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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial cells form the luminal vascular surface and thus have a central role in the regulation of coagulation. One important way in which endothelial cells control the clotting system is by regulating the expression of binding sites for anticoagulant and procoagulant factors on the cell surface. In the quiescent state, endothelial cells maintain blood fluidity by promoting the activity of numerous anticoagulant pathways, including the protein C/protein S pathway. After activation, as can be brought about by cytokines, the balance of endothelial properties can be tipped to favor clot formation through coordinated induction of procoagulant and suppression of anticoagulant mechanisms. Tumor necrosis factor suppresses the endothelial anticoagulant cofactor thrombomodulin and induces expression of the procoagulant cofactor tissue factor. Working in concert, these changes can allow fibrin formation to proceed in an inflamed focus but maintain blood fluidity in the surrounding area of normal vasculature. Recent studies suggest that similar changes in endothelial coagulant properties can be induced by advanced glycosylation end products, proteins modified by glucose that accumulate in the vasculature at a rapid rate in diabetic subjects, indicating the potential relevance of these mechanisms in diabetic vascular disease.
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PMID:Endothelium and regulation of coagulation. 206 Apr 25

Increasing evidence suggests that the formation of oxidized low-density lipoprotein (Ox-LDL) in vivo is associated with the development of atherosclerotic vascular disease. We investigated the effects of Ox-LDL on two vascular endothelial cell coagulant properties, tissue factor expression, and protein C activation. The Ox-LDL increased human arterial and venous endothelial cell tissue factor activity, with 100 micrograms/ml of Ox-LDL increasing factor activity fourfold. Native LDL modified by incubation with cultured human arterial and venous endothelial cells also induced endothelial cell tissue factor activity. This modification was blocked by coincubation with the antioxidants, probucol or ascorbic acid. It was determined, based on inhibition by known scavenger receptor antagonists (fucoidin, dextran sulfate), that binding of Ox-LDL via the acetyl LDL (scavenger) receptor was partially responsible for the increase in tissue factor expression. Whereas endothelial cell tissue factor expression was increased by incubation with Ox-LDL, protein C activation was reduced approximately 80% by incubating cultured endothelial cells with Ox-LDL. The effect of Ox-LDL on protein C activation was not inhibited by antagonists to the scavenger receptor. These data indicating that an atherogenic lipoprotein can regulate key vascular coagulant activities provide an additional link between vascular disease and thrombosis.
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PMID:Oxidized low-density lipoprotein increases cultured human endothelial cell tissue factor activity and reduces protein C activation. 206 93

Because diabetic vascular disease is accompanied by a state of hypercoagulability, manifested by increased thrombin activity and foci of intravascular coagulation, we investigated whether a specific procoagulant property of the endothelium--production and surface expression of tissue factor--is modified by elevated glucose concentrations. In unperturbed human vascular endothelial cells, tissue factor mRNA and expression of the functional protein were undetectable and were not induced by 10-12 days of exposure to 30 mM glucose. In thrombin-stimulated cultures, tissue-factor expression was related inversely to cellular density, with confluent cultures producing (per 10(5) cells) half the amount of tissue factor measured in sparse cultures. Cells exposed to high glucose and studied when cell number and thymidine incorporation were identical to control cells manifested increased tissue-factor mRNA level and functional protein production in response to thrombin (P = .002). This effect was not attributable to hypertonicity and was not observed after short exposure to high glucose. In contrast, the tissue-factor response to interleukin 1, a modulator of endothelial function in the context of host defense, was decreased in cells cultured in high glucose (P = .04). These findings indicate that exposure to high glucose can alter tissue-factor gene expression in perturbed vascular endothelium. The reciprocal effects of high glucose on the tissue-factor response to thrombin and interleukin 1 points to different pathways of tissue-factor stimulation by the two agents and suggests functional consequences pertinent to the increased thrombin activity and compromised host-defense mechanisms observed in diabetes.
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PMID:Modification of tissue-factor mRNA and protein response to thrombin and interleukin 1 by high glucose in cultured human endothelial cells. 278 75

The studies discussed have established that inflammatory or immune cytokines, such as IL-1, TNF, and LT, as well as bacterial endotoxin, can act directly on vascular endothelial cells to modulate two important functional properties. The first of these, the inducible expression of E-LAMs, provides a mechanism for the local regulation of leukocyte-vessel wall interactions. This endothelial-dependent mechanism may be relevant to a broad spectrum of pathologic processes, including inflammation, delayed hypersensitivity reactions, and atherogenesis. The second, modulation of endothelial tissue factor PCA and fibrinolytic components, has important implications for the local balance of prothrombotic and antithrombotic influences at the blood-vessel wall interface. Thus, under the influence of inflammatory stimuli, vascular endothelial cells may actively contribute to the development and maintenance of intravascular or perivascular fibrin. Although the endothelial effector mechanisms of these functional alterations are distinct, their induction by similar stimuli points to important interrelationships of leukocyte-vessel wall adhesion and thrombosis. Further understanding of the regulation of endothelial expression of E-LAMs and coagulant properties should contribute to our understanding of vascular disease.
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PMID:Inducible endothelial functions in inflammation and coagulation. 312 25

Elevated blood levels of homocysteine represent an independent risk factor for premature arterial vascular disease and thrombosis. We investigated whether homocysteine could induce tissue factor (TF) procoagulant activity in cultured human endothelial cells. Homocysteine increased cellular TF activity in a time- and concentration-dependent manner. Low concentrations of homocysteine (0.1 to 0.6 mmol/L), similar to those found in the blood of patients with homocystinuria, enhanced TF activity by 25% to 100%. Other sulfur-containing amino acids (cystine, homocystine, cysteine, and methionine) induced less TF activity than did homocysteine; however, beta-mercaptoethanol and dithiothreitol were more effective than homocysteine in increasing TF activity. Preincubation of homocysteine with a sulfhydryl inhibitor such as N-ethylmaleimide prevented homocysteine induction of TF activity. A quantitative polymerase chain reaction method indicated that homocysteine increased TF mRNA in endothelial cells. These results indicate that an atherogenic amino acid, homocysteine, can initiate coagulation by the TF pathway through a mechanism involving the free thiol group of the amino acid and by TF gene transcription. These data support the hypothesis that perturbation of vascular coagulant mechanisms may contribute to the thrombotic tendency seen in patients with homocystinuria.
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PMID:Homocysteine, a risk factor for premature vascular disease and thrombosis, induces tissue factor activity in endothelial cells. 836 16

Herpesviruses have been previously correlated to vascular disease and shown to cause thrombogenic and atherogenic changes to host cells. Herein we show that even in the absence of cells, purified cytomegalovirus (CMV) and herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) can initiate thrombin production. Functional assays demonstrated that purified HSV-1 and HSV-2 provide the necessary phospholipid (proPL) for assembling the coagulation factors Xa and Va into prothrombinase, which is responsible for generating thrombin. These observations are consistent with our earlier studies involving CMV. The presence of proPL on all three herpesviruses was confirmed directly by flow cytometry and electron microscopy by using annexin V and factor Va, respectively, as proPL-specific probes. Of equal importance, we found that CMV, HSV-1, and HSV-2 were also able to facilitate factor Xa generation from the inactive precursor factor X, but only when factor VII/VIIa and Ca2+ were present. Monoclonal antibodies specific for tissue factor (TF), the coagulation initiator, inhibited this factor X activation and, furthermore, enabled identification of TF antigen on each virus type by flow cytometry and electron microscopy. Collectively, these data show that CMV, HSV-1, and HSV-2 can initiate the generation of thrombin by having essential proPL and TF activities on their surface. Unlike the normal cellular source, the viral activity is constitutive and, therefore, not restricted to sites of vascular injury. Thus cell-independent thrombin production may be the earliest event in vascular pathology mediated by herpesviruses.
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PMID:Coagulation initiated on herpesviruses. 939 Oct 56

Hemodynamic forces such as fluid shear stress have been shown to modulate the activity of an expanding family of genes involved in vessel wall homeostasis and the pathogenesis of vascular disease. We have investigated the effect of shear stress on tissue factor (TF) gene expression in human endothelial cells (ECs) and in a rat arterial model of occlusion. As measured by reverse transcriptase polymerase chain reaction, exposure of ECs to 1.5 N/m2 shear stress resulted in a time-dependent induction of endogenous TF transcripts of over 5-fold. Transient transfection of TF promoter mutants into cultured ECs suggests the involvement of the transcription factor Egr-1 in mediating the response of the TF promoter to shear stress. To address the importance of flow induction of Egr-1 in vivo, we have established a flow-restricted rat arterial model and determined the level of expressed Egr-1 and TF at the site of restricted flow using immunohistochemistry. We report an increase in the level of Egr-1 and TF protein in ECs expressed at the site of restricted flow. Elevated expression of Egr-1 and TF is restricted to a highly localized area, as evidenced by the fact that no significant increase in level can be detected at arterial sites distal to the site of occlusion. These findings suggest a direct role for Egr-1 in flow-mediated induction of TF and further substantiate the importance of shear stress as a modulator of vascular endothelial gene function in vivo.
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PMID:Fluid shear stress induction of the tissue factor promoter in vitro and in vivo is mediated by Egr-1. 997 8

Patients with diabetes have an increased prevalence of premature atherosclerotic vascular disease, and alterations in plasma coagulation proteins have been incriminated as a possible cause. The roles of hyperglycemia and hyperinsulinemia in the pathogenesis of these changes are unknown. To examine the effects of prolonged hyperglycemia and of selective hyperinsulinemia on the tissue factor pathway of blood coagulation, nine healthy young men were infused with glucose to maintain levels at 11.1 mmol/l (approximately 200 mg/dl) for 18-72 h (hyperglycemia-hyperinsulinemia group). Five normal men were infused with regular insulin to maintain levels comparable to that in the previous group (900 pmol/l, approximately 150 microU/ml) and with glucose to maintain levels at 5.6 mmol/l (approximately 100 mg/dl) (euglycemia-hyperinsulinemia group). Measured were plasma activated factor VII activity (FVIIa), FVII coagulant (FVIIC) activity, FVIII coagulant (FVIIIC) activity, tissue factor pathway inhibitor (TFPI) antigen, and thrombin markers; and serum glucose, insulin, and electrolytes. Plasma FVIIa, FVIIC, FVIIIC, and TFPI rose during hyperglycemic-hyperinsulinemia but not during euglycemic-hyperinsulinemia. Markers of thrombin generation rose transiently and inconsistently during hyperglycemia-hyperinsulinemia. We concluded that in normal subjects, hyperglycemia-hyperinsulinemia induced activation of the tissue factor pathway, reflected by increases in plasma FVIIa, FVIIC, and TFPI. This activation was independent of hyperinsulinemia, hypertriglyceridemia, and hyperosmolality. The elevations in plasma coagulation factors during hyperglycemia-hyperinsulinemia, characteristic of type 2 diabetes, may constitute a potential for enhanced thrombin generation and thrombosis when triggered by exposure of tissue factor, such as during arterial plaque rupture.
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PMID:Activation of the tissue factor pathway of blood coagulation during prolonged hyperglycemia in young healthy men. 1033 23

Atherosclerosis is vascular disease characterized by thickening, hardening, and remodelling of the arterial wall. Occlusive vascular disease most often results from thrombosis superimposed on atherosclerotic plaque. Lipoproteins enter the vessel wall, promoting the recruitment of monocytes, which imbibe lipids and become foam cells. Smooth muscle cells invade these early plaques, producing connective tissue fibrils that form a fibrous cap over the lipid center; rupture of this cap is an important cause of thrombosis. The specific topography of early atherosclerotic lesions is primarily attributed to wall shear stress, one of hemodynamic forces. Inflammatory mediators regulate processes that determine the composition of the plaque's fibrous cap, a structure that separates blood from the thrombogenic lipid core. Factors involved in coagulation, such as thrombin, can regulate non-thrombotic functions of vascular wall cells such as smooth muscle proliferation or cytokine release. Tissue factor is a major regulator of coagulation and hemostasis. When the plaques are ruptured or eroded, exposure of cellular and extracellular tissue factor to circulating blood play a pivotal role in mediating fibrin-rich thrombus formation leading to acute coronary syndromes. Several serial angiographic studies have demonstrated that over 70% of acute coronary syndromes evolve from mildly to moderately obstructive atherosclerotic plaques.
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PMID:[Atherosclerosis]. 1042 66

The starting point of blood coagulation in vivo is the formation of a complex between tissue factor (TF), which is exposed following vascular disease or trauma, and activated blood coagulation factor VII (FVIIa). This blinded, random, paired study evaluates whether active site-blocked activated FVII (FVIIai, ASIS), which binds avidly to TF but is unable to initiate the coagulation processes, inhibits experimental thrombosis. Arteriotomy and deep vessel wall trauma were performed in the central arteries of rabbits' ears. The topical administration of ASIS (0.5 mg in 200 microl vehicle) resulted in a distinct antithrombotic effect compared to vehicle alone. Patency rates at 30 and 120 min after reperfusion were 85% and 75% in the ASIS group and 45% and 30% in the vehicle group, respectively (P = 0.008 and P = 0.004). In contrast, intravenous administration of ASIS (4 mg/kg) produced no antithrombotic effect. Arteriotomy bleeding times were 1.5 min in the ASIS group and 2.0 min in the vehicle group (medians, P = 1). Local application of ASIS produces a pronounced antithrombotic effect in rabbits without giving rise to antihaemostatic side-effects. This mode of treatment may have a potential for a variety of clinical interventions in injured or diseased vessels.
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PMID:Effect of locally-applied active site-blocked activated factor VII (ASIS) on experimental arterial thrombosis. 1085 May 81


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