sphingosine-1-phosphate and Thrombosis

Sphingosine 1-phosphate (S1P) is a potent lipid mediator that works on five kinds of S1P receptors located on the cell membrane. In the circulation, S1P is distributed to HDL, followed by albumin. Since S1P and HDL share several bioactivities, S1P is believed to be responsible for the pleiotropic effects of HDL. Plasma S1P levels are reportedly lower in subjects with coronary artery disease, suggesting that S1P might be deeply involved in the pathogenesis of atherosclerosis. In basic experiments, however, S1P appears to possess both pro-atherosclerotic and anti-atherosclerotic properties; for example, S1P possesses anti-apoptosis, anti-inflammation, and vaso-relaxation properties and maintains the barrier function of endothelial cells, while S1P also promotes the egress and activation of lymphocytes and exhibits pro-thrombotic properties. Recently, the mechanism for the biased distribution of S1P on HDL has been elucidated; apolipoprotein M (apoM) carries S1P on HDL. ApoM is also a modulator of S1P, and the metabolism of apoM-containing lipoproteins largely affects the plasma S1P level. Moreover, apoM modulates the biological properties of S1P. S1P bound to albumin exerts both beneficial and harmful effects in the pathogenesis of atherosclerosis, while S1P bound to apoM strengthens anti-atherosclerotic properties and might weaken the pro-atherosclerotic properties of S1P. Although the detailed mechanisms remain to be elucidated, apoM and S1P might be novel targets for the alleviation of atherosclerotic diseases in the future.

Topics: Animals; Apolipoproteins M; Apoptosis; Atherosclerosis; Cell Line; Coronary Artery Disease; Homeostasis; Humans; Inflammation; Lipoproteins, HDL; Lymphocyte Activation; Lysophospholipids; Receptors, LDL; Sphingosine; Thrombosis; Vasodilation

Blood platelets are the first line of defense against hemorrhages and are also strongly involved in the processes of arterial thrombosis, a leading cause of death worldwide. Besides their well-established roles in hemostasis, vascular wall repair and thrombosis, platelets are now recognized as important players in other processes such as inflammation, healing, lymphangiogenesis, neoangiogenesis or cancer. Evidence is accumulating they are key effector cells in immune and inflammatory responses to host infection. To perform their different functions platelets express a wide variety of membrane receptors triggering specific intracellular signaling pathways and largely use lipid signaling systems. Lipid metabolism is highly active in stimulated platelets including the phosphoinositide metabolism with the phospholipase C (PLC) and the phosphoinositide 3-kinase (PI3K) pathways but also other enzymatic systems producing phosphatidic acid, lysophosphatidic acid, platelet activating factor, sphingosine 1-phosphate and a number of eicosanoids. While several of these bioactive lipids regulate intracellular platelet signaling mechanisms others are released by activated platelets acting as autocrine and/or paracrine factors modulating neighboring cells such as endothelial and immune cells. These bioactive lipids have been shown to play important roles in hemostasis and thrombosis but also in vessel integrity and dynamics, inflammation, tissue remodeling and wound healing. In this review, we will discuss some important aspects of platelet lipid signaling in thrombosis and during sepsis that is an important cause of death in intensive care unit. We will particularly focus on the implication of the different isoforms of PI3Ks and on the generation of eicosanoids released by activated platelets.

Topics: Animals; Blood Platelets; Humans; Inflammation; Lipid Metabolism; Lysophospholipids; Phosphatidylinositol 3-Kinases; Signal Transduction; Sphingosine; Thrombosis; Type C Phospholipases

Beyond key functions in hemostasis and thrombosis, platelets are recognized as key players of inflammation, an underlying feature of a variety of diseases. In this regard, platelets act as a circulating source of several pro- and anti-inflammatory molecules, which are secreted from their intracellular stores upon activation. Among them, mounting evidence highlights a crucial role of sphingosine-1-phosphate (S1P), a multifunctional sphingoid mediator. S1P-induced pleiotropic effects include those crucial in inflammatory processes, such as the maintenance of the endothelial barrier integrity, and leukocyte activation and recruitment at the injured site. This review outlines the peculiar features and molecular mechanisms that allow platelets for acting as a unique factory that produces and stores S1P in large quantities. A particular emphasis is placed on the autocrine and paracrine roles of S1P derived from the "inflamed" platelets, highlighting the role of its cross-talk with endothelial and blood cells involved in inflammation, and the mechanisms of its contribution to the development and progression of inflammatory diseases. Finally, potential clinical implications of platelet-derived S1P as diagnostic tool of inflammatory severity, and as therapeutic target in inflammation are discussed.

Topics: Anti-Inflammatory Agents; Autocrine Communication; Biological Transport; Blood Platelets; Endothelium, Vascular; Humans; Inflammation; Leukocytes; Lysophospholipids; Molecular Targeted Therapy; Platelet Activation; Signal Transduction; Sphingosine; Thrombosis

Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are potent bioactive phospholipids with specific and multiple effects on blood cells and cells of the vessel wall. Released by activated platelets, LPA and S1P mediate physiological wound healing processes such as vascular repair. Evidence is accumulating that these lipid mediators can, however, under certain conditions become athero- and thrombogenic molecules that might aggravate cardiovascular disease. For example, LPA present in minimally modified LDL and within the intima of atherosclerotic lesions may play a role in the early phase of atherosclerosis by inducing barrier dysfunction and increased monocyte adhesion of the endothelium, as well as in the late phase by triggering platelet activation and intra-arterial thrombus formation upon rupture of the atherosclerotic plaque. Moreover, LPA and S1P, by stimulating the proliferation of fibroblasts and by enhancing the survival of inflammatory cells are likely to play a central role in the excessive fibroproliferative and inflammatory response to vascular injury that characterizes the progression of atherosclerosis. Furthermore, LPA can cause the phenotypic dedifferentiation of medial vascular smooth muscle cells, and S1P is able to stimulate the migration and proliferation of intimal vascular smooth muscle cells; both processes ultimately lead to the formation of the neointima. Most importantly, as LPA and S1P bind to and activate multiple G-protein receptors, it emerges that the beneficial or harmful action of LPA and S1P are critically dependent on the expression profile of their receptor subtypes and their coupling to different signal transduction pathways in the target cells. By targeting specific subtypes of LPA and S1P receptors in selective cells of the vascular wall and blood, new strategies for the prevention and therapy of cardiovascular diseases can be envisioned.

Topics: Animals; Arteriosclerosis; Cell Membrane Permeability; Endothelium, Vascular; Humans; Lysophospholipids; Platelet Activation; Sphingosine; Thrombosis

Sphingosine 1-phosphate (S1P) is a highly active lysophospholipid implicated in various cardiocerebrovascular events such as coagulation, myocardial infarction and stroke. However, as the functional S1P receptor antagonist, whether the S1P mimetic FTY720 can modulate coagulation and/or thrombotic formation remains largely unknown. We investigated the effects of FTY720 on adenosine diphosphate (ADP)-induced platelet aggregation, coagulation parameters and thrombus formation in rats. Pretreatment with FTY720 (2.5 mg/kg) inhibited platelet aggregation induced by ADP, elongated the thrombin time and decreased the fibrinogen levels. However, FTY720 produced no significant effects on the arteriovenous bypass thrombus formation or the FeCl3-induced thrombus formation in the inferior vena cava and the common carotid artery. Our data suggest that FTY720 can exert an inhibitory effect on platelet aggregation and coagulation-related parameters. These characteristics of FTY720 could be useful as an adjunct in the treatment of ischemic diseases such as ischemic stroke and myocardial infarction.

Topics: Adenosine Diphosphate; Animals; Anticoagulants; Arteriovenous Shunt, Surgical; Biomimetic Materials; Blood Platelets; Carotid Artery, Common; Chlorides; Disease Models, Animal; Ferric Compounds; Fibrinolytic Agents; Fingolimod Hydrochloride; Humans; Lysophospholipids; Male; Platelet Aggregation; Platelet Function Tests; Rats; Rats, Sprague-Dawley; Receptors, Lysosphingolipid; Sphingosine; Thrombosis; Vena Cava, Inferior

Sphingosine-1-phosphate (S1P) has been known to promote endothelial cell (EC) proliferation and protect Syndecan-1 (SDC1) from shedding, thereby maintaining this antithrombotic signal. In the present study, we investigated the effect of S1P in the construction of a functional tissue-engineered blood vessel by using human endothelial cells and decellularized human umbilical vein (DHUV) scaffolds. Both human umbilical vein endothelial cells (HUVEC) and human cord blood derived endothelial progenitor cells (EPC) were seeded onto the scaffold with or without the S1P treatment. The efficacy of re-cellularization was determined by using the fluorescent marker CellTracker CMFDA and anti-CD31 immunostaining. The antithrombotic effect of S1P was examined by the anti-aggregation tests measuring platelet adherence and clotting time. Finally, we altered the expression of SDC1, a major glycocalyx protein on the endothelial cell surface, using MMP-7 digestion to explore its role using platelet adhesion tests in vitro. The result showed that S1P enhanced the attachment of HUVEC and EPC. Based on the anti-aggregation tests, S1P-treated HUVEC recellularized vessels when grafted showed reduced thrombus formation compared to controls. Our results also identified reduced SDC1 shedding from HUVEC responsible for inhibition of platelet adherence. However, no significant antithrombogenic effect of S1P was observed on EPC. In conclusion, S1P is an effective agent capable of decreasing thrombotic risk in engineered blood vessel grafts.. Sphingosine-1phosphate (S1P) is a low molecular-weight phospholipid mediator that regulates diverse biological activities of endothelial cell, including survival, proliferation, cell barrier integrity, and also influences the development of the vascular system. Based on these characters, we the first time to use it as an additive during the process of a small caliber blood vessel construction by decellularized human umbilical vein and endothelial cell/endothelial progenitor. We further explored the function and mechanism of S1P in promoting revascularization and protection against thrombosis in this tissue engineered vascular grafts. The results showed that S1P could not only accelerate the generation but also reduce thrombus formation of small caliber blood vessel.

Topics: Blood Coagulation; Blood Vessel Prosthesis; Cell Adhesion; Endothelial Progenitor Cells; Endothelium, Vascular; Fluorescent Antibody Technique; Glycocalyx; Human Umbilical Vein Endothelial Cells; Humans; Kinetics; Lysophospholipids; Matrix Metalloproteinase 7; Models, Biological; Platelet Adhesiveness; Sphingosine; Syndecan-1; Thrombosis; Tissue Scaffolds; Umbilical Veins

Platelets are known to play a crucial role in hemostasis. Sphingosine kinases (Sphk) 1 and 2 catalyze the conversion of sphingosine to the bioactive metabolite sphingosine 1-phosphate (S1P). Although platelets are able to secrete S1P on activation, little is known about a potential intrinsic effect of S1P on platelet function.. To investigate the role of Sphk1- and Sphk2-derived S1P in the regulation of platelet function.. We found a 100-fold reduction in intracellular S1P levels in platelets derived from Sphk2(-/-) mutants compared with Sphk1(-/-) or wild-type mice, as analyzed by mass spectrometry. Sphk2(-/-) platelets also failed to secrete S1P on stimulation. Blood from Sphk2-deficient mice showed decreased aggregation after protease-activated receptor 4-peptide and adenosine diphosphate stimulation in vitro, as assessed by whole blood impedance aggregometry. We revealed that S1P controls platelet aggregation via the sphingosine 1-phosphate receptor 1 through modulation of protease-activated receptor 4-peptide and adenosine diphosphate-induced platelet activation. Finally, we show by intravital microscopy that defective platelet aggregation in Sphk2-deficient mice translates into reduced arterial thrombus stability in vivo.. We demonstrate that Sphk2 is the major Sphk isoform responsible for the generation of S1P in platelets and plays a pivotal intrinsic role in the control of platelet activation. Correspondingly, Sphk2-deficient mice are protected from arterial thrombosis after vascular injury, but have normal bleeding times. Targeting this pathway could therefore present a new therapeutic strategy to prevent thrombosis.

Topics: Animals; Arachidonic Acid; Blood Coagulation; Blood Coagulation Tests; Blood Platelets; Carotid Artery Injuries; Disease Models, Animal; Erythrocytes; Lysophospholipids; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Phosphotransferases (Alcohol Group Acceptor); Platelet Adhesiveness; Platelet Aggregation; Platelet Function Tests; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors; Thrombosis; Thromboxane A2; Vascular System Injuries

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (SIP) are potent bioactive lipids with specific and multiple effects on cells of the vessel wall and blood platelets. In this paper we suggest that these lipid molecules are involved in atherogenesis, pathological vasoconstriction, plaque rupture, and intravascular thrombus formation, which leads us to propose new strategies for the prevention and therapy of cardiovascular diseases. The conclusions are hypothetical, in that the studies were so far mainly carried out on isolated cells or cultured cells in vitro and the results were extrapolated to the situation in vivo.

Topics: Arteriosclerosis; Cardiovascular Diseases; Endothelium, Vascular; Humans; Lysophospholipids; Phosphorylation; Signal Transduction; Sphingosine; Thrombosis