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Biology of monocyte interactions with the endothelium : the platelet factor
da Costa Martins, P.A.
Publication date
2005
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Citation for published version (APA):
da Costa Martins, P. A. (2005). Biology of monocyte interactions with the endothelium : the
platelet factor.
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Chapterr 7
"" Discussion, concluding remarks and
futuree perspectives "
Cellularr components play a major role in atherogenesis and the related, final acutee cardiovascular symptoms. While influx of inflammatory cells is seen in early atheroscleroticc plaque formation, plaque disruption and endothelial erosion initiate platelet-mediatedd thrombus formation as a cause for final vascular obstruction in acutee coronary syndromes or stroke. The critical role of platelets in atherosclerosis is ann old concept, originally proposed by Ross in 1986 1. Since then platelets are consideredd as crucial mediators of coronary thrombosis in cardiovascular disease andd have been identified as the major target in both therapeutic and preventive intervention.. The inflammatory nature of atherosclerosis involves chronic stimulation off the endothelial cells that line the intima, the innermost layer of arteries, and an activee inflammatory response 2'3 initiating the atherogenic mechanism. While under normall circumstances the endothelial monolayer in contact with flowing blood cells resistss firm adhesion of leukocytes, a strong adhesive capacity of platelets and/or monocytes/lymphocytess to the endothelium is essential in the development of atherosclerosis. .
Inn this thesis, important interactions between platelets and leukocytes are highlighted.. Platelet binding to monocytes enhances the adhesive capacity of monocytess to the endothelium and results in a general activation of the interacting cells.. We thus propose this adhesive synergy as a new proatherogenic mechanism thatt may become a valuable target of new therapeutic strategies.
Monocytess and T lymphocytes in atherogenesis
Adhesionn of leukocytes is essential for their role in atherogenesis; however, thee normal arterial endothelium resists prolonged contact with leukocytes. Chronic activationn of endothelial cells results in increased expression and increased binding affinityy of various adhesion molecules on the cell surface that will mediate leukocyte adhesion. .
Thee first steps in the mechanism of leukocyte recruitment to inflammatory sites are tetheringg and rolling. Two types of leukocyte tethering can be distinguished: primary tetheringg of leukocytes directly to the endothelial surface and secondary tethering to alreadyy adhered leukocytes 4'5. Both mechanisms lead to leukocyte firm adhesion; however,, only secondary tethering is associated with cluster formation 6. Secondary tetheringg facilitates monocyte adhesion downstream to other, already adhered, monocytes.. As a result, strings of cells in the direction of the flow are formed 5.
Inn atherosclerotic inflammation, mostly monocytes and T lymphocytes penetrate the vascularr wall along a chemoattractant gradient. Various and specific chemokines cann mediate this so-called diapedesis though the endothelium, e.g. monocyte chemoattractantt protein-1 (MCP-1) interacts with its receptor CCR2 on monocytes.
Underr the influence of oxidized lipoproteins, monocytes can acquire the morphologicall characteristics of macrophages and later of lipid-loaded foam cells, the latterr being characteristic of early atherosclerotic lesions. As monocytes produce and expresss coagulation-activating tissue factor, monocyte-derived macrophages, in their turn,, also play a role in the thrombotic complications of atherosclerosis by producing matrixx metalloproteinases (MMPs). MMPs degrade the extracellular matrix leading to increasedd plaque instability, easy plaque rupture and subsequent thrombus formation (seee reference 3 for review).
Besidess MCP-1, human atheromas overexpress other chemokines that may contributee to lymphocyte recruitment, including a trio of CXC chemokines induced by interferon-yy (IFN-y) that bind to the CXCR3 receptor on T lymphocytes. Once resident inn the intima, T lymphocytes may become activated by endogenous or microbial antigenss and therefore, amplify the inflammatory response e.g. by cytokine release (seee reference 3 for review).
Platelets:: only important players in the late atherosclerotic process?
Mechanicall disruption of the endothelial monolayer and subendothelial matrix exposuree e.g. after plaque rupture, lead to immediate strong platelet activation, adhesionn and aggregation. Additionally to this primary platelet-mediated hemostasis, tissuee factor and platelet-derived phospholipids initiate coagulation and fibrin formation,, resulting in a so-called "mixed thrombus" and, sometimes, in fatal occlusionn of the blood vessel. Once adhered, platelets participate in plaque progressionn and complications encountered after plaque rupture whether via surface expressionn of P-selectin or via release of proinflammatory chemokines. P-selectin is ann important adhesion ligand in further leukocyte recruitment to these sites. Indeed, infusionn of activated platelets into Apo-E-deficient mice potentiates atherosclerosis by increasingg localization of monocytes at the vessel wall 7. Furthermore, a relatively recentt study not only shows a proatherogenic role for endothelial-derived P-selectin butt also for platelet-derived P-selectin8.
Whenn platelets are circulating through vessels into an intact, healthy endothelium, thee platelets remain in their original, unactivated state. The absence of activating factorss and the release of prostacyclin by the healthy endothelium support this state. However,, when a platelet encounters a break in the endothelium, it encounters moleculess that trigger its activation such as collagen, ADP and thrombin. Platelets willl then change in shape and expose certain molecules (e.g. P-selectin) that, altogether,, will allow platelets to slow down in their velocity and interact with the injuredd vessel wall via selectin- and/or vWF-dependent mechanisms 9"11. However, thesee interactions are often transient, suggesting that platelets are less involved in
earlyy atherogenesis when the endothelial monolayer is not yet disrupted. In this thesiss we suggest that activated platelets in the circulation are able to also accelerate thee early inflammatory atherogenic process.
Platelet-derivedd P-selectin and proinflammatory activity.
Oncee activated, platelets can interact with leukocytes via their surface-expressedd P-selectin, leading to the formation of leukocyte-platelet aggregates (LPAs).. P-selectin on platelets mainly binds to P-selectin glycoprotein ligand-1 (PSGL-1)) on resting monocytes, neutrophils or other leukocytes. Normally located randomlyy on the cell at the tips of the microvilli, upon cell activation PSGL-1 moleculess are rapidly redistributed over the cell surface, changing the avidity and affinityy for its ligands 12. In neutrophils, clustering of PSGL-1 leads to weaker interactionss with P-selectin; however, this seems to be different for other leukocytes ass suggested by the fact most LPAs in the circulation consist of platelets complexed withh monocytes or eosinophils 1314. Increased levels of LPA, termed platelet-monocytee complexes (PMC), have been found in stable and acute coronary vascular diseasess (CVD) 15,16 and are currently considered as sensitive markers of vascular diseasee and its prognosis 1?.
However,, besides being markers of CVD, we found that PMC formation also influencess the first steps in the process of monocyte recruitment to the endothelium. Thee suggested role for these complexes in promoting plaque progression is compatiblee with an earlier report in which it was shown that platelets enhance primaryy tethering and adhesion of monocytes or THP-1 (monocytoid) cells to endotheliall cells 7'18.
Rolee of platelet-monocyte complexes in promoting plaque progression
Ass mentioned before, there are two types of cell tethering: primary and secondaryy tethering, the latter being associated with downstream formation of cell clusters6.. PMC appear to be better primary tethers than bare monocytes (Chapter 2). Thesee complexes roll with a lower velocity over the endothelial cell ligands, leading nott only to more efficient interactions between adhesion receptors but also to longer interactionn times between endothelium-released cytokines and leukocytes and thus too more efficient cytokine activation of additional adhesion molecules. The subsequentt secondary tethering of circulating monocytes over previously adhered monocytess is normally mediated by L-selectin interaction with PSGL-1 19. In addition andd as described in Chapter 2, platelet binding to monocytes increases their
clusteringg capacity. In the presence of PMC, the additional P-selectin-mediated primaryy and secondary tethering seems to overshadow the typical L-selectin-mediatedd clustering. Only at higher shear stress, when all adhesive interactions becomee critical and adhesive redundancy is increased, L-selectin contributes to clustering.. This suggests that mainly monocytes with platelets bound to their surface (PMC)) are interacting with the already adhered monocytes via P-selectin on their platelets. .
PMCC were shown to adhere two times better to the endothelium as compared to "baree monocytes" (<5% PMC). This increase in adhesion correlates to an increase in bothh primary and secondary tether formation, indicating that platelets on the monocytee surface are able to enhance monocyte adhesion and clustering by "bridging"" interactions with other monocytes via P-selectin - PSGL-1 interactions Altogether,, the platelet-mediated adhesion-enhancing mechanism described in Chapterr 2 suggests that PMC play a role in promoting plaque progression. The presencee of PMC in vivo as a marker of cardiovascular disease may, by this adhesion-enhancingg mechanism, accelerate the development of disease and explain itss association with disease outcome.
PSGL-1:: crucial molecule that mediates platelet, monocyte and/or platelet-monocytee complex tethering
PSGL-11 is a general selectin ligand present on most leukocytes 20,21 and plateletss 22. With the highest affinity for P-selectin, PSGL-1 also binds L- and E-selectinn 523. Leukocyte PSGL-1 mediates primary tethering and subsequently total adhesionn of multiple leukocyte subtypes to endothelial P- and E-selectin under physiologicallyy relevant shear stress 23"25. By binding to L-selectin on other leukocytes,, PSGL-1 is known to be involved in homotypic interactions that result in secondaryy tethering or cluster formation of neutrophils or monocytes at the endotheliumm 5'19. Although the role of L-selectin, in the presence of PMC, is overshadowedd by the PSGL-1 - P-selectin interactions, its general clustering potentiall becomes clear at higher shear stress (Chapter 2). Additional to its role in secondaryy tethering, our experiments also showed a role of L-selectin in primary tethering,, suggesting the presence of strong endothelial ligands for this selectin. Althoughh several ligands on endothelial cells, e.g CD34 and MadCAM-1 26,27, have beenn associated with L-selectin, so far no specific ligands for selectins on endothelial cellss have been described.
Againstt this background, incubation of endothelial cells with a specific antibody againstt PSGL-1 provided strong evidence that functional PSGL-1 is present on stimulatedd endothelial cells. By means of Western blot analysis, flowcytometry and
immunostainingg we have additionally shown in Chapter 3 that PSGL-1 is expressed andd constitutively present on endothelial cells. Although activation of endothelial cells,, with TNF-a or IL-1(3, did not affect PSGL-1 expression, activation of cells was necessaryy for optimal functionality of PSGL-1 as a selectin ligand on endothelium. Thiss may be explained by the fact that PSGL-1 binding to selectins and thus functionalityy depends on its proper sulfation, fucosylation and sialylation 2a. To be ablee to bind P-selectin, leukocyte PSGL-1 needs to be tyrosine sulfated and properly decoratedd with core 2-based O-glycans expressing sialyl Lewisx 29,30. In a similar way,, functionality of endothelial PSGL-1 seems to depend on sulfotransferases GST-11 and, partially, GST-2, whose expression is indeed dependent on activation of the endotheliall cells with TNF-a. The functional presence of this powerful ligand on activatedd endothelial cells in vitro is responsible for platelet and monocyte primary tethering.. PSGL-1 is thus presented as a new ligand for L- and/or P-selectin on endotheliumm that may be able to modulate platelet and monocyte/PMC primary tetheringg to the endothelium in vivo.
PSGL-11 as a signaling molecule
Previouss studies showed platelet involvement in direct interactions between leukocytess and endothelium 31,32. However, intravital microscopy7 and our own observationss characterized platelet interactions with the endothelium, at relatively low shearr rates, as transient and rapidly reversible. This leads to some speculation on howw platelets can mediate monocyte/PMC primary tethering to endothelium, under thesee conditions.
Thee expression of P-selectin on the platelet surface following platelet stimulation and granulee secretion 33,34 allows interaction of P-selectin with specific ligands, e.g. PSGL-1,, on other cells. In this manner, and as described above, P-selectin mediates cell-celll interactions. Besides this docking function, these adhesion molecules are alsoo involved in signal transduction. Indeed, engagement of the extracellular domain off PSGL-1 by P-selectin, initiates an array of intracellular events within the leukocyte. Itt has been shown that monocytes, which do not demonstrate constitutive expression off tissue factor under normal conditions, show activation of the tissue factor gene and,, in several hours, expression of functional tissue factor35 after P-selectin ligation too PSGL-1. Some earlier studies also suggested that P-selectin promotes fo integrin -- dependent homotypic neutrophil aggregation and neutrophil-platelet conjugation 36,37
.. Furthermore, platelet-derived P-selectin has also been shown to increase monocytee adhesivity and monocyte adhesive strength to immobilized VCAM-1, indicatingg that P-selectin binding enhances a4 integrin activity on monocytes
738 . We extendedd these findings by showing that platelet binding to monocytes not only
providess P-selectin as an extra rolling receptor but also changes the monocyte repertoiree of expressed cell adhesion molecules (Chapter 4), both quantitatively and qualitatively.. Platelet binding results in decreased expression of L-selectin on the monocytee surface and increased expression and activity of both Pi and p2 integrins. Altogether,, these findings indicate a general activation of the monocyte upon platelet binding.. Furthermore, expression and activity of 0C4P1 and amP2 integrins were increasedd upon platelet/P-selectin Fc chimera binding to monocytes. This increased integrinn expression and activity correlated with an increase in monocyte/PMC adhesivityy to several immobilized Pi and p2 integrin ligands (fibronectin, VCAM-1, fibrinogenn and ICAM-1) and to stimulated endothelial cells (also expressing ICAM-1 andd VCAM-1).
Althoughh a general increase in monocyte adhesivity was observed upon either platelett or P-selectin-Fc chimera binding, the strongest effect was obtained after formationn of PMC by adding platelets to the monocytes. In agreement, ligation of PSGL-11 by P-selectin was recently shown to induce an intermediate state of neutrophill activation characterized by increased affinity/avidity and subsequent functionalityy of integrin amp2
39
but not by changes in its expression levels. Additional exposuree to biologically relevant stimuli such as PAF and IL-8 seems to change the intermediatee state of activation to a high affinity one 39. It is known that platelets, uponn binding, are able to release similar stimuli and chemokines 40. Moreover, monocytess exposed to platelets and the platelet-derived chemokine, RANTES, secretee cytokines such as IL-8 and MCP-1 41,42 that are also likely to act in a paracrinee stimulating and synergistic fashion. These cytokines or chemoattractants, byy enhancing integrin activation, might act in concert with PSGL-1 engagement to inducee optimal activation of integrins. Therefore, platelet- and, subsequently, monocyte-releasedd chemokines will optimize monocyte activation, and this may explainn the stronger activation of monocytes by platelet binding as compared to P-selectin-Fcc chimera that we observed (Chapter 4).
Otherr mechanisms of leukocyte recruitment to endothelium
Otherr important inflammatory and thus proatherogenic mechanisms and molecules,, involved in leukocyte recruitment to endothelium are additionally describedd in this thesis. Low-density lipoprotein (LDL) receptor-related protein (LRP) iss a member of the LDL-receptor family and is known to be expressed in leukocytes 43,444
and on brain vascular endothelial cells 45. So far, LRP was shown to be involved inn the regulation of the vascular permeability of the blood-brain barrier 45 and to mediatee calcium-signaling in primary neurons 46. In Chapter 5 we describe an additionall role of LRP regulating p2 integrin-dependent leukocyte adhesion to
endothelium.. LRP seems, in this respect, to be required for proper positioning of p2 integrinss and thus facilitate the interaction with counterreceptors such as fibrinogen, ICAM-11 or ICAM-2. Additionally to mediating these "cis" interactions, LRP seems ablee to bind p2 integrins on other leukocytes. These "trans" interactions may lead to clusterr formation and therefore, be strongly involved in leukocyte secondary tethering.. Altogether, these evidences link LRP to the inflammatory system.
Ass we showed in Chapter 3, the functionality of endothelial PSGL-1 is strongly carbohydrate-dependent.. This seems to be common to other molecules involved in leukocytee recruitment to the endothelium. Chapter 6 describes a similar mechanism thatt mediates the interaction between immature dendritic cells (DCs) and the endothelium.. DCs are recruited from blood into tissues to patrol for foreign pathogens 47
.. After antigen intake and processing DCs mature, migrate to secondary lymphoid organss and initiate a specific immune response. Specific homing and trafficking of DCss therefore should be critically organized for the proper function of these later antigen-presentingg cells. DCs express a specific C-type lectin, known as DC-SIGN, whichh not only acts as a recognition receptor but also as an adhesion molecule 48. DC-SIGN,, by interacting with ICAM-2, mediates rolling and adhesion of DCs over endotheliall cells 49. In Chapter 6 we show evidence that expression of the Lewis Y epitopee on ICAM-2 is crucial for DC-SIGN-mediated cell rolling interactions. Again, theree seems to be a strong carbohydrate-dependency for optimal receptor-ligand interactionn and subsequent functionality because ICAM-2 expressed on endothelial cellss can only be recognized by DC-SIGN when it is properly glycosylated. Indeed, fucosylationn is essential for the rolling and adhesion of DCs to endothelial cells, and LewisYY was found to be the major carbohydrate ligand for DC-SIGN. Altogether, the findingss concerning both PSGL-1 and DC-SIGN open new possibilities in the modulationn of leukocyte migration by post-transcriptional glycosylation of these receptors. .
Concludingg remarks and future perspectives
Activatedd platelets can bind monocytes in the circulation, resulting in the formationn of PMC. Low numbers of PMC are sufficient to increase both primary and secondaryy tethering and thus overall monocyte recruitment to the endothelium. This PMC-mediatedd effect on monocyte adhesion is dependent on the presence of platelet-derivedd P-selectin as a powerful selectin that is able to overcome monocyte activation-mediatedd shedding of L-selectin from the surface of monocytes within the PMC.. Additionally, platelet binding to monocytes increases expression and functionalityy of both pi and p2 integrins, which also results in stronger firm adhesion capacity.. The change in integrin functionality seems to be caused by a combination
off P-selectin-mediated signaling, via PSGL-1, and platelet-released products. Besidess its role in firm adhesion, this platelet-mediated increase in integrin functionalityy also leads to increased migratory capacity of the monocytes. Platelet-inducedd signaling on monocytes not only increases the monocyte adhesivity and migratoryy capacity but, in general, it seems to induce a higher activation state and subsequentlyy a stronger proinflammatory and proatherogenic phenotype of the monocyte. .
Ourr studies, by identifying molecules that are crucial in platelet-monocyte contact, andd thus platelet-monocyte cross talk, as well as other molecules that mediate monocytee recruitment to the endothelium, are highly relevant to the understanding of potentt atherogenic mechanisms. By investigating the consequences of PMC as strongg thrombo- and atherogenic entities, our studies have crucial relevance in the developmentt of new therapeutics tools to prevent or improve vascular disease, namelyy atherosclerosis. In this respect, inhibition of PMC formation by modulation of P-selectin-PSGL-11 interactions and subsequent inhibition of monocyte adhesivity seemss to be an interesting and potential approach.
RemainingRemaining questions and remarks:
1.. Platelets, by binding to monocytes and forming PMC, induce monocyte adhesion andd clustering to the endothelium by providing P-selectin and thus enhance the monocytee adhesive capacity. Moreover, PMC formation results in upregulation of (3i andd p2 integrin expression and functionality on monocytes. As a consequence, not onlyy an increase in integrin-dependent firm adhesion of monocytes occurs but also ann increase in monocyte migration is observed. It is, so far, unclear how P-selectin bindingg to monocytes and the triggered signaling pathways further determine the fate off PMC in the vessel wall. This mechanism is however unclear. Preliminary experimentss suggest that platelets might act as a touring car, dropping off its passengerss (monocytes/eosinophils), at the respective stops (activated endothelial cells),, and afterwards detach to further continue their journey, possibly to further pick upp and drop off other passengers. In this perspective, engagement of monocyte integrinss (Pi or (32 integrins such as VLA-4 or Mac-1, respectively) by the respective ligandd on the endothelium might act as the detaching (stop) signal for the platelets (touringg car). This mechanism, as well as the use of these signaling pathways as targetss of therapeutic intervention, needs further investigation. Similarly interesting is thee role of additional mechanisms of PMC formation and PMC behavior in vivo.
2.. The precise rote of activated platelets and PMC in the acceleration of early atherogenesiss and cardiovascular disease in vivo still needs confirmation. In this respect,, the therapeutic efficacy of inhibitors of PMC formation and function, such as thee well-known platelet activation inhibitors or the recently available P-selectin antagonists,, should be reviewed against this background. However, such studies shouldd take into account the difficulties related to PMC measurements, because plateletss easily become activated in vitro. Preliminary studies in baboons, using orally administeredd P-selectin antagonists, showed decreased formation of LPA and subsequentlyy of atherosclerosis. In a near future and in the light of our own studies, suchh an approach may become efficient in preventing cardiovascular disease in humans. .
3.. By acting in a similar integrin-activating way as platelets, also LRP may play a rolee in monocyte recruitment to the endothelium. Some preliminary data suggest that LRPP may be involved in monocyte secondary tethering. Whether LRP on the surface off one monocyte can interact in "trans" with (32 integrins or even other LRP molecules onn the surface of other monocytes and, in such way, lead to the formation of cell stringss or clusters is currently under investigation.
4.. PSGL-1 was shown to be strongly implicated in monocyte recruitment to the endotheliumm not only by binding L-selectin and mediating monocyte-monocyte interactionss but, more importantly, by binding P-selectin on platelets and thus facilitatingg PMC formation. Besides being expressed on activated endothelial cells, PSGL-11 is also able to directly interact with ligands on the monocyte and also, in theory,, on the platelet surface, and directly recruit these cells to the endothelium. Endotheliall PSGL-1 - mediated monocyte recruitment to the endothelium is modulatedd by activation of the endothelium, which provides crucial changes on the PSGL-11 molecule, thus increasing the affinity for its ligands. This is true for endotheliall cell activation with TNF-a. However, whether PSGL-1 functionality is dependentt on the type of cytokine or stimulus still has to be investigated. Notwithstandingg the evident power of P-selectin/PSGL-1 - blocking antibodies, modulationn of endothelial PSGL-1 glycosylation may also become an efficient tool in preventingg or diminishing cardiovascular disease. In a similar way, modulation of PSGL-11 glycosylation on monocytes may inhibit PMC formation.
5.. Platelet binding to certain leukocytes (monocytes and eosinophils) has been shownn to increase the leukocyte recruitment to the endothelium and enhance the developmentt of cardiovascular disease. However, this platelet-mediated enhancementt of cell binding capacity is not necessarily always bad. Platelet binding
too other cells, e.g. dendritic cells, may improve the homing of such cells and thus enhancee the patrol of foreign pathogens. Possible interactions of platelets with cells otherr than monocytes or eosinophils and their (patho)physiological role would also be ann interesting topic of investigation.
References s
1.. Ross R. The pathogenesis of therosclerosis - an update. New Eng J Med. 1986; 314:488-500. 2.. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002; 105:1135-1143. .
3.. Libby P. Inflammation in atherosclerosis. Nature. 2002; 240:868-874.
4.. Alon R, Fuhlbrigge RC, Finger EB, Springer TA. Interactions through L-selectin between leukocytess and adherent leukocytes nucleate rolling adhesion on selectins and VCAM-1 in shear flow. JJ Cell Biol. 1996; 135:849-865.
5.. Walcheck B, Moore KL, McEver RP, Kishimoto TK. Neutrophil-neutrophil interactions under hydrodynamicc shear stress involve L-selectin and PSGL-1. A mechanism that amplifies initial leukocytee acumulation of P-selectin in vitro. J Clin Invest. 1996; 98:1081-1087.
6.. Van Zanten GH, de Graaf S, Slootweg PJ, Heijnen HF, Connolly TM, de Groot PG, Sixma JJ. Increasedd platelet deposition on atherosclerotic coronary arteries. J Clin Invest. 1994; 93:615-632. 7.. Huo Y, Schober A, Forlow SB, Smith DF, Hyman MC, Jung S, Liftman DR, Weber C, Ley K. Circulatingg activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med.. 2003; 9:61-67.
8.. Burger PC, Wagner DD. Platelet P-selectin faciliates atherosclerotic lesion development. Blood. 2003;; 101:2661-2666.
9.. Frenette PS, Johnson RC, Hynes RO, Wagner DD. Platelets roll on stimulated endothelium in vivo;; an interaction mediated by endothelial P-selectin. Proc Natl Acad Sci USA. 1995; 92:7450-7454. 10.. Frenette PS, Moyna C, Hartwell DW, Lowe JB, Hynes RO, Wagner DD. Platelet-endothelial interactionss in inflamed mesenteric venules. Blood. 1998; 91:1318-1324.
11.. Theilmeier G, Michiels C, Spaepen E, Vreys I, Collen D, Vermylen J, Hoylaerts MF. Endothelial vonn Willebrand factor recruits platelets to atherosclerosis-prone sites in response to hypercholesterolemia.. Blood. 2002, 99:4486-4493.
12.. Bruehl RE, Moore KL, Lorant DE, Borregaard N, Zimmerman GA, McEver RP, Bainton DF. Leukocytee activation induces surface redistribution of P-selectin glycoprotein ligand-1. J Leukoc Biol. 1997;; 61:489.
13.. Symon FA, Lawrence MB, Williamson ML, Walsh GM, Watson SR, Wardlaw AJ. Functional and structurall characterization of the eosinophil P-selectin ligand. J Immunol. 1996; 157:1711.
14.. Ulfman LH, Joosten DP, van Aalst CW, Lammers JW, van de Graaf EA, Koenderman L, Zwaginga JJ.. Platelets promote eosinophil adhesion of patients with asthma to endothelium under flow
conditions.. Am J Respir Cell Mol Biol. 2003; 28:512-519.
15.. Furman Ml, Benoit SE, Barnard MR, Valeri CR, Borbone ML, Becker RC, Hechtman HB, Michelsonn AD. Increased platelet reactivity and circulating monocyte-platelet aggregates in patients withh stable coronary artery disease. J Am Coll Cardiol. 1998; 31:352-358.
16.. Sarma J, Laan CA, Alam S, Jha A, Fox KA, Dransfield I. Increased platelet binding to circulating monocytess in acute coronary syndromes. Circulation. 2002; 105:2166-2171.
17.. Furman Ml, Barnard MR, Krueger LA, Fos ML, Shilale EA, Lessard DM, Marchese P, Frelinger III AL,, Goldberg RJ, Michelson AD. Circulating monocyte-platelet aggregates are an early marker of acutee myocardial infarction. J Am Coll Cardiol. 2001; 38:1002-1006.
18.. Theilmeier G, Lenaerts T, Remade C, Collen D, Vermylen J, Hoylaerts MF. Circulating activated plateletss assist THP-1 monocytoid/endothelial cell interactions under shear stress. Blood. 1999; 94:2725-2734. .
19.. Luscinskas FW, Kansas GS, Ding H, Pizcueta P, Schleiffenbaum BE, Tedder TF, Gimbrone MA Jr.. Monocyte rolling, arrest and spreading on IL-4 - activated vascular endothelium under flow is mediatedd via sequential action of L-selectin, beta 1-integrins and beta 2-integrins. J Cell Biol. 1994; 125:1417-1427. .
20.. Moore KL, Stutts NL, Diaz S et al. Identification of a specific glycoprotein ligand for P-selectin (CD62)) on myeloid cells. J Cell Biol. 1992; 118:445-456.
21.. Ma L, Raycroft L, Asa D, Anderson DC, Geng J-G. A sialoglycoprotein from human leukocytes functionss as a ligand for P-selectin. J Biol Chem. 1994; 269:27739-27746.
22.. Frenette PS, Denis CV, Weiss L, et al. P-selectin glycoprotein ligand-1 (PSGL-1) is expressed on plateletss and can mediate platelet-endothelial interactions in vivo. J Exp Med. 2000; 98:1081-1087. 23.. Li F, Wilkins PP, Crawley S, Weinstein J, Cummings RD, McEver RP. Post-translational modificationss of recombinant P-selectin glycoprotein ligand-1 required for binding to P- and E-selectin. JJ Biol Chem. 1996; 271:3255-3264.
24.. Moore KL, Patel KD, Bruehl RE, Fugang L, Jonhson DA, Lichenstein HS, Cummings RD, Bainton DF,, McEver RP. P-selectin glycoprotein ligand-1 mediates rolling of human neutrophils on P-selectin. JJ Cell Biol. 1995;128:661-671.
25.. Norman KE, Moore KL, McEver RP, Ley K. Leukocyte rolling in vivo is mediated by P-selectin glycoproteinn ligand-1. Blood. 1995; 86:4417-4421.
26.. Rosen SD, Bertozzi CR. Two selectins converge on sulphate. Leukocyte adhesion. Curr Biol. 1996;6:261-264. .
27.. Lasky LA. Selectin-carbohydrate interactions and the initiation of the inflammatory response. Annu Revv Biochem. 1995; 64:113-139.
28.. Vestweber D, Blanks JE, Mechanisms that regulate the function of the selectins and their ligands. Physioll Rev. 1999; 79:181-213.
29.. Leppanen A, Mehta P, Ouyang YB et al. A novel glycosulfopeptide binds to P-selectin and inhibits leukocytee adhesion to P-selectin. J Biol Chem. 1999; 274:24838-24848.
30.. Smith MJ, Smith BR, Lawrence MB, Snapp KR. Functional analysis of the combined role of the O-linkedd branching enzyme core 2 beta-1-6-N-glucosaminyltransferase and dimerization of P-selectin glycoproteinn ligand-1 in rolling on P-selectin. J Biol Chem. 2004; 279:21984-21991.
31.. Ruggeri ZM. Mechanisms initiating platelet thrombus formation. Thromb Haemost. 1997; 78:611-616. .
32.. Barry OP, Pratico D, Savani RC, FitzGerald GA. Modulation of monocyte-endothelial cell interactionss by platelet microparticles. J Clin Invest. 1998; 1:136-144.
33.. Furie B, Furie BC, Flaumenhaft R. A journey with platelet P-selectin: the molecular basis of granulee secretion, signaling and cell adhesion. Thromb Haemost. 2001; 86:214-221.
34.. McEver RP. Selectins: lectins that initiate cell adhesion under flow. Curr Opin Cell Biol. 2002; 14:581-586. .
35.. Celi A, Pellegrini G, Lorenzet R, de Blasi A, Ready N, Furie BC, Furie B. P-selectin induces the expressionn of tissue factor on monocytes. Proc Natl Acad Sci. 1994; 91:8767-8771.
36.. Evangelista V, Manarini S, Rotondo S, Martelli N, Polischuk R, McGregor JL, de Gaetano G, Cerlettii C. Platelet/polymorphonuclear leukocyte interaction in dynamic conditions: evidence of adhesionn cascade and cross talk between P-selectin and the beta 2 integrin CD11b/CD18. Blood. 1996;; 88:4183-4194.
37.. Evangelista V, Manarini S, Sideri R et al. Platelet/polymorphonuclear leukocyte interaction: P-selectinn triggers protein-tyrosine phosphorylation -dependent CD11b/CD18 adhesion: role of PSGL-1 ass a signaling molecule. Blood. 1999; 93:876-885.
38.. Yago T, Tsukuda M, Minami M. P-selectin binding promotes the adhesion of monocytes to VCAM-11 under flow conditions. J Immunol. 1999; 163:367-373.
39.. Ma Y-Q, Plow EF, Geng J-G. P-selectin binding to P-selectin glycoprotein ligand-1 induces an intermediatee state of aMp2 activation and acts cooperatively with extracellular stimuli to support maximall adhesion of human neutrophils. Blood. 2004; 104:2549-2556.
40.. Von Hundelshausen P, Weber KS, Huo Y, Proudfoot AE, Nelson PJ, Ley K, Weber C. RANTES depositionn by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation.. 2001; 103:1772-1777.
41.. Weyrich AS, Elstad MR, McEver RP, Mclntyre TM, Moore KL, Morrissey JH, Prescott SM, Zimmermann GA. Activated platelets signal chemokine synthesis by human monocytes. J Clin Invest.
1996;97:1525-1534. .
42.. Weyrich AS, Mclntyre TM, McEver RP, Prescott SM, Zimmerman GA. Monocyte tethering by P-selectinn regulates monocyte chemotactic protein-1 and tumor necrosis factor alpha secretion. Signal integrationn and NF-kappa B trasnlocation. J Clin Invest. 1995; 95:2297-2303.
43.. Moestrup SK, Glieman J, Pallesen G. Distribution of the alpha 2-macroglobulin receptor/low densityy lipoprotein receptor-related protein in human tissues. Cell Tissue Res. 1992; 269:375-382. 44.. Moestrup SK, Kaltoft K, Peterson SM et al. Immunocytochemical identification of the human alpha 2-macroglobulinn receptor in monocytes and fibroblasts: monoclonal antibodies define the receptor as a monocytee differentiation antigen. Exp Cell Res. 1990; 190:195-203.
45.. Yepes M, Sandkvist M, Moore EG et al. Tissue-type plasminogen activator induces opening of the blood-brainn barrier via the LDL-receptor - related protein. J Clin Invest. 2003; 112:1533-1540. 46.. Bacskai BJ, Xia MQ, Strickland DK, Rebeck GW, Hyman BT. The endocytic receptor protein LRP alsoo mediates neuronal calcium signaling via N-methyl-D-aspartate receptors. Proc Natl Acad Set USA.. 2000;97:11551-11556.
47.. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998; 392:245-252. .
48.. Geitenbeek TB, Torensma R, van Vliet SJ, van Duijnhoven GC, Adema GJ, van Kooyk Y et af. Identificationn of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immunee responses. Cell. 2000; 100:575-585.
49.. Geitenbeek TB, Krooshoop DJ, Bleijs DA, van Vliet SJ, van Duijnhoven GC, Grabovsky V et al. DC-SIGN-ICAM-22 interaction mediates dendritic cell trafficking. Nat Immunol. 2000; 1:353-357.
