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CORD-19:9717bf810e0bed806f32d85343b4210f37a9a319 JSONTXT 8 Projects

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Id Subject Object Predicate Lexical cue
T1 0-77 Sentence denotes Microvesicles at the crossroads between infection and cardiovascular diseases
T2 79-87 Sentence denotes Abstract
T3 88-304 Sentence denotes Observational and experimental studies continue to support the association of infection and infection-stimulated inflammation with development of cardiovascular disease (CVD) including atherosclerosis and thrombosis.
T4 305-564 Sentence denotes Microvesicles (MV) are heterogeneous populations of sealed membrane-derived vesicles shed into circulation by activated mammalian cells and/or pathogenic microbes that may represent an interface between bacterial/microbial infection and increased risk of CVD.
T5 565-726 Sentence denotes This review evaluates how MV act to modulate and intersect immunological and inflammatory responses to infection with particular attention to progression of CVD.
T6 727-940 Sentence denotes While infection-related stimuli provoke release of MV from blood and vascular cells, MV express phosphatidylserine (PS) and other procoagulant factors on their surface which initiate and amplify blood coagulation.
T7 941-1138 Sentence denotes In addition, MV mediate cell-cell adhesion which may stimulate production of pro-inflammatory cytokines in vascular cells, which in turn aggravate progression of CVD and propagate atherothrombosis.
T8 1139-1289 Sentence denotes MV transfer membrane receptors, RNA and proteins among cells, and present auto-antigens from their cells of origin to proximal or remote target cells.
T9 1290-1529 Sentence denotes Because MV harbor cell surface proteins and contain cytoplasmic components of the parent cell, they mediate biological messages and play a pivotal role in the crossroad between infection-stimulated inflammation and cardiovascular diseases.
T10 1531-1757 Sentence denotes Both chronic and acute infection, especially when provoked by gram-negative bacteria, increase risk of cardiovascular events including instability of atherosclerotic plaques and formation of microvascular thrombi (1) (2) (3) .
T11 1758-2084 Sentence denotes Increased risk of thrombosis does not seem to be specific for one type of infection but rather seems to be a universal potential consequence of infection regardless of the organ system affected: dental infections including periodontitis (4) , infection of the urinary tract (5) and upper airway (5, 6) or systemic sepsis (7) .
T12 2085-2255 Sentence denotes In addition, exposure to infections and their subsequent inflammatory responses may contribute to increased incidence of venous thromboembolism with hospitalization (8) .
T13 2256-2521 Sentence denotes In addition to risk for thrombosis, gram-negative bacteria, for example, Chlamydia pneumoniae (C. pneumoniae) that causes upper respiratory tract infection, may exacerbate coronary artery disease (CAD) as C. pneumoniae has been cultured from atherosclerotic plaque.
T14 2522-2759 Sentence denotes Also found in monocytes, macrophages and foam cells, C. pneumoniae seems to be ubiquitous in all populations with CAD and contributes to the pathobiology of atherosclerotic plaque by causing inflammation and endothelial dysfunction (9) .
T15 2760-3010 Sentence denotes Other microbes may also participate in development of vascular disease processes as 26 different microbes including Staphylococcus, Streptococcus, Escherichia coli, and Propionibacterium acnes, have been cultured from calcific aortic aneurysms (10) .
T16 3011-3234 Sentence denotes However, mechanisms by which these microbes and their byproducts initiate atherosclerotic injury, facilitate its progression, or merely colonize preexisting atheromas to modify disease progression remain controversial (9) .
T17 3235-3669 Sentence denotes One mechanism that has emerged to link infection-stimulated inflammation with altered thrombotic potential of the blood and atherogenic processes is that infection increases production of activated cell membrane-derived pro-inflammatory and procoagulant microvesicles (MV) from invading microbes and host cells which then activate other host cellular and soluble components of the cardiovascular system (10) (11) (12) (13) (14) (15) .
T18 3670-3827 Sentence denotes This review will focus first on the generation of MV during infection and then focus on direct and indirect impact of MV on the onset and progression of CVD.
T19 3828-4049 Sentence denotes Understanding how infection contributes to production and propagation of MV may suggest possible new early diagnostic and prognostic tests and therapeutic targets for prevention and treatment to reduce progression of CVD.
T20 4050-4255 Sentence denotes MV are heterogeneous populations of activated cell membrane-derived sealed vesicles, ranging from 20 nm to 1μm, shed from the cell surface in response to activation and apoptosis (16) (17) (18) (19) (20) .
T21 4256-4352 Sentence denotes The terms 'microvesicles' and 'microparticles' have been used interchangeably in the literature.
T22 4353-4659 Sentence denotes But a distinction is warranted as microparticles and microvesicles may overlap in size, but a distinct double membranous border distinguishes MV from other similar size microparticles present in the blood including lipoproteins, protein aggregates, and protein-mineral aggregates (10, (21) (22) (23) (24) .
T23 4660-4831 Sentence denotes The literature is further confused by the term "ectosome" which refers to "membrane released vesicles with rightside-out oriented vesicles with cytoplasmic content" (25) .
T24 4832-5037 Sentence denotes Because MV and ectosomes are sealed membrane vesicles, they bear antigens of their cellular origin and also may retain proteins, receptors and some functional properties of their parent cell (18, 25, 26) .
T25 5038-5278 Sentence denotes Thus, they facilitate transcellular communication throughout the circulation by delivering bioactive molecules and even genetic information when they come in contact with or bind to other cells in the circulation or the blood vessels (27) .
T26 5279-5428 Sentence denotes Elevated levels of circulating platelet-, monocyte-or endothelial-derived MV are associated with inflammation and CVD (11, (28) (29) (30) (31) (32) .
T27 5429-5534 Sentence denotes Both mammalian cells and gram-negative bacteria and other microbial pathogens release MV (Table 1) (26) .
T28 5535-5815 Sentence denotes Thus, infectious agents could promote formation of MV from host cells; conversely, host-cell-derived MV could provide a feedback loop to either exacerbate or reduce infection, inflammation, vascular dysfunction and thrombotic processes at sites distant from the site of infection.
T29 5816-5960 Sentence denotes MV are released during physiological processes from certain types of cells and during pathological processes from every type of mammalian cells.
T30 5961-6231 Sentence denotes For example, only plateletderived MV are observed in blood of healthy humans and mice and are released following activation of platelets by a variety of stimuli including adrenaline, ADP, thrombin, collagen, Ca 2+ ionophore A23187, complement and shear stress (33, 34) .
T31 6232-6469 Sentence denotes In general, formation of MV may begin within minutes after addition of an agonist, with the rise of intracellular calcium, which in platelets can be inhibited by calcium chelators (EDTA or EGTA) commonly used as anticoagulants (35, 36) .
T32 6470-6669 Sentence denotes Increases in cytosolic calcium initiate kinase mediated reorganization of the cytoskeleton including myosin light-chain kinase (37) , Rho-associated kinases (38) and proteases like calpain (39, 40) .
T33 6670-6791 Sentence denotes However, formation of MV is not a uniform process; release of MV differs quantitatively and phenotypically among stimuli.
T34 6792-7091 Sentence denotes For example, endothelial cells release phenotypically different MV following exposure to the pro-inflammatory cytokine, tumor necrosis factor α (TNFα) which initiated receptor mediated intracellular signaling as compared to exposure to media stripped of growth factors which induced apoptosis (19) .
T35 7092-7334 Sentence denotes Endothelial cell-derived MV generated by plasminogen activator inhibitor -1 (PAI-1) and those produced by TNFα have overlapping but distinct protein compositions, with some proteins distinctively and exclusively related to one stimulus (41) .
T36 7335-7435 Sentence denotes Early studies which analyzed purified MV by SDS-PAGE revealed a pattern of limited complexity (42) .
T37 7436-7741 Sentence denotes However, proteomic analysis of the composition of MV from CEM T-lymphocytic cells following stimulation with phytohemagglutinin for 72 h or actinomycin for 18 h support the idea that the spectrum of proteins found in MV is influenced in part by the type of stimulus which stimulates their formation (43) .
T38 7742-7874 Sentence denotes Confocal and electron microscopic images of MV formation provide evidence for selective arrangement and sorting of certain proteins.
T39 7875-7951 Sentence denotes Thus, translocation of cellular molecules into MV might not be random (44) .
T40 7952-8251 Sentence denotes Additional work is needed to fully appreciate differential signaling systems induced by various stimuli and to determine if phenotypic assessment of MV might provide useful information reflecting the nature of cell activation and injury as a diagnostic or prognostic tool or treatment options (45) .
T41 8252-8389 Sentence denotes Upon release, MV transport their biologically active contents including lipid, protein, RNA and cell surface receptors among cells (18) .
T42 8390-8529 Sentence denotes Specific surface receptors and cellular markers can be used to identify the origin and physiological status of the parent cell ( Table 2) .
T43 8530-8744 Sentence denotes By identifying the cellular origin and establishing a reference range of blood borne MV in healthy individuals, it will be possible to understand which subpopulation may contribute to specific pathogenic processes.
T44 8745-9054 Sentence denotes Bacterial derived MV are made up of an outer membrane which engulfs periplasmic components (46, 47) and which serves as a delivery system of genetic material, protein, and lipopolysaccharide (LPS) (47) (48) (49) (50) , and promotes adherence of the bacterium to infect host cells (51) or other bacteria (47) .
T45 9055-9200 Sentence denotes MV formation may be a functional requirement for bacteria as DNA packaged within MV can be protected from degradation by soluble DNase (50, 52) .
T46 9201-9328 Sentence denotes Resistance to antibiotics can be acquired by the recipient bacteria by integrating MV from the parental bacteria species (47) .
T47 9329-9549 Sentence denotes MV released by bacteria may contribute to infection-induced cardiovascular diseases like coronary artery diseases since virulence genes, LPS and other toxins and enzymes carried by MV can be absorbed by host cells (53) .
T48 9550-9784 Sentence denotes MV from certain species of bacteria like P. gingivalis (a gram-negative bacteria related to chronic periodontitis) activate platelets (54, 55) , suggesting a possible mechanism by which bacteria-derived MV increase risk of thrombosis.
T49 9785-9963 Sentence denotes However, even though bacterial-derived MV can be detected in infected human tissues (56) , no studies have evaluated how bacteria-derived MV lead to onset and progression of CVD.
T50 9964-10086 Sentence denotes In addition, most information regarding production of bacterial MV was obtained during normal growth of bacteria in vitro.
T51 10087-10296 Sentence denotes Little is known about mechanisms underlying production and release of bacterial derived MV, or about what and how stimuli regulate their production and composition by the host in vivo (49, 54, (57) (58) (59) .
T52 10297-10585 Sentence denotes Bacteria activate host cells mainly through the binding of LPS, the major pathogenic molecule of outer membrane component of gram-negative bacteria to toll-like receptor 4 (TLR4), a transmembrane glycoprotein present on platelets, leukocytes, lymphocytes, and endothelium (60) (61) (62) .
T53 10586-10789 Sentence denotes In pigs, infusion of LPS (10 mg/kg/ per hr) and in mice a single intraperitoneal injection of endotoxin (7.5 mg/kg), increased platelet-derived MV within 3 and 6 hours, respectively (63) (64) (65) (66) .
T54 10790-11176 Sentence denotes Experiments like these, while providing support for the concept that infection stimulates production of platelet-derived MV, should be interpreted with caution as measurement of a MV from a single cellular origin does not provide information about generation of MV from other cell types or interactions among MV of different cellular origin or interactions of MV with other blood cells.
T55 11177-11294 Sentence denotes In addition, depending on the dose of LPS or type of bacterial infection, receptors other than TLR4 may be activated.
T56 11295-11464 Sentence denotes Therefore, complement activation or cytokine-mediated mechanisms in vascular cells complicate unraveling mechanisms of LPS induced production of host MV (67) (68) (69) .
T57 11465-11570 Sentence denotes In vitro studies can be used to identify effects of LPS on blood elements and cells of the vascular wall.
T58 11571-11757 Sentence denotes In diluted blood which prevents cell-cell interactions, addition of LPS (500 ng or 1 μg/mL) increased the number of TF-bearing MV and MV from platelets after 4 hours of incubation (70) .
T59 11758-11948 Sentence denotes Incubation of human monocytes with LPS (5 μg/mL for 5 hours) increased the total number of MV, TF-bearing MV and those bearing phosphatidylserine (PS) and other adhesion molecules (42, 71) .
T60 11949-12096 Sentence denotes MV formation visualized by fluorescence microscopy occurred in leukocytes and endothelial cells after incubation of LPS (5 μg/mL) for 90 min (72) .
T61 12097-12192 Sentence denotes Thus, LPS stimulates MV production from circulating blood cells and cells of the vascular wall.
T62 12193-12358 Sentence denotes In unpublished work by our group, incubation of whole blood with LPS for one hour at a dose which stimulated TLR-4 receptors did not increase the total number of MV.
T63 12359-12499 Sentence denotes However, leukocyte-derived MV were associated with platelets which subsequently altered the reactivity status of the platelets ( Figure 1 ).
T64 12500-12690 Sentence denotes These data provide evidence as have other studies that MV generated by one cell type in response to LPS alter reactivity of other cell types within the circulation (69, (73) (74) (75) (76) .
T65 12691-12909 Sentence denotes Although existing data provide evidence that LPS induces MV release from isolated cell or cells in vitro, more studies are needed to understand how other bacterial proteins affect MV production from host cells in vivo.
T66 12910-13137 Sentence denotes In particular, studies are needed to determine whether and how LPS, as a natural component of bacteria and a content of bacteria-derived MV, affects composition of infected mammalian cell-derived MV distinct from other stimuli.
T67 13138-13384 Sentence denotes Mammalian cells release MV in response to a variety of stimuli associated with infection, many of which are considered conventional biomarkers for CVD including inflammatory cytokines, lipids and lipidperoxidation, oxidative stress and apoptosis.
T68 13385-13487 Sentence denotes These stimuli are also important participants in the defense mechanisms and pathogenesis of infection.
T69 13488-13653 Sentence denotes Pro-inflammatory agents-Release of cytokines provoked in the host cells by invading micro-organisms may in turn stimulate release of MV from non-infected cells (9) .
T70 13654-13877 Sentence denotes For example, pro-inflammatory cytokines such as TNFα or interleukin-1 (IL-1) stimulate MV production from endothelial cells and monocytes which contain tissue factor (TF) and have high procoagulant activity (75) (76) (77) .
T71 13878-13993 Sentence denotes Activated complement component (C5a) also increases the release of cellular MV from endothelia and platelets (78) .
T72 13994-14187 Sentence denotes Leukocyte-derived MV significantly increased after 1h incubation with 10μM fMLP(formylmethionyl-leucylphenylalanine, a formylated tripeptide originally isolated from bacterial filtrates) (79) .
T73 14188-14404 Sentence denotes C-reactive protein (CRP), which promotes agglutination and bacterial phagocytosis, is an acute-phase response protein produced by the liver in response to infection as well as by cytokines IL-6, IL-1, and TNFα (80) .
T74 14405-14577 Sentence denotes CRP is elevated in individuals at risk for recurrent myocardial infarction, coronary heart disease or stroke and may predict the risk of future cardiovascular events (81) .
T75 14578-14739 Sentence denotes However, circulating CRP is used as a biomarker of inflammation but not as a specific biomarker linking the inflammation to an acute or chronic infection in CVD.
T76 14740-14951 Sentence denotes Oxidative stress and metabolic failure-Oxidative stress, characterized by disruption of oxidant and antioxidant systems within cells, increases with infection, inflammation and immunological disorders (82, 83) .
T77 14952-15057 Sentence denotes Reactive oxygen species (ROS) damage cellular membrane structures leading to release of MV (39, 84, 85) .
T78 15058-15285 Sentence denotes Oxidative stress is a common mechanism underlying cardiovascular diseases (86, 87) , and diverse therapeutic interventions such as antioxidants can impede or delay the onset and progression of cardiovascular diseases (88, 89) .
T79 15286-15393 Sentence denotes Oxidative stress markers independently increase the total number of MV and MV derived from platelets (90) .
T80 15394-15599 Sentence denotes Energetic failure within platelets is also associated with increased shedding of thrombogenic MV, which may result from decreases in activity of enzymes of the mitochondrial electron transport chain (91) .
T81 15600-15721 Sentence denotes Oxidative stress also causes membrane phospholipid rearrangement and PS-bearing MV to be shed from red blood cells (92) .
T82 15722-15844 Sentence denotes Oxidative stress in endothelial cells increases release of MV expressing vascular cell adhesion molecular-1 (VCAM-1) (93).
T83 15845-15993 Sentence denotes Endothelium-derived MV released in response to oxidative stress stimulated neutrophil adhesion via platelet-activating factor (PAF) receptors (84) .
T84 15994-16287 Sentence denotes However, the exact mechanism of how oxidative stress and metabolic failure lead to MV release is not clear, but chronic treatment with antioxidants, such as vitamin C or carvedilol, decreases circulating endothelial MV in patients with heart failure and exhibits a protective effect (94, 95) .
T85 16288-16580 Sentence denotes Monocyte-derived MV released during apoptosis induce production of superoxide anion in endothelial cells (96) , suggesting that production of reactive oxygen species are both the result of and stimulus for release of MV and thus, represent a mechanism of positive feedback to cellular injury.
T86 16581-16702 Sentence denotes Reactive oxygen species promote a procoagulant phenotype through up-regulation of TF expression and activity in MV (97) .
T87 16703-16882 Sentence denotes Apoptosis-Release of membrane blebs or MV are an early feature of apoptosis activated by various stressors including bacterial infection, cytokines and oxidative stress (83, 98) .
T88 16883-17116 Sentence denotes Release of MV may be a protective mechanism against intracellular stress as MV containing caspase 3 prevent intracellular accumulation of the enzyme which could allow escape from apoptosis and thus, contribute to cell survival (99) .
T89 17117-17195 Sentence denotes Mechanisms leading to release of MV upon apoptosis are only partly understood.
T90 17196-17283 Sentence denotes Loss of tumor suppressor gene p53 leads to an increased release of TF-bearing MV (100).
T91 17284-17411 Sentence denotes MV are not released from MCF-7 cells lacking caspase-3 but release is restored by transfection with functional caspase-3 (101).
T92 17412-17478 Sentence denotes These results implicate both p53 and caspase-3 in formation of MV.
T93 17479-17688 Sentence denotes As with oxidative stress, MV released as a result of apoptosis can stimulate apoptosis in other cells as platelet-derived MV containing functional active caspase-3 induce apoptosis of human macrophages (102) .
T94 17689-17772 Sentence denotes CVD, in particular, atherosclerosis is described as an inflammatory disease (103) .
T95 17773-17896 Sentence denotes However, the source of inflammation is usually attributed to disruptions in metabolism related to altered lipid metabolism.
T96 17897-18000 Sentence denotes The preceding discussion expands this view to include processes associated with infection and immunity.
T97 18001-18177 Sentence denotes Indeed, pro-inflammatory cytokines are independent risk factors for CVD, and in persons with chronic infections, inflammatory responses increase risk of atherosclerosis (104) .
T98 18178-18403 Sentence denotes The number and type of MV generated during infection, inflammation, and thrombotic complications suggest that MV may provide an interface between infection, initiation and amplification of cardiovascular diseases (Figure 2) .
T99 18404-18605 Sentence denotes During formation of MV, the normal phospholipid asymmetry of the membrane is changed, exposing negatively charged phospholipids such as PS from the inner membrane leaflet to the outer membrane leaflet.
T100 18606-18744 Sentence denotes Thrombin generation capacity of MV is proportional to the amount of PS bearing on the surface (105) or the number of MV bearing PS (106) .
T101 18745-18995 Sentence denotes Surface PS offers binding sites for coagulant factors II, Va, and Xa and provides a platform for the assembly of the prothrombinase complex, accelerating the conversion of prothrombin into thrombin and supporting a procoagulant phenotype (107, 108) .
T102 18996-19081 Sentence denotes MV also represent a reservoir of blood borne tissue factor (TF) activity (109, 110) .
T103 19082-19254 Sentence denotes Monocytes and polymorphonuclear leukocytes are one source of TF-bearing MV, which when transferred or in association with platelets, trigger and propagate thrombosis (76) .
T104 19255-19308 Sentence denotes Whether platelets produce TF is controversial (109) .
T105 19309-19360 Sentence denotes There may be three distinct sources of platelet TF:
T106 19361-19619 Sentence denotes 1) TF taken up from circulating monocyte-derived MV; 2) TF stored in the αgranules of platelets from precursor bone megakaryocytes or taken up from other sources; 3) TF that is synthesized and expressed on the plasma membrane of mature platelets (111, 112) .
T107 19620-19761 Sentence denotes The rate of accumulation of TF in platelet-rich thrombi cannot be explained by recruitment of leukocytes onto adherent platelets (113, 114) .
T108 19762-19966 Sentence denotes One mechanism to explain this discrepancy is that TF-bearing MV adhere to platelets through binding of P-selectin glycoprotein ligand-1 (PSGL-1) on the MV and P-selectin on the platelets (113, 115, 116) .
T109 19967-20144 Sentence denotes Tissue factor exists in the blood in an inactive (latent) and active configuration (117) as TF-bearing MV circulate in healthy persons while TF activity was not detected (118) .
T110 20145-20330 Sentence denotes In addition to contributing to thrombin formation, fusion between TF-bearing MV and activated platelets facilitates transfer of both proteins and lipids to the platelet membrane (116) .
T111 20331-20448 Sentence denotes Therefore, MV modulate coagulation by directly initiating coagulation cascade or indirectly via activating platelets.
T112 20449-20685 Sentence denotes It is proposed that TF bearing MV, mainly of monocytic and lymphocytic origin, contribute to thrombus formation following rupture of atherosclerotic plaque by binding to activated platelets at the site of plaque rupture (14, 113, 119) .
T113 20686-20907 Sentence denotes Using rat aortic rings as a bioassay, MV from patients with acute myocardial infarction initiated reduced endothelium-dependent relaxations and release of nitric oxide compared to MV from patients without ischemia (120) .
T114 20908-21149 Sentence denotes These reductions in endothelium-dependent relaxations are consistent with general vasomotor dysfunction observed after myocardial infarction, and potentially would contribute to increased formation of thrombus and decreased tissue perfusion.
T115 21150-21301 Sentence denotes Endothelium-dependent vasodilatation induced by acetylcholine was significantly reduced by circulating MV from patients with metabolic syndrome (121) .
T116 21302-21599 Sentence denotes MV derived from diabetic patients and HIV-infected individuals also reduce acetylcholine-induced and attenuate shear stress-induced vasodilatation through stimulating expression of caveolin-1 and downregulation of endothelial nitric oxide synthase (eNOS) in cultured human endothelial cells (77) .
T117 21600-21750 Sentence denotes T-lymphocyte-derived MV may increase inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2) through NF-κB -dependent transcription (122) .
T118 21751-21896 Sentence denotes MV derived from monocytes and lymphocytes are found in atherosclerotic plaques in greater concentrations than those derived from platelets (14) .
T119 21897-22130 Sentence denotes This condition is opposite to the various numbers of MV found in blood and may reflect the activation of these cells as they migrate into vascular lesions or that the leukocyte-derive MV may be associated with platelets in the blood.
T120 22131-22283 Sentence denotes Regardless of their cellular origin (bacterial or host), MV can amplify progression of CVD through the transfer of biological information between cells.
T121 22284-22419 Sentence denotes Transfer of integrins and selectins to target cells through MV facilitate leukocyte adhesion and interaction with vascular endothelium.
T122 22420-22581 Sentence denotes In addition, platelet-derived MV enhance binding of neutrophils to other neutrophils under flow conditions via P-selectin on MV and PSGL-1 on neutrophils (123) .
T123 22582-22817 Sentence denotes Monocyte-endothelial interactions stimulated by platelet-derived MV up-regulated expression of cellular adhesion molecules (ICAM-1) on endothelium and CD11b/CD18 on monocytes, a process related to metabolism of arachidonic acid (124) .
T124 22818-22961 Sentence denotes Adhesion of monocytes and neutrophils to the endothelium is considered a crucial step in the early processes of atherosclerotic lesions (125) .
T125 22962-23235 Sentence denotes It is likely that platelet-derived MV, rather than platelets deliver long-range signals to other cells throughout the circulation since the aggregation and binding properties of activated platelets make it difficult for them to travel through the circulatory system (126) .
T126 23236-23380 Sentence denotes Consequently, MV, instead of intact platelets, may be critical in enhancing thrombosis and modulating both innate and adaptive immune responses.
T127 23381-23453 Sentence denotes Processes of how MV attach to target cells is not completely understood.
T128 23454-23647 Sentence denotes In addition to fusion of the cell membranes, receptor binding, as described in other sections, is important, and the receptors involved may differ depending upon the stimulus for MV generation.
T129 23648-23855 Sentence denotes MV bearing ICAM-1 resulting from TNF-α stimulation of endothelial cells bind to β2 integrin on monocytes increasing TF gene expression in monocytes and induction of TF-dependent procoagulant activity (127) .
T130 23856-23976 Sentence denotes Alternatively, Fas/Fas ligand receptor interaction might be important in binding of apoptotic MV to target cells (122) .
T131 23977-24151 Sentence denotes As discussed above, LPS on the outer membrane of gram-negative bacteria or associated with bacterial derived MV activate host cells in part through TLR4 signaling mechanisms.
T132 24152-24284 Sentence denotes Mutational deletion of TLR4 decreased risk of development of atherosclerosis but increased susceptibility for infection (128, 129) .
T133 24285-24515 Sentence denotes Other genetic polymorphisms of monocyte chemoattractant protein (MCP-1) and its receptor CCR2 (chemokine {C-C motif} receptor 2) may increase susceptibility for chronic stable angina pectoris and myocardial infarction (129, 130) .
T134 24516-24693 Sentence denotes While pro-inflammatory cytokines stimulate MV production, MV in turn stimulate production of these same cytokines thus amplifying the signal through a type of positive feedback.
T135 24694-24867 Sentence denotes For example, stimulation of leukocytes with endotoxin (a complex, not purified LPS) induced shedding of MV containing PAF, an agonist which stimulates innate immunity (72) .
T136 24868-25035 Sentence denotes Furthermore, after priming THP-1 monocytes with LPS, stimulation of those cells with ATP generated MV which were both PS positive and contained bioactive IL-1β (131) .
T137 25036-25243 Sentence denotes This convergent response initiated by two different agonists suggests that generation and release of MV could be a general pathway for secretion of some cytoplasmic proteins which modulate the immune system.
T138 25244-25329 Sentence denotes Stimulation of dendritic cells by IL-1β initiates acute inflammatory response (132) .
T139 25330-25417 Sentence denotes In addition to initiating immune response, MV contribute to maturation of immune cells.
T140 25418-25581 Sentence denotes MV generated from thrombin-activated platelets carry CD40L and initiate maturation of monocyte-derived dendritic cells which in turn activate naïve T-cells (133) .
T141 25582-25722 Sentence denotes CD40L in platelet MV can be transferred to the adaptive immune B-cell compartments that may be distant from the site of platelet activation.
T142 25723-25804 Sentence denotes This "long-range" signaling results in production of antigen-specific IgG (134) .
T143 25805-26042 Sentence denotes MV generated from endothelial cells in response to bacterial infection induce maturation of plasmacytoid dendritic cells, secretion of inflammatory cytokine (IL-6 and IL-8, but not IFN-α) and proliferation of allogenic naïve CD4+ T-cell.
T144 26043-26123 Sentence denotes These responses are not activated by either platelet or T-cell derived MV (75) .
T145 26124-26323 Sentence denotes Collectively these responses demonstrate a coordinated interaction among processes responding to infection, vascular cell activation and cytokines implicated in progression of cardiovascular disease.
T146 26324-26559 Sentence denotes MV derived from invading pathogens and host cells can be considered as vectors of transcellular exchange of signals common to infection, general inflammation, and procoagulant properties of the blood contributing to progression of CVD.
T147 26560-26833 Sentence denotes The virulent potential of MV derived from pathogens may explain in part the consistent finding that the burden of infection increases development of CVD in the absence of consistent identification of specific pathogens within atherosclerotic lesions (9, (135) (136) (137) .
T148 26834-27057 Sentence denotes While the literature abounds in studies of generation of cell-specific MV and their characterization in various diseases, general methodological challenges remain in the development of MV as a diagnostic or prognostic tool.
T149 27058-27353 Sentence denotes These challenges include the need for standardized methods of blood collection and processing including issues related to anticoagulants and cell-free plasma preparation after blood collection which may themselves affect production, adhesion or secretion of MV in the collected sample (31, 36) .
T150 27354-27560 Sentence denotes A second challenge is to better understand how different stimuli affect production and content of MV or to differentiate a non-specific "molecular switch" common to generation of MV from various cell types.
T151 27561-27722 Sentence denotes A third challenge is to define how sex and age modulate formation of MV in various cell types which might influence thrombosis, immunity and vascular reactivity.
T152 27723-27908 Sentence denotes For example, estrogen receptor beta knockout female mice show higher PS-expressing platelet-derived MV in the plasma and thrombin-generating capacity compared with wild type mice (91) .
T153 27909-28227 Sentence denotes In addition, total numbers of MV, those derived from platelets, monocytes and vascular endothelium, and those positive for phosphatidylserine and tissue factor were significantly greater (P<0.05) in newly menopausal women (circulating estrogen < 20pg/ml) compared to age-matched women who had estrogen >40pg/mL (138) .
T154 28228-28305 Sentence denotes These results infer hormonal regulation on MV generation and thrombotic risk.
T155 28306-28576 Sentence denotes Since incidence of immunologic disorders and cardiovascular risk diverge with age and sex (139, 140) , understanding the contribution of MV in association with these important variables will facilitate development of more effective preventive strategies for individuals.
T156 28577-28790 Sentence denotes ATP secretion in response to thrombin (0.1 U/mL) (black bars) and platelets associated with leukocyte-derived MV (gray bars) after whole blood from mice was incubated with LPS (5 μg/mL) or saline (control) for 1h.
T157 28791-28810 Sentence denotes P<0.01 vs. Control.
T158 28811-28937 Sentence denotes Schematic of how MV of gram-negative bacteria may interface with host cells to increase progression of cardiovascular disease.
T159 28938-29011 Sentence denotes Table 1 Comparison between pathogen-derived and mammalian cell-derived MV