-regulation of cellular adhesion molecules and monocyte adhesion to the endothelium in the retina during the development of fatal murine cerebral malaria.

The relationships between increased vascular permeability to protein, monocyte adherence to the endothelium, and expression of the cell adhesion molecules, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the central nervous system microvasculature were studied during the progression of fatal murine cerebral malaria. CBA mice were inoculated with Plasmodium berghei ANKA, and changes in the retinal microvasculature were examined on days 3, 5, and 7 postinoculation (p.i.). Evans blue dye and horseradish peroxidase (HRP) were administered intravenously to assess vascular permeability to macromolecules macroscopically and by light and electron microscopy. ICAM-1 and VCAM-1 expression were examined by immunohistochemistry. HRP leakage into the retinal parenchyma was seen macroscopically at a low level on day 3 p.i., increasing progressively at day 5 (the earliest time at which cerebral symptoms were observed) and day 7 (the day on which animals showed severe behavioral abnormalities and died). The inner retinal vascular plexus showed a slight increase in vascular permeability to intravenous Evans blue at day 3 p.i. and congestion, monocyte adherence to the endothelium, and increased vascular permeability to both Evans blue and HRP at day 7 p.i. Electron microscopic observations were consistent with these findings and also revealed disrupted light junctions and the coating of monocytes and endothelium with HRP at day 7 p.i. Immunohistochemical staining and densitometry showed a progressive increase from day 3 to day 7 p.i. in the densities of ICAM-1 and VCAM-1 on the venular endothelium of the inner retinal vascular plexus, with the appearance of adherent ICAM-1+ monocytes at the terminal stage of the disease. None of the pathological changes associated with the inner retinal plexus were seen at any stage in the outer retinal plexus. These results suggest the following sequence of events in the inner retinal vessels, particularly the venules, during the progression of fatal murine cerebral malaria: 1) a mild increase in vascular permeability at approximately day 3 p.i., 2) a progressive increase in endothelial expression of the cell adhesion molecules ICAM-1 and VCAM-1, commencing at approximately day 3 p.i., 3) monocyte adhesion to the endothelium starting at approximately day 5 p.i., and 4) frank disruption of endothelial integrity at the terminal stage (day 7 p.i.), leading to edema and hemorrhage. Similar changes in cerebral vessels may underlie the neurological complications of the disease.     

The expression of leukocyte-endothelial adhesion molecules is increased in perennial allergic rhinitis.

Accumulating evidence supports the importance of leukocyte-endothelial cell adhesion molecule (CAM) expression as an initiating process in tissue inflammation. To investigate the relevance of CAM expression to allergic airways inflammation, nasal biopsies from patients with perennial allergic rhinitis (n = 8) and from nonatopic healthy volunteers (n = 8) were immunostained with monoclonal antibodies directed against the CAMs, intercellular adhesion molecule-1 (ICAM-1), endothelial cell adhesion molecule-1 (ELAM-1), and vascular cell adhesion molecule-1 (VCAM-1). The endothelial staining of these CAMs was related to the number of vessels within each biopsy, delineated by a monoclonal antibody against Ulex europaeus-1 lectin bound to endothelial cells, and to the number of tissue leukocytes staining for one of the ligands of ICAM-1, the beta 2 integrin, lymphocyte function-associated antigen (LFA-1). Expression of CAMs was related to the number of infiltrating neutrophils, eosinophils, and lymphocytes identified immunohistochemically within the biopsies. ICAM-1 was the most prominent CAM present on the endothelium of the normal nasal mucosa, with less expression of ELAM-1 and only minimal or absent expression of VCAM-1. In perennial rhinitis, both ICAM-1 (P less than 0.05) and VCAM-1 (P less than 0.01) expression on endothelial cells were increased and were positively correlated in their level of expression (P less than 0.002). The number of tissue LFA-1-positive cells was significantly greater (P less than 0.05) in the biopsies from the perennial rhinitics (median, 27.3/mm2) than from the healthy controls (median, 5.3 cells/mm2). LFA-1 expression significantly correlated with the number of ICAM-1-positive vessels (P less than 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)     

Deletion of tenascin-C gene exacerbates atherosclerosis and induces intraplaque hemorrhage in Apo-E-deficient mice

AimsTenascin-C (TNC), a matricellular protein, is up-regulated in atherosclerotic plaques. We investigated whether the deletion of TNC gene affects the development of atherosclerosis in a murine model.MethodsTNC?/?/apo E?/? mice were generated and used for atherosclerosis studies. We compared these results to those observed in control groups of apo E?/? mice.ResultsThe en face analysis of aortic area showed that the mean aortic lesion area of the double knockout (KO) mice was significantly higher than that of control mice at different times after feeding of atherogenic diet; the accumulation of lesional macrophages and lipids was significantly higher. Analysis of cell adhesion molecules revealed that vascular cell adhesion molecule-1 (VCAM-1), but not intercellular adhesion molecule-1, was up-regulated 1 week after feeding of atherogenic diet in the double KO mouse as compared to apo E?/? mouse. Cell culture studies revealed that the expression of VCAM-1 in endothelial cells isolated from the double KO mouse is more sensitive to the tumor necrosis factor α stimulation than the cells isolated from apo E?/? mice. Cell adhesion studies showed that the adherence of RAW monocytic cells to the endothelial cells was significantly enhanced in the cultured endothelial cells from the TNC gene-deleted cells. Following the prolonged feeding of an atherogenic diet (28–30 weeks), the aortic and carotid atherosclerotic lesions frequently demonstrated large grossly visible areas of intraplaque hemorrhage in the double KO mice compared to control.ConclusionsThese data unveil a protective role for TNC in atherosclerosis and suggest that TNC signaling may have the potential to reduce atherosclerosis, in part by modulating VCAM-1 expression.     

Human papillomavirus-16-E7 oncoprotein enhances the expression of adhesion molecules in cervical endothelial cells but not in human umbilical vein endothelial cells.

OBJECTIVES: E7 is one of the oncoproteins encoded by human papillomavirus-16 (HPV-16), the major etiologic factor responsible for cervical cancer. Human papillomavirus-16-E7 expressed by human uterine cervix carcinoma cells is also released in the extracellular compartment where it induces immune suppression. We investigated whether E7 was also responsible for the enhanced endothelial adhesiveness required in cancer progression. STUDY DESIGN/METHODS: We treated cervical microvascular endothelial cells (CrMVEn) and human umbilical vein endothelial cells (HUVEC) with E7, tumor necrosis factor-alpha (TNF-alpha), and hydrogen peroxide (H2O2) and measured the expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) by fluorescent-activated cell sorter analysis. RESULTS: E7 strongly induced the expression of E-selectin, ICAM-1, and VCAM-1 in CrMVEn, but not in HUVEC. Tumor necrosis factor-alpha further increased the endothelial expression of adhesion molecules in CrMVEn. Hydrogen peroxide pre-treatment resulted in an enhanced ICAM-1 and a decreased E-selectin and VCAM-1 expression. We also show indirect effects when endothelial cells were stimulated with the supernatant of E7-pretreated macrophages. CONCLUSIONS: These results show that HPV-16-E7 oncoprotein strongly induces adhesion molecules expression in organ-specific endothelial cells.