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Received July 9, 1997
Metabolites of polyunsaturated fatty acids, primarily arachidonic acid, are important physiological regulators of blood coagulation. In contrast to many other substances involved in coagulation, eicosanoids affect virtually all links of hemostasis; they are responsible for blood vessel wall thromboresistance and its acquisition of procoagulant properties in response to various agonists, regulate the extent of cell-to-cell interactions, modulate reactions of plasma hemostasis and blood fibrinolytic activity, and change hemodynamic parameters. Such complex effects of eicosanoids on thrombogenesis suggest that they are unique and extremely important biologically active substances that strongly determine the balance of anticoagulant and procoagulant factors.
KEY WORDS: polyunsaturated fatty acids, arachidonic acid, oxylipins, eicosanoids, blood coagulation system
Abbreviations: AA) arachidonic acid; GP) glycoprotein; HETE) hydroxyeicosatetraenoic acids; 13-HODE) 13-hydroxyoctadecadienoic acid; HPETE) hydroperoxyeicosatetraenoic acids; IL) interleukin; LT) leukotriene; NO) nitric oxide; PG) prostaglandin; PGI2) prostacyclin; PUFA) polyunsaturated fatty acids; TNF) tumor necrosis factor; TXA2) thromboxane A2.
In the whole body free of any pathological factors, the liquid state of
the blood is maintained by an equilibrium of factors that facilitate
and counteract coagulation. The blood coagulation potential is
maintained within physiological limits by a complex mechanism involving
many factors of peptide and other natures and maintaining certain
physical and physicochemical constants that determine the intensity of
interactions between separate components of the blood coagulation
system. In this situation, polyunsaturated fatty acids and products of
their metabolism perform unique functions. These substances are
involved in regulation of virtually all links of homeostasis, through
both direct effects on components of this process and indirect effects
through coupled physiological systems. Polyunsaturated fatty acids are
structural and functional components of absolutely all tissues and
their metabolites are essential factors of cellular activities [1]; therefore, full characterization of pathways of
influences of these biologically active substances on the blood
coagulation system is virtually impossible. Another aspect of effects
of endogenous oxylipins is their involvement in pathogenic reactions
that are the basis for various diseases. We think that reviewing this
function of metabolites of polyunsaturated fatty acids is a separate
task requiring thorough analysis of pathogeneses of each disease, which
is beyond the scope of this review. Therefore, we found it expedient to
consider only the most important (and probably the least extensively
studied) aspects of interactions of certain natural oxylipins on blood
coagulation in the absence of systemic diseases that could cause
prothrombogenic changes (atherosclerosis, diabetes, malignant tumors,
etc.). Before reviewing data available from the literature, it should
be noted that no direct evidence exists for the presence of
physiologically significant amounts of certain endogenous oxylipins
in vivo at the site of thrombus formation [2]. Although in vitro studies and in
vivo evaluation of their effects as exogenous substances showed
that these substances are involved in thrombogenesis, their
significance for regulation of hemostasis is difficult to determine [3].
Among all derivatives of polyunsaturated fatty acids (PUFA), metabolites of arachidonic acid play the most important role in normal functioning of hemostasis in mammals. The main fraction of arachidonic acid in cells is bound to membrane phospholipids. The level of free arachidonic acid (AA) is very low and is one of the most important factors determining the rate of generation of eicosanoids [4]. Two pathways provide the necessary levels of AA for the synthesis of blood oxylipins. First, AA can be released from membrane phospholipids by phospholipase A2. Second, plasma low-density lipoproteins can be sources of AA [5]. After liberation of AA from reserves, its metabolism follows several enzymatic pathways. Metabolites produced by all enzymatic processes are involved in regulation of hemostasis.
As pointed out above, metabolites of PUFA, AA metabolites in particular, are involved in regulation of virtually all links of the blood coagulation system. These metabolites facilitate the manifestations of thromboresistant and procoagulant properties of vascular walls, modulate the interactions between cells of the same type (aggregation) and different types (adhesion), interfere with processes of plasma hemostasis, change the blood fibrinolytic potential, and affect hemodynamic conditions. It should be noted, however, that cells involved in hemostasis are probably the main targets of thrombomodulatory effects of oxylipins, whereas all other effects are mainly of a secondary nature and can be explained by effects of PUFA metabolites on metabolic processes in particular cells.
Undamaged endotheliocytes that form the vessel lining are thromboresistant [6]. What causes the thromboresistance of intact vascular walls remains largely unclear; however, PUFA metabolites are certainly necessary components of this complex physiological system [7]. Most authors suggest that intact endothelial cells cannot synthesize and release prostacyclin (PGI2) or other oxylipins [8-10], although a rapid but short-term increase in the level of PGI2 occurs in response to various agonists, such as thrombin, AA, and trypsin, that increase the level of intracellular calcium ions [11, 12]. Induction of PGI2 synthesis requires a relatively high level of intracellular free calcium, which should be higher than that required for initiation of NO formation [12, 13]. However, physiological values of shear stress in vivo are probably sufficient for obtaining a level of cytoplasmic Ca2+ that would stimulate endothelial cells to produce and release factors, including prostacyclin, that impart thromboresistant properties to vascular walls [14, 15].
Among PUFA metabolites, PGI2 is not the only factor of thromboresistance of vascular walls. The release of AA from membrane phospholipids is known to occur only upon stimulation of cells by agonists. Lipoxygenase remains active even in resting cells; however, in this case its main substrate is linoleic acid derived from cell triglycerides. Triglyceride metabolism is a permanent process in intact neutrophils, tumor cells, macrophages, fibroblasts, epithelial cells, platelets, endotheliocytes, smooth muscle cells, and some other cell types [16-18]; in these processes, triglycerides liberate linoleic acid, which in endotheliocytes is metabolized by 15-lipoxygenase to 13-hydroxyoctadecadienoic acid (13-HODE).
Stimulation of endotheliocytes with thrombin, endotoxin, interleukin-1 (IL-1), and certain other cytokines, rapidly decreases the synthesis of 13-HODE. In contrast, increases in the level of intracellular cAMP activate the formation of 13-HODE [17], and natural metabolites that increase the intracellular cAMP level, such as PGI2 and 6-keto-PGE1, can initiate the metabolism of triglycerides in endothelial cells after a transitory inhibition of this process caused by damage of vascular wall thromboresistance, e.g., of traumatic origin [19]. The amount of 13-HODE in intact endothelial cells was shown to inversely correlate with the degree of thrombogenicity of endotheliocyte plasma membranes [2, 20]. Studies of the mechanism of anti-adhesive effects of 13-HODE showed that this metabolite regulates the expression of adhesion receptors (primarily vitronectin receptors) on the surface of endothelial cells. 13-HODE and vitronectin receptors are known to have the same cellular localization; they are found in vesicles placed directly under the plasma membrane. In intact endotheliocytes, 13-HODE interacts with lipophilic sites of vitronectin receptors, thereby decreasing their expression on the plasma membrane [2]. In stimulated endothelial cells, complexes of 13-HODE and vitronectin receptors dissociate with expression of active integrins on the apical surface of endotheliocytes; this increases their ability to interact with platelets and other circulating blood cells. An interesting finding was that 13-HODE is expressed not only on the apical surface of endotheliocytes but also on their basal surface, thereby maintaining the thromboresistance of subendothelial structures [2, 20, 21]. Such a localization of 13-HODE is an important factor modulating thrombogenesis, because the maximum activity of tissue factor expressed by stimulated vascular walls (one of the main components determining the extent of thrombogenesis possible under given conditions) is known to be related exactly to the basal surface of endothelial cells [22-24].
Most probably, metabolites of gamma-linolenic acid (18:3, n-6) are involved in maintenance of thromboresistant properties of cell walls. At least, there is evidence that adding black currant oil, which contains high levels of linoleic and gamma-linolenic acids, to rabbit diet causes a much greater increase in 13-HODE synthesis in comparison to nut oil that contains linoleic acid only [21]. This is probably related to an increase in the rate of synthesis of dihomo-gamma-linolenic acid and then PGE1 from gamma-linolenic acid; PGE1 promotes the accumulation of cAMP in endotheliocytes, thereby activating linoleic acid metabolism and synthesis of 13-HODE [25]. Functional or morphological damage to vascular wall changes the thromboresistant properties of its luminal surface to procoagulant properties; this process can initiate thrombogenesis [6]. Depending on the nature of the damaging factor, these changes can be transitory or display properties of a chronic process [13]. In the former case, initial stimulation of endotheliocytes is mainly mediated by thrombin. Chronic disorders in vascular wall thromboresistance can be caused by certain factors such as endotoxin and pro-inflammatory cytokines, especially IL-1 and tumor necrosis factor; in this case, there is a considerable suppression of anticoagulant mechanisms, including the inhibition of prostacyclin synthesis [13, 26].
Upon interaction of thrombin with specific receptors on endotheliocytes, the cells synthesize, express, and liberate into the environment a range of biologically active substances causing procoagulant and anticoagulant effects. When applied to endotheliocytes, thrombin primarily causes a rapid increase in the rate of synthesis and secretion of strong anti-aggregants (PGI2 and NO) capable of limiting the development of intravascular coagulation. Soon after application of weak stimuli to endothelial cells, there is an increase in the release of endothelial relaxing factor (NO) only, whereas liberation of PGI2 requires much stronger stimuli, probably because of different pathways of transduction of signals inducing the synthesis of these mediators [12]. Such a sequence of liberation of NO and PGI2 can be explained by biological expediency because NO is sufficient to block probable prothrombogenic reactions to weak stimulation of endothelium. This is also related to the fact that the initial stage of thrombogenesis is accompanied by active adhesion of cells to the surface of the vascular wall, making the synthesis of NO the most expedient response because this substance displays not only anti-aggregatory but also strong anti-adhesive effects [27-29]. After the formation of a monolayer of deposited platelets, their further accumulation mainly obeys the laws of platelet--platelet interaction (aggregation). This explains a short time delay in PGI2 synthesis; this substance is one of the most potent natural anti-aggregatory agents; it can potentiate both the anti-aggregatory and disaggregatory effects of NO [27], but its physiological concentrations do not modulate adhesion to an appreciable extent [30] because the anti-adhesive effect develops only in the presence of high concentrations of PGI2 causing an increase in intracellular cGMP level [27, 31].
Activation of endotheliocytes causes the formation of not only AA metabolites of the cyclooxygenase pathway, but also its metabolites of the lipoxygenase pathway, which also can modulate blood coagulation. Hydroxyeicosatetraenoic acids (HETEs) were shown to increase the rate of PGI2 synthesis [32] thereby inhibiting thrombogenesis. However, HETEs can compete with arachidonic acid for lipoxygenase, cyclooxygenase, or both enzymes [33, 34], thereby inducing disorders in normal metabolism of PUFA. In this context, the observed decrease in the synthesis of PGI2 by endothelial cells exposed to HETEs [35] is most probably a result of exhaustion of cyclooxygenase in the presence of excess substrate [2]. 15-Hydroperoxyeicosatetraenoic acid (15-HPETE) and 15-HETE can also decrease the procoagulatory activity of endotheliocytes stimulated by tumor necrosis factor alpha (TNF-alpha); this effect is mediated by neither a decrease in TNF-alpha binding to specific cell receptors nor a decrease in expression and/or synthesis of the tissue factor [36].
The loss of thromboresistance of endotheliocytes is accompanied by activation of blood coagulation. All blood cells are involved in thrombogenesis; however, the procoagulant function is the main function of platelets. Platelets are not only the main cell type involved in thrombogenesis in arteries and important factors of phlebothrombosis, but also strongly affect other links of blood coagulation: they supply activated phospholipid surfaces necessary for plasma hemostasis [37, 38], release certain blood coagulation factors in the blood [39], modulate fibrinolysis [40], and alter hemodynamic constants by causing a transitory vasoconstriction induced by their release of thromboxane A2 (TXA2) [41] and producing and releasing mitogens that induce hyperplasia of vascular walls [42]. Initiation of thrombogenesis is accompanied by activation of platelets and induction of their adhesion, release reaction, and aggregation; adhesion is the first step of hemostasis, which precedes the release reaction and aggregation [43, 44]. Platelet activation caused by vascular wall lesions, rheological disorders, etc., is due to interaction of surface receptors of these cells with certain agonists [45, 46]. Collagen and thrombin [47] are primary inducers appearing most frequently at the site of a vascular lesion; however, the complete formation of a platelet thrombus requires many other molecules as well. It should be noted that activated platelets display much higher affinities for ligands [47, 48]. Thus, glycoprotein (GP) IIb/IIIa of intact platelets can interact only with immobilized fibrinogen [49], whereas GPIIb/IIIa receptors of activated platelets display affinities for at least four different molecules: fibrinogen, von Willebrand's factor, fibronectin, and vitronectin [50].
Interactions of platelet receptors with specific ligands initiates a range of biochemical responses including the activation of G-proteins and phospholipases, phospholipid turnover, formation of second messengers, protein phosphorylation, metabolism of AA, interactions of actin and myosin, Na+/H+ exchange, expression of fibrinogen receptors, and redistribution of Ca2+ [51-55]. An obligatory stage of platelet activation is liberation of arachidonic acid with subsequent formation of TXA2 [56], which stimulates the liberation of AA from platelet membrane phospholipids, thereby maintaining the cell activation [57]. However, TXA2 alone cannot maintain platelet--platelet interactions because the initiation of platelet aggregation requires stimulation of receptors capable of inducing responses related to phospholipases A2 and C [53].
In addition to TXA2, other metabolites of AA are involved in platelet adhesion and aggregation. Platelets are known to produce more 12-HETE than TXA2 [2]. 12-HPETE and 12-HETE can probably produce synergistic responses or are necessary for platelets to display their functional properties [20, 58, 59]. 12-HPETE, a precursor of 12-HETE, was found to potentiate platelet aggregation induced by arachidonic acid by inducing disorders in membrane permeability, thereby making more arachidonic acid available to cells [58]. In addition, selective inhibition of the 12-lipoxygenase pathway in platelets is known to decrease their adhesive ability independently of the effect of this treatment on platelet aggregation [60]. Adhesion of platelets to thrombogenic surfaces is accompanied by spreading the cells over the surface. This ensures better interactions of platelet GPIIb/IIIa receptors with fixed ligands and promotes thrombogenesis because this provides a stronger attachment of adherent cells with vascular walls and allows immobilized fibrinogen and von Willebrand's factor to act as platelet agonists that activate these cells [43]. Oxylipins are strongly involved in regulation of platelet spreading. Arachidonic acid liberated from activated cells is metabolized by lipoxygenase, and biologically active substances generated in this process initiate the production of diacylglycerol, which activates phospholipase C required for the cell spreading [61]. Functioning of platelets probably involves epoxyeicosatrienoic acids and 20-HETE (arachidonic acid metabolites synthesized in reactions involving cytochrome P-450), which are liberated from membrane phospholipids upon platelet stimulation [62].
In response to stimulation by agonists, platelets also liberate certain stable prostaglandins (PG) having two double bonds, such as PGE2, PGF2alpha, and PGD2. PGD2 can inhibit platelet aggregation [63], PGF2alpha activates these cells [64], and the effects of PGE2 on platelets can vary [65] depending on whether adenylate cyclase is activated or inhibited by this substance [66]. We cannot exclude the possibility that all these compounds are involved in thrombogenesis [67]. Mechanisms of action of these eicosanoids are mediated by receptors found on platelet membranes [45].
In addition to stable prostaglandins, mainly PGE2 and small amounts of thromboxane A2, vascular walls produce prostacyclin, which is the main metabolite of the cyclooxygenase pathway in this tissue. PGI2 is known to be produced in endothelial cells from not only endogenous labile peroxides, but also from exogenous, platelet-derived PGG2 and PGH2 [68]. In addition, PGI2 can be synthesized in whole blood in the absence of endothelial cells [69]; this synthesis probably occurs in leukocytes and/or monocytes [70]. Prostacyclin is one of the most potent natural anti-aggregatory substances [71]. PGI2 can increase the level of intracellular cAMP by activating adenylate cyclase; this suppresses the primary and secondary phases of platelet aggregation, suppresses the mobilization of intracellular Ca2+, and inhibits the procoagulant activity of platelets [72].
Probably, not only PGI2 proper but also its metabolic products are involved in regulation of thrombogenesis. PGI2 is converted to certain stable but inactive products, mainly PGF1alpha. It was suggested that endothelial cells can produce 6-keto-PGE1, an active metabolite of PGI2 [2]. This prostanoid has an anti-aggregatory effect comparable to that of PGI2 but causes no appreciable hypotensive effect [73]. In the absence of any stimuli, 6-keto-PGE1 is probably not synthesized by vascular walls (the only exception may be heart endotheliocytes), and production of its physiologically significant amounts occurs only upon cell--cell interactions [2]. The production of 6-keto-PGE1 is probably a transcellular process. However, it should be noted that certain authors regard 6-keto-PGE1 detection in vitro and in vivo as an artefact due to methodological flaws [74].
Among natural oxylipins, not only prostacyclin causes a strong inhibitory effect on platelet functions. PGE1 synthesized in cells from dihomo-gamma-linolenic acid is a very important substance involved in regulation of blood coagulation. PGE1 inhibits platelet aggregation [75, 76], increases the level of intracellular cAMP, inhibits the activation of protein kinase C and myosin light chain kinase in platelets stimulated by thrombin, and suppress their phosphatidylinositol-4,5-bisphosphate hydrolysis [76, 77] thereby preventing platelet activation through pathways dependent on and independent of AA metabolites of the cyclooxygenase pathway.
The functional balance between antithrombogenic and prothrombogenic reactions can be disturbed by interference of not only activated platelets but also other blood cells subjected to appropriate stimulation. For example, interactions between erythrocytes and activated platelets increase their reaction abilities [78]. In addition, erythrocytes, like other blood cells, promote the synthesis of thrombin [79]. Leukocytes are another cell type involved in blood coagulation and fibrinolysis. They provide, upon stimulation, an active surface for initiation of hemostasis [80] and liberate substances that facilitate the involvement of other cells in blood coagulation and stimulate these cells [37, 81, 82]. Under certain conditions, leukocytes express endotoxin, which can increase vascular permeability independently of cell adhesion [83]; it also causes liberation of tissue factor and promotes the initiation of blood coagulation in the intrinsic pathway [37]. Activated monocytes secrete a range of cytokines, including IL-1alpha and IL-1beta, tumor necrosis factor, and probably IL-6 [84]; these can induce reactions of the blood coagulation cascade [13, 85].
Adhesion of white blood cells to vascular walls caused by low-density lipoprotein oxidation products, bacterial lipopolysaccharides, cytokines, and other agonists [86] has certain consequences important not only for the development of inflammatory reactions but also for an increase in the risk of thrombogenesis. This process causes disorders in interactions between separate endotheliocytes [87] which can increase vascular wall permeability and facilitate the access of procoagulant factors to subendothelial structures, thereby considerably increasing the probability of blood coagulation under certain conditions. In addition, adherent leukocytes can increase the prothrombogenic activity of vascular walls, probably through potentiation of production of a platelet aggregation factor by endothelial cells [88], liberating cytokines from activated cells, and/or a directly activating effect on endotheliocytes caused by adherent leukocytes [89]. All these processes lead to an increase in expression of tissue factor by endothelial cells. White blood cells are also involved in regulation of fibrinolysis. They activate alpha2-antiplasmin, an important inhibitor of plasmin [90] and facilitate the utilization of soluble fibrin complexes [91]; on the other hand, they synthesize cytokines that suppress fibrinolysis by decreasing the liberation of tissue plasminogen activator from endotheliocytes and increasing the level of tissue plasminogen inhibitor [13].
A very important effect of activated leukocytes is their ability to produce and liberate mitogens that cause vascular wall proliferation [92] (which can lead to a disorder of synthesis and interaction of endothelial anticoagulation factors [93]), change hemodynamic constants, and induce acute thromboses.
These data suggest that erythrocytes and white blood cells are strongly involved in reactions of the blood coagulation cascade; therefore, modulation of their functions by metabolites of polyunsaturated fatty acids is important for maintaining a physiological balance between procoagulant and anticoagulant links of the blood coagulation system.
Studies of eicosanoids as substances affecting the functional activity of erythrocytes showed that PGI2 increases the fluidity of these cells [94], thereby preventing probable rheological disorders and stasis. Lipoxygenase metabolites 15-HPETE, 15-HETE, and 12-HETE produce dose-dependent potentiation of adhesion of platelets to endothelial cells of large blood vessels and capillaries; the effects of 12-HETE are mediated by vitronectin receptors [95].
Studies of the effects of eicosanoids on white blood cells showed that PGI2 considerably suppresses the procoagulant activity of monocytes, which prevents, to some extent, the induction of certain blood coagulation reactions [96]. The thrombogenicity of monocytes can be decreased by other oxylipins, especially 5-, 12-, and 15-HETE [97]. However, other authors showed that platelet 12-HETE, a lipoxygenase metabolite of arachidonic acid, stimulates the procoagulant activity of monocytes and promotes the expression of tissue factor on the surface of these cells [98]. AA metabolites are also involved in regulation of production of cytokines. The rate of production of TNF-alpha and IL-1 by monocytes is determined by the rate ratio of generation of PGE2 and TXA2 by these cells; the latter substance increases the ability of nonadherent monocytes to synthesize cytokines [99]. Prostacyclin, another prostanoid, inhibits the liberation of cytokines, primarily tumor necrosis factor and IL-1, from monocytes and macrophages [100].
Interactions of platelets and polymorphonuclear neutrophils at the sites of a vascular lesions can promote thrombogenesis [101, 102]. Adhesion of these cells to each other provokes transcellular exchange of mediators and intermediate metabolites. This process requires the expression of P-selectin, which is responsible for "recognition" of platelets by polymorphonuclear neutrophils [103] on the platelet surface. However, a decrease in platelet reactivity decreases the expression of these surface receptors and this prevents the activation of the coagulation cascade as a result of platelet--leukocyte interactions. On the other hand, initiation of the intrinsic pathway of blood coagulation by leukocytes is accompanied by the formation of 5-lipoxygenase metabolites of arachidonic acid (leukotriene B4 (LTB4) and cysteine-containing leukotrienes) in human peripheral monocytes in a process largely independent of thrombin production [104]. This can result in creation of conditions for further promotion of coagulation. Certain studies showed that LTB4 mediates the liberation of lysosomal enzymes from leukocytes, mobilization of calcium, and the formation of reactive oxygen species [105]. LTB4, which is involved in pathophysiological processes of inflammation [106], causes adhesion of neutrophils to vascular walls followed by diapedesis and cell migration to the extracellular space [107]. This suggests that LTB4 plays an anti-inflammatory role and can be involved in reactions leading to suppression of thromboresistance of endotheliocytes [88]. Lipoxin A4, another arachidonic acid metabolite of the lipoxygenase pathway, can inhibit certain effects of LTB4. In particular, lipoxin A can inhibit leukocyte migration and increase in vascular permeability induced by LTB4 [108], thereby preventing the development of disorders caused by blood coagulation and inflammation.
Oxylipins can also produce secondary effects on plasma hemostasis, mainly through modulation of the procoagulant properties of cytoplasmic membranes. As pointed out above, activation of many cells involved in hemostasis is accompanied by expression of tissue factor on their surface. When the level of tissue factor increases to a certain value, it imparts thrombogenic properties to vascular walls [109] or other surfaces involved. The tissue factor (thromboplastin) is a transmembrane protein, which possesses no enzymatic activity but acts as a cofactor of the activated factor VII. The complex of tissue factor--factor VII can activate factors X and IX, which ultimately results in generation of thrombin [110]. Thrombin produced in this process is a key enzyme mediating the transformation of fibrinogen into fibrin and causing an additional activation of platelets [111]. Therefore, thrombin induces cell-mediated hemostasis and facilitates plasma-mediated reactions by strongly increasing the procoagulant properties of membranes of activated cells [112]. In addition to this mechanism, thrombin can also increase the probability of platelet involvement in blood coagulation by increasing their expression of surface receptors for TXA2/PGH2 [113]. In this process, prostacyclin, which increases the level of cyclic nucleotides in endothelial cells, is involved in regulation of processes that facilitate the inactivation of thrombin found in the vascular lumen. At high levels of cAMP in endotheliocytes, the expression of thrombomodulin, which acts as a receptor of activated thrombin, increases on the luminal surface of the intima. Thrombin bound to thrombomodulin undergoes conformational changes that prevent its involvement in fibrin formation but make it highly active in reactions of cleavage of protein C zymogen, thereby facilitating its anticoagulatory effect [114].
Prostacyclin causes considerable activating effects on the blood fibrinolytic potential. PGI2, which stimulates fibrinolysis in vivo, causes no profibrinolytic effect in vitro upon its direct application on fibrin plates [115]. An increase in fibrinolytic activity caused by PGI2 administration can be caused by induction of liberation of tissue plasminogen activator from vascular walls [116]. A certain role in PGI2-mediated modulation of the blood fibrinolytic potential can be played by its ability to inhibit platelet functions. Platelets are known to be strongly involved in regulation of thrombolysis. First of all, they are an important source of tissue plasminogen activator and alpha2-antiplasmin [117]. When exposed to agonists, platelets can liberate these substances from intracellular organelles, thereby suppressing fibrinolysis [40]. However, platelets accumulate endogenous prourokinase on their surface [118], a phenomenon whose physiological significance is still unknown [118], and platelet-associated prourokinase can activate plasminogen at the site of thrombogenesis [37, 119]. Plasmin generated simultaneously can cause a direct stimulatory effect on platelets [120] and thus increased the risk of thrombosis. These data indicate that the profibrinolytic effect of platelets is of less significance than their antifibrinolytic effects. Thus, oxylipins, inhibit the release reaction, and activate adenylate cyclase, thereby preventing platelets from realizing their ability to decrease the blood fibrinolytic potential, whereas pro-aggregatory eicosanoids decrease the intensity of thrombolysis. The profibrinolytic effect of prostacyclin can also be mediated by another mechanism. Depression of fibrinolysis is known to be partly mediated by plasma carboxypeptidase-U-coenzyme which is activated by thrombin-induced proteolysis. Therefore, the PGI2-mediated decrease in thrombin production can facilitate the activation of blood clot lysis [121].
The size of the vascular lumen is an important factor maintaining normal function of the blood coagulation system. It should be noted that it is exactly the physiological values of forces generated by mechanical interaction of blood flow with vascular walls that strongly determine the thromboresistance of endothelium. Even a small local decrease in vascular lumen sharply increases shear rates [122] to values that can activate cellular links of hemostasis, primarily platelets and leukocytes, with their further adhesion and aggregation [50, 102, 122]. These changes can proceed when the vascular wall conserves its anticoagulant properties [123]. On the other hand, an increase in the intensity of mechanical stimulation of the vascular intima is accompanied by activation of synthesis of vasodilator substance such as prostacyclin by endotheliocytes [14]. Release of PGI2 into the bloodstream decreases the activity of blood cells, including platelets, and causes vasodilation. The latter response results in hemodynamic conditions that decrease the probability of procoagulant reactions. However, shear rate can be decreased abruptly by excess production of endogenous substances, especially in the presence of a functionally damaged vascular wall. In this situation, activation of endothelial cells by certain agonists, such as pro-inflammatory cytokines, can increase the expression of tissue factor not only on the basal but also on the luminal surface of endotheliocytes with further activation of plasma hemostasis and fibrin deposition [109]. A low blood flow velocity probably provides optimal conditions for delivery of procoagulant factors to particular sites of the vascular wall and promotes intermolecular interactions [123, 124]. A sharp decrease in shear rates under physiological conditions decreases the rates of synthesis and liberation of vasodilators (including PGI2 and NO) and increases the level of plasma endothelin [125, 126], which not only decreases platelet responses but primarily is a potent vasoconstrictor [127]. Endothelin initiates protein kinase C, which in turn activates phospholipase A2, which results in liberation of arachidonic acid with further increase in PGI2 production [128]. These data suggest that prostacyclin is a component of the system maintaining normal hemodynamic conditions.
Products of the lipoxygenase pathway of arachidonic acid metabolism are active regulators of vascular tone, and they can either increase or decrease the vascular lumen. Thus, low concentrations of 15-HETE induce vasodilation, whereas its high concentrations cause vasoconstriction. This vasodilation is probably related to activation of prostacyclin synthesis, whereas the 15-HETE-induced increase in the vascular wall tone is due to expression of thromboxane receptors on vascular smooth muscle cells [129, 130]. Cysteine-containing leukotrienes can influence the microvascular tone and induce a transitory arteriolar constriction [131]. In contrast to leukotrienes, lipoxins can cause arteriolar dilatation [132]. Arachidonic acid metabolites synthesized by the cytochrome P-450-dependent pathway are strong vasodilators [133]. Recent studies showed that after inhibition of NO synthase and cyclooxygenase, the vasodilator function of blood vessels is maintained by generation of an endothelial hyperpolarization factor [134] which can be a cytochrome P-540-dependent metabolite of arachidonic acid [134, 135]. The effects of prostacyclin on the vascular lumen is not restricted to its direct vasodilator effect. The ability of this eicosanoid to decrease the proliferative activity of the vascular wall smooth muscle cells is similarly important. This effect is caused by a decrease in liberation of vascular hyperplasia-inducing agents, such as platelet growth factor and platelet factor 4, from blood platelets; however, the antiproliferative effect of PGI2 can be independent from platelet inactivation [136]. In contrast to PGI2, TXA2 stimulates hyperplasia of vascular walls [137]. There is evidence to suggest that 12-lipoxygenase metabolites of arachidonic acid, especially 12-HETE, may also be involved in regulation of proliferative processes. Mitogenic cell responses to angiotensin II and platelet growth factor were shown to require the activation of 12-lipoxygenase, which can act as a key factor of this process [138, 139].
Thus, numerous studies have shown that many oxylipins are much involved in regulation of blood coagulation; they maintain, in cooperation with other components of this system, a state of balance of procoagulant and anticoagulant processes under physiological conditions. Modulation of virtually all steps of hemostasis by metabolites of AA and other PUFA indicates that these substances display unique properties among all other biologically active substances affecting the mechanism of blood coagulation. Further studies of the possible physiological role of oxylipins in maintenance of the blood coagulation potential at an optimal level are extremely important because this research can expand our knowledge of normal physiology of hemostasis and have applied significance: it may find the causes and pathways of development of many severe diseases and show possible approaches to pharmacological and other therapeutic interventions to prevent and correct a number of pathological states.
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