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ABSTRACT: Angiogenesis plays an important role in the progression of astrocytic tumors and its evaluation is a major prognostic factor. Although the form of proliferating vessels ranges from fine capillaries to well-developed vascular structures with a smooth muscle layer, the characteristics of vascular smooth muscle cells (SMCs) are not understood in detail. We therefore examined the density, size and shape of tumor vessels, as well as CD34-immunoreactive (CD34-Vs) or α-smooth muscle actin-immunoreactive (SMA-Vs) vessels in 46 primary astrocytomas (grade II diffuse astrocytomas, n=11, grade III anaplastic astrocytomas, n=15, grade IV glioblastomas, n=20) and in normal brain tissues from 10 autopsies. We also examined the expression of high molecular weight caldesmon (h-CD, a marker of the contractile phenotype of smooth muscle) and of platelet-derived growth factor receptor β (PDGFR-β). The SMA-Vs were significantly more dense and larger in grade IV than grade III, whereas those of CD34-Vs did not differ between grade III and IV. Changes in the shape of CD34-Vs and SMA-Vs correlated with histological grading. The expression of h-CD was reduced, whereas that of PFGFR-β was increased in high grade-astrocytomas. Kaplan-Meier analysis indicated that the density of SMA-Vs, the size of both CD34 and SMA-Vs and PDGFR-β expression were significant prognostic factors. These findings suggest that SMA-Vs are significantly associated with the progression of astrocytomas and that these vessels provide useful information for the histological diagnosis and survival of patients with these types of brain tumors.
Histology and histopathology 04/2011; 26(4):497-504. · 2.48 Impact Factor
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ABSTRACT: To determine the proportion of platelets and fibrin in coronary thrombi.
Immunohistochemical and morphometric means to examine the coronary arteries of 31 patients who died of acute myocardial infarction.
Fresh thrombi were detected in the feeding arteries of infarction areas in 23 cases (74%) and were associated with plaque rupture in 18 (78%) and plaque erosion in 5 (22%). An immunohistochemical study showed that the thrombi consisted of a mixture of fibrin and platelets as well as some other types of blood cells. The fibrin and platelet positive areas in the thrombi associated with plaque rupture accounted for 74 (19)% and 35 (20)% (p < 0.01) and those associated with erosion accounted for 51 (6)% and 70 (21)%, respectively, of the total areas. Areas of positive immunoreactivity for tissue factor and C reactive protein were also significantly greater in ruptured than in eroded plaques.
These results indicate that the proportions of fibrin and of platelets differ in coronary thrombi on ruptured and eroded plaques. Higher proportions of tissue factor and C reactive protein contribute more significantly to thrombus formation on plaque rupture than on plaque erosion.
Heart (British Cardiac Society) 05/2005; 91(4):526-30. · 4.22 Impact Factor
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ABSTRACT: Thrombus formation and neointimal growth are the critical events in restenosis after balloon angioplasty. However, the responses of diseased vessels to injuries caused by balloon angioplasty have not been well examined. We investigated the thrombus formation and neointimal development following the balloon injury to the previously induced neointima in the rabbit aorta and the effects of recombinant tissue factor pathway inhibitor (rTFPI) on these responses. Rabbit thoracic aortas were subjected to injury with a Fogarty 4F balloon catheter at 1.75 atm (first injury), and 4 weeks later the same vessels were subjected to the second injury with a Swan-Ganz 5F balloon catheter at 1.4 atm (mild-injury group) or 1.8 atm (severe-injury group), and immediately after that a retrograde bolus injection of rTFPI (100 microg/kg body weight) or saline was performed into the injured segments via the central tube of the Swan-Ganz catheter. Twenty minutes after the second injury, the injured surfaces were covered with platelet-rich thrombi in the mild-injury group and with fibrin-rich thrombi in the severe-injury group. Damaged intimal smooth muscle cells, which were immunohistochemically positive for tissue factor (TF), were observed beneath the fibrin-rich thrombi. The neointima 4 weeks after the second injury was significantly thicker in the severe-injury group than in the mild-injury group. The bolus infusion of rTFPI markedly inhibited fibrin formation on the injured surfaces, and significantly reduced the neointimal development in the severe-injury group at 4 weeks after the second injury. These results indicate that TF-dependent coagulation pathway is primarily responsible for fibrin-rich thrombus formation and may play an important role in neointimal development following the balloon injury to the rabbit aortic neointima. Additionally the bolus administration of rTFPI to the injured vessels could prevent mural thrombus formation and neointimal growth after balloon angioplasty.
Thrombosis and Haemostasis 10/1998; 80(3):506-11. · 5.04 Impact Factor
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ABSTRACT: Tissue factor (TF) is a primary initiator of the extrinsic pathway of blood coagulation. Recently TF has been shown to be overexpressed in atherosclerotic lesions and it is thought to contribute to the thrombogenicity of the plaques. We studied TF expression in the media and the neointima of rabbit aortas at various intervals after balloon injury. TF protein was immunohistochemically detected in smooth muscle cells (SMCs) of the inner layer of the media at 2 h after injury and was subsequently detected in SMCs in the neointima, whereas no TF expression was detected in the uninjured aortas except for the adventitia. Immunohistochemical and immunoelectron microscopic studies revealed that TF-positive SMCs were of an immature or synthetic phenotype and TF protein was detected in the rough endoplasmic reticulum in SMCs. TF mRNA in the intima and media increased at 2 h after injury and returned to near baseline levels at 12-24 h, whereas TF activity also increased at 2 h and continued at similar levels over the next 72 h. TF mRNA and activity increased markedly at 2-8 weeks after injury. These data suggest that TF is rapidly induced in the medial SMCs and hereafter is constitutively expressed in the neointima. TF expressed in the neointima may contribute to hypercoagulable properties of injured arteries.
Atherosclerosis 09/1998; 139(2):265-71. · 3.79 Impact Factor
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ABSTRACT: TF is a major regulator of coagulation and hemostasis. High levels of TF antigen and activity are detected in atherosclerotic lesions, particularly in the advanced lesions. When the plaques are ruptured or eroded, exposure of cellular and extracellular TF to circulating blood play a pivotal role in mediating fibrin-rich thrombus formation leading to acute coronary syndromes. On the other hand, activation of blood coagulation and deficiency of coagulation inhibitors, without endothelial cell denudation, are considered to be an important factor of thrombogenesis in the microcirculation. The imbalance between TF and TFPI seems to be important in promoting fibrin thrombus formation in the lung of endotoxin induced DIC condition.
Journal of atherosclerosis and thrombosis 02/1998; 4(3):135-9. · 2.69 Impact Factor
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ABSTRACT: Disseminated intravascular coagulation (DIC) is a frequent complication of endotoxin shock, and modulation of endothelial cell hemostatic properties has been proposed to play an important role in its onset. We examined the in vivo expression of tissue factor (TF) and TF pathway inhibitor (TFPI) in rat lungs of a lipopolysaccharide (LPS)-induced DIC model. Light and electron microscopic studies showed that fibrin-rich thrombi were present in the pulmonary microvasculature 3 hours after intraperitoneal injection of LPS (7.5 mg/kg) and increased in number at 6 hours. In an immunohistochemical study, an increase in number of monocytes in the microvasculature was observed after LPS injection, and many of these cells (> 90%) were positive for TF antigen. However, no TF expression in endothelial cells was detected. Pulmonary endothelial cells showed positive reaction for TFPI antigen before LPS injection, but TFPI-positive endothelial cells markedly decreased in number after LPS injection. mRNA expression of TF increased and that of TFPI decreased in the lung tissue 3 and 6 hours after LPS injection. High values of TF activity were detected in the lung tissue and plasma, whereas TFPI activities decreased after LPS injection. These results indicate that imbalance between TF and TFPI, overexpression of TF, and underexpression of TFPI in the lung may contribute to thrombus formation in this LPS-induced DIC model.
Laboratory Investigation 12/1997; 77(6):581-9. · 3.64 Impact Factor
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ABSTRACT: Tissue factor (TF) is a transmembrane protein that serves as the major initiator of the blood coagulation cascade. The overexpression of TF antigen and mRNA has previously been reported in advanced atherosclerotic lesions. Recently TF procoagulant activity has also been identified in these lesions. However, localization and activity of TF in various stages of atherosclerosis have not yet been reported. We studied TF localization and its activity in three stages of the human atherosclerotic lesions (diffuse intimal thickening, fatty streak, and atheromatous plaque). The thoracic aortas were obtained from 23 autopsy cases and were examined immunohistochemically using an anti-human TF polyclonal antibody and biotinylated factor VIIa (FVIIa) as a probe to test the FVIIa-binding ability of TF. In addition, the TF-mediated activation of factor X (FX) was quantitatively assessed using a chromogenic assay. In lesions of the diffuse intimal thickening and the fatty streak, almost all of intimal smooth muscle cells (SMCs), macrophages, and endothelial cells were positive for TF. In the atheromatous plaques, TF antigen was detected extensively in the extracellular matrix as well as in the intimal cells. TF in all stages of atherosclerotic lesions had the ability to bind biotinylated FVIIa. TF activity was detected in each lesion and was more prominent in fatty streaks and atheromatous plaques than in the diffuse intimal thickening. These results indicate that active TF is expressed in the early stage of atherosclerotic lesions as well as in the advanced stage, and it contributes to the thrombotic property of human atherosclerotic lesions.
Atherosclerosis 10/1997; 133(2):213-9. · 3.79 Impact Factor
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ABSTRACT: Tissue factor (TF), a transmembrane glycoprotein, forms a high affinity complex with factor VII/VIIa (FVIIa) and thereby initiates blood coagulation. Tissue factor pathway inhibitor (TFPI) is an endogenous protease inhibitor of TF/FVIIa-initiated coagulation. We previously reported that TF was a strong chemotactic factor for cultured vascular smooth muscle cells (SMCs). In this study, we examined the contribution of FVIIa and the effect of TFPI to TF-induced cultured SMC migration. TF/FVIIa complex showed a strong migration ability, however, neither TF alone nor FVIIa induced SMC migration. TF/FVIIa treated by a serine protease inhibitor and the complex of TF and inactivated FVIIa (DEGR-FVIIa) did not stimulate SMC migration. Pretreatment with hirudin and the antibodies to alpha-thrombin and factor X had no effect on TF/FVIIa-induced SMC migration, although alpha-thrombin and factor Xa also induced SMC migration respectively. TFPI markedly inhibited TF/FVIIa-induced SMC migration in a concentration-dependent manner, but did not affect the SMC migration induced by platelet-derived growth factor (PDGF)-BB, basic fibroblast-growth factor (bFGF), or alpha-thrombin. These results indicate that the catalytic activity of TF/FVIIa complex is important on SMC migration, and TFPI can reduce SMC migration as well as thrombosis.
Thrombosis and Haemostasis 10/1997; 78(3):1138-41. · 5.04 Impact Factor
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ABSTRACT: To investigate the expression of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in human colorectal carcinomas, Northern blot analysis was performed in a series of human colorectal carcinoma cell lines and in normal or tumoral colorectal tissues. Of 16 human colorectal carcinoma cell lines examined, most expressed TF mRNA, though the levels of expression varied significantly. Considerably higher expression was observed in the cell line CaR-1, while lines established from metastatic lesions tended to express abundant TF mRNA. By contrast, TFPI mRNA levels were low in these high TF-expressing cell lines. TFPI was expressed abundantly in WiDr and in a few other cell lines which expressed a very low level of TF mRNA. Immunocytochemically, both proteins were stained predominantly on the cell surface; however, diffuse cytoplasmic staining for TF also was observed in CaR-1 cells. In addition, the cell surface TF activity was significantly higher in CaR-1 cells than in WiDr cells, confirming the results of mRNA analysis. The level of TF mRNA in colorectal carcinoma tissue in vivo and its ratio to the normal counterpart also varied significantly among the cases. To search for a possible role of TF/TFPI in metastasis of colorectal carcinoma cells, the expression of these genes was compared between a rectal adenocarcinoma cell line, RCM-1, and its highly metastatic subline, RCM-1 L-10. Compared with the parent line, RCM-1 L-10 expressed 7.5-fold higher levels of TF mRNA, whereas TFPI expression was not altered significantly or even decreased slightly. The higher cellular TF activity was confirmed in the metastatic subline in comparison with the parent line.
International Journal of Cancer 10/1997; 72(5):878-84. · 5.44 Impact Factor
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ABSTRACT: Balloon catheter de-endothelialization is the most popular means of arterial injury in experimental animals and has been used as the model system to investigate atherogenesis and restenosis after percutaneous transluminal coronary angioplasty (PTCA). The aim of this study was to examine the relationship between balloon inflation pressure and vascular damage and also subsequent intimal hyperplasia. Retrograde pullback balloon injury of rabbit aortas was made at three different balloon pressures (1.5, 1.75, and 2.0 atm). The medial injuries, such as necrosis of smooth muscle cells and disruption of elastic lamina, were occasionally found in the injured segment of the aorta by balloon catheter at 1.75 atm and more frequently at 2.0 atm. No prominent medial injury was observed in the aortic segment to balloon catheter injury at 1.5 atm; Intimal hyperplasia developed in each animal and increased with time, 2, 4, and 8 weeks after injury. The intimal hyperplasia followed by balloon injury at 1.75 and 2.0 atm was more prominent than that at 1.5 atm, however, the development of the intimal hyperplasia was not parallel to the degree of inflation pressure. On the other hand, decrease of DNA content of the media and reduction of norepinephrine-induced vasoconstriction were observed in a pressure-dependent manner after balloon injury. These findings indicate that intimal hyperplasia is not proportionally correlated to the severity of the vascular injury. The control of inflation pressure is very important in order to examine vascular injuries, subsequent intimal hyperplasia and vasomotor responses in animal models of balloon catheter injury.
Atherosclerosis 04/1996; 121(1):45-53. · 3.79 Impact Factor
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ABSTRACT: Tissue factor (TF) plays a key role as a primary initiator on the extrinsic coagulation cascade. Recently, upregulation of TF has been reported in human atherosclerotic lesions. We investigated the effects of TF on migration and proliferation of cultured smooth muscle cells (SMCs) from rabbit aortas. We tested three kinds of recombinant human TF (L-TF: the full length of TF with relipidation, NL-TF: the full length of TF without relipidation, and S-TF: a soluble form of TF1-219). Only L-TF had coagulant activity. All kinds of TF showed the chemotactic migration activity for SMCs. The migration ability of TFs was comparable to those of platelet-derived growth factor (PDGF)-BB and basic fibroblast-growth factor (bFGF), and was inhibited by anti-TF polyclonal and monoclonal antibodies. On the other hand, none of the forms of TF induced SMC proliferation. These results indicate that TF is not only a coagulation factor but also a strong chemotactic factor for vascular SMCs, and suggest that TF could play an important role in atherogenesis as well as in hemostasis and thrombosis.
Thrombosis and Haemostasis 04/1996; 75(3):389-92. · 5.04 Impact Factor
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ABSTRACT: Effects of a new prostacyclin analogue, TFC-132, on neointimal thickening following intimal mechanical injury and on the proliferation of cultured aortic smooth muscle cells (SMCs) were studied. The intimal injury was induced by indwelling of polyethylene tubing for 24 h in the rabbit aorta. Rabbits were killed 10 days after drawing out the tubing. TFC-132 (0.6 mg/kg or 1.2 mg/kg) was given orally at 8-h intervals through the experiment. The serum concentrations of the analogue rose significantly 1 and 2 h after administration. The mean intimal thickening in the TFC-132 treated groups was significantly thinner than in the control one. Human aortic SMCs were cultured and 3H-thymidine incorporation into DNA (DNA synthesis) was measured at the varying concentrations of TFC-132. The analogue inhibited DNA synthesis of cultured SMCs at 10(-6) and 10(-5) M. These data indicate that a new prostacyclin analogue, TFC-132, has an inhibitory effect on the neointimal thickening after intimal injury and on the aortic SMC proliferation.
Prostaglandins Leukotrienes and Essential Fatty Acids 11/1994; 51(4):245-8. · 3.37 Impact Factor
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ABSTRACT: Endothelial cell injury is considered to be a primary event in the pathogenesis of atherosclerosis. In this study, we investigated the aortic intimal lesion after balloon catheterization in hypercholesterolemic and normocholesterolemic rabbits with or without probucol, an antioxidant. After deendothelialization, the rabbits were divided into four groups: 1) a control group fed a standard diet; 2) a probucol-treated group; 3) a cholesterol-fed group; and 4) a group fed a mixed cholesterol and probucol diet. Four animals from each group were killed at 2, 4, and 8 weeks after deendothelialization. The aortic segments of nonendothelialized areas, borderline areas, and uninjured areas were histologically and immunohistochemically examined. Deendothelialized areas showed various degrees of intimal thickening, which was mainly composed of smooth muscle cells in rabbits from groups 1 and 2. The intimal thickness of group 3 was significantly larger than that of other groups in any area examined. The intimal thickness of group 4 was less than that of group 3 despite the hypercholesterolemic state in the former group. The intima of borderline areas was generally thicker than that of nonendothelialized areas. Although the borderline lesions of groups 3 and 4 contained numerous macrophages, the number of macrophages was lower in the nonendothelialized compared with the reendothelized lesion. These data indicate that endothelial cell injuries can cause intimal thickening. The regenerated endothelial covering is favorable for monocyte migration and attachment. This process, together with the proliferation of smooth muscle cells, greatly contributes to the progression of atherosclerosis, which appears to involve lipid oxidation. Probucol prevented intimal thickening to a certain degree in this experiment in the normocholesterolemic as well as the hypercholesterolemic state.
Arteriosclerosis and thrombosis: a journal of vascular biology / American Heart Association 11/1992; 12(10):1198-205.
