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Originally published online as doi:10.1189/jlb.0708400 on October 23, 2008

Published online before print October 23, 2008
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(Journal of Leukocyte Biology. 2009;85:195-204.)
© 2009 Society for Leukocyte Biology

Molecular and functional interactions among monocytes, platelets, and endothelial cells and their relevance for cardiovascular diseases

Janine M. van Gils*, Jaap Jan Zwaginga*,{dagger} and Peter L. Hordijk*,1

* Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and
{dagger} Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands

1 Correspondence: Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail: p.hordijk{at}sanquin.nl


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ABSTRACT
 
Platelets, monocytes, and endothelial cells are instrumental in the development and progression of cardiovascular diseases. Inflammation, a key process underlying cardiovascular disorders, is accompanied and amplified by activation of platelets and consequent binding of such platelets to the endothelium. There, platelet-derived chemokines, in conjunction with increased expression of adhesion molecules, promote the recruitment of circulating monocytes that will eventually migrate across the endothelial lining of the vessel into the tissues. Additionally, platelets may already become activated in the circulation and may form platelet-monocyte complexes, which show increased adhesive and migratory capacities themselves but also facilitate recruitment of noncomplexed leukocytes. They should therefore be considered as important mediators of inflammation. In molecular terms, these events are additionally governed by chemokines released and presented by the endothelium as well as the different classes of endothelial adhesion molecules that regulate the interactions among the various cell types. Most important in this respect are the selectins and their ligands, such as P-selectin glycoprotein (GP) ligand 1, and the integrins binding to Ig-like cell adhesion molecules as well as to GP, such as von Willebrand factor, present in the extracellular matrix or on activated endothelium. This review aims to provide an overview of these complex interactions and of their functional implications for inflammation and development of cardiovascular disease.

Key Words: inflammation • adhesion • endothelium


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INTRODUCTION
 
Cardiovascular diseases are the number one cause of death in the Western world and are predicted to remain so. Atherosclerosis, the primary cause of cardiovascular disease, is a systemic inflammatory disease. The inflammatory nature of atherosclerosis involves chronic stimulation of the endothelial cells (EC) that line the intima, the innermost layer of the vessel wall. In addition, the inflammatory response is characterized by the accumulation of inflammatory cells in the intima, thus initiating the atherogenic process [1 , 2 ].

The role of platelets in atherosclerosis was initially only believed to be in thrombus formation upon rupture of the more developed atherosclerotic plaques. Now, platelets are also known to assist and modulate inflammatory reactions and immune responses [3 ]. Therefore, platelets, together with inflammatory cells, are regarded as important players by integrating inflammatory responses, thrombosis, and atherogenesis. Activated platelets, adhered to a damaged vessel wall or to activated endothelium, have been shown to further promote local recruitment of leukocytes. As monocyte adhesion to the vascular wall, transendothelial migration, and differentiation toward macrophages are critical for the formation of atherosclerotic lesions, it is important to realize that these events are subject to regulation by platelet adhesion molecules and platelet-derived chemokines and cytokines.

Platelet activation results in an increase in circulating leukocyte-platelet aggregates. In particular, platelet-monocyte complexes (PMC) have been observed in clinical conditions such as peripheral vascular disease, hypertension [4 ], acute or stable coronary syndromes [5 6 7 ], stroke [8 ], or diabetes [9 ]. Increased levels of PMC are also an early marker of acute myocardial infarction [7 ]. Conversely, high dietary intake of omega-3 fatty acids induces a reduction in activated platelets and PMC level [10 ]. However, the presence of PMC is not just a sensitive marker for in vivo platelet activation and cardiovascular diseases but is also regarded more and more as a cardiovascular risk factor [8 , 11 ].

The importance of activated platelets and PMC in vascular disease is underscored by several studies that showed that prevention of platelet adhesion to monocytes by interfering with the binding of platelet P-selectin to P-selectin glycoprotein (GP) ligand 1 (PSGL-1) reduces inflammation. Infusion of human recombinant (r)PSGL-1 in animal models of vascular injury preserved vascular endothelial function [12 , 13 ]. Also, the absence of P-selectin in mice diminishes lesion formation [14 , 15 ]. Furthermore, infusion of activated but not of P-selectin-deficient platelets results in increased formation of atherosclerotic lesions [16 ]. All of these data indicate a role of P-selectin–PSGL-1 interactions in atherosclerosis. Moreover, the platelet chemokines platelet factor 4 (PF4) and RANTES contribute to lesion progression by inducing monocyte survival and differentiation into macrophages [17 ]. PF4 also facilitates the esterification and promotes the uptake of oxidized low-density lipoprotein by macrophages and thereby, promotes foam cell development [18 ]. Additionally, RANTES contributes to smooth muscle cell proliferation [19 ], mediating progression to a fibrous plaque [2 ].

Clearly, PMC are not merely a reflection of platelet activation, but platelet binding also leads to an activated and thus more proatherogenic monocyte phenotype, not only by inducing expression and secretion of cytokines and active substances from platelets and monocytes but most importantly, by amplifying monocyte adhesion and migration and by promoting monocyte differentiation toward macrophages. Increased levels of PMC in patients with cardiovascular disease have so far been regarded as a parameter-reflecting disease, but in view of the above, PMC also seem able to play a key role in disease pathogenesis.

This review will discuss in more detail the molecular mechanisms involved in cell–cell interactions among platelets, monocytes, and EC and the consequences of these interactions for the development of cardiovascular diseases as well as possibilities for intervention.


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PLATELET ACTIVATION AND ADHESION TO THE VASCULAR WALL
 
Molecular ligands
The function of blood platelets is to arrest bleeding (hemostasis) by formation of stable blood clots following activation of the coagulation cascade. In addition, platelets may contribute to the integrity of the endothelium [20 ] and participate in inflammatory processes [21 ]. Healthy, nonactivated endothelium normally prevents adhesion of platelets to the vessel wall by its antithrombotic properties, involving release of platelet activation-inhibiting substances such as NO, prostacyclin, and cyclo-oxygenase-2 [22 ]. However, in an inflamed vessel wall, the endothelial phenotype can change to prothrombotic by release of platelet-binding and stimulating agents such as ADP and multimeric Von Willebrand factor (VWF) and the up-regulation of expression of tissue factor (TF) and of adhesion molecules [23 ]. VWF especially mediates direct interaction of platelets with intact, activated EC, even under high shear-stress conditions [24 , 25 ]. Platelet adherence is even more stimulated upon vessel wall damage when extracellular matrix (ECM) proteins are exposed. ECM, such as collagen and VWF, are strong ligands of platelet GP. Rapid platelet adhesion to the ECM followed by their activation is the primary event in thrombus formation.

Under physiological flow conditions, platelet adhesion at sites of vascular injury involves initial tethering and rolling over the ECM and intact endothelium. This process is mediated by adhesion to VWF via the membrane adhesion receptor GP complex Ib-IX-V, also known as the VWF receptor complex, and to collagen via GPVI [26 , 27 ]. Rolling on intact endothelium is also mediated by binding of GPIb to P-selectin on EC [25 , 28 ]. Additionally, P-selectin and GPIb can mediate rolling interactions between platelets that are still in the circulation and those that are already adhered to the vessel wall. Finally, platelets activated already can tether and roll on PSGL-1 and GPIb on activated EC even under high shear [29 , 30 ] (Fig. 1 ).


Figure 1
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  		Figure 1. Platelet–endothelial molecular interactions. Schematic overview of the various interactions between endothelial and platelet surface molecules. The ligand-receptor combinations P-selectin, PSGL-1, and GPIb are involved in the tethering and rolling of platelets on the EC. Upon activation of integrins, platelets firmly adhere to the endothelium, mainly via the additional bridging molecules fibronectin (Fn), fibrinogen (Fg), collagen, and VWF. Upon firm adhesion, also CD40 ligand (CD40L)–CD40, TNF superfamiliy 14 (TNFSF14)–TNFSF14R, and junctional adhesion molecule A (JAM-A)–JAM-A interactions are initiated. CD40L and TNFSF14 binding to the endothelial ligands induces an inflammatory response in the EC.

Stable adhesion, however, requires additional contacts between the platelets and the ECM or the endothelium (Fig. 1) . The initial contact by GPIb-IX-V and GPVI binding to VWF and collagen, respectively, results in platelet activation via a complex series of intracellular reactions. As a result, the integrins {alpha}IIbβ3 (GPIIbIIIa, fibrinogen receptor) and {alpha}2β1 (collagen receptor) are activated [26 , 31 ]. The VWF–GPIb-IX interaction has been shown to induce Syk phosphorylation and {alpha}IIbβ3 integrin activation [31 ]. These activated integrins are required and essential for stable platelet adhesion to the ECM and EC. This can be through direct binding of the integrins to collagen, VWF, or endothelial adhesion molecules or indirectly via additional bridging molecules. The latter involves platelet-bound fibrinogen, fibronectin, and VWF, which bind to endothelial ICAM-1, {alpha}vβ3 integrin, and GPIb, respectively [30 , 32 ] (Fig. 1) . The requirement for {alpha}IIbβ3 in mediating firm adhesion of platelets to the endothelium was shown by using platelets defective in {alpha}IIbβ3 or by adding β3-integrin antagonists or a blocking antibody [33 , 34 ]. Conversely, in mice lacking ICAM-1, platelet adhesion to activated EC is strongly reduced. Furthermore, JAM-A and platelet-associated TNFSF14 (also known as LIGHT, identified in ADP-stimulated platelets) contribute to firm adhesion of platelets to the endothelium [35 , 36 ] (Fig. 1) . In conclusion, multiple interactions between surface receptors on EC and platelets result in firm adhesion of platelets at sites of vascular injury.

Activation of EC by adhesion of platelets
Stable binding of platelets to the endothelium or to ECM results in strong activation of these platelets, reflected by spreading and increased surface expression of adhesion molecules, such as CD40L, TNFSF14, and P-selectin, but also by secretion of potent inflammatory substances, such as IL-1β and PF4 [37 , 38 ]. IL-1β is synthesized and released by platelets in significant amounts and has been identified as a key mediator of platelet-induced activation of EC, inducing MCP-1, GM-CSF, and IL-6 secretion, ICAM-1 and {alpha}vβ3 integrin expression, and NF-{kappa}B activation [39 , 40 ]. CD40L (CD154) is stored in high amounts and released by platelets within seconds after GPIIbIIIa ligation [41 , 42 ]. This results in stimulation of EC through the cognate receptor CD40, known to signal inflammatory reactions within EC, including increased secretion of IL-8 and MCP-1, expression of adhesion molecules, urokinase-type plasminogen activator (uPAR), and matrix metalloproteinase (MMP)-2 and -9, and production of reactive oxygen species (ROS) [41 42 43 ]. Also, TNFSF14 can induce an inflammatory response in EC, reflected by up-regulation of adhesion molecules (E-selectin and VCAM-1) and release of chemokines (MCP-1 and IL-8) [38 ]. E-selectin expression via activation of the NF-{kappa}B pathway is also induced by platelet-released PF4 [44 ]. Finally, ligation of platelet P-selectin rapidly stimulates Weibel-Palade body release, resulting in, next to VWF release, P-selectin expression on the endothelium [45 ]. In conclusion, platelet adhesion endows the endothelium with a proinflammatory phenotype (Fig. 2 ).


Figure 2
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  		Figure 2. Endothelial activation upon platelet binding. Platelet interaction with EC mediates deposition of platelet-derived chemokines, such as RANTES and PF4 (1). Intracellular signaling induced upon platelet binding results in NF-{kappa}B activity and ROS production (2). Furthermore, a series of adhesion molecules is up-regulated (3), and secretion of several cytokines, VWF, and MMPs is induced by platelet binding (4).

Platelets adherent to EC recruit monocytes
Atherosclerosis is characterized by monocyte and macrophage accumulation in the vascular intima. Adhered platelets efficiently mediate monocyte rolling and arrest, even at high shear. Rolling is mediated by P-selectin on activated platelets and PSGL-1, constitutively expressed on monocytes [46 ]. Besides PSGL-1, CD15 (Lewis X) on monocytes has also been shown to bind platelet P-selectin [47 ]. The initial association between platelet P-selectin and monocyte PSGL-1 leads to increased expression of the β2-integrin CD11b/CD18 [{alpha}Mβ2, membrane-activated complex 1 (Mac-1)] on the monocytes [48 ], which itself supports interactions with platelets. Mac-1 on leukocytes binds to GPIb [49 ] and to JAM-C on platelets [50 ]. Besides direct interaction, similar bridging mechanisms as described above for platelets and EC also mediate platelet-monocyte binding. On monocytes, fibrinogen is linked to Mac-1 and its platelet surface counterpart GPIIbIIIa [32 ]. Also, bridging by thrombospondin of the CD36 antigens (present on monocytes and platelets) was shown [51 ]. Additional interactions between platelets and monocytes include CD40L–CD40 [52 ] and monocyte triggering receptor expressed on myeloid cell 1 (TREM-1) to platelet-expressed TREM-1 ligand [53 , 54 ] (Fig. 3 ).


Figure 3
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  		Figure 3. Platelet–monocyte molecular interactions. P-selectin mediates the initial binding contact with monocytes via PSGL-1 and CD15. The ligation of PSGL-1 induces integrin activation on monocytes, resulting in further binding interactions, in part, mediated by additional bridging molecules. Further interactions are through CD40L–CD40, TREM-1 ligand–TREM-1, which may also promote integrin expression, and CD36–CD36 via thrombospondin.

Next to adhesion molecules, also, chemokines deposited on the endothelium are facilitating recruitment of monocytes. For instance, RANTES and PF4 can be deposited on EC by activated platelets or platelet microparticles upon adhesion or even during transient interaction through JAM-A or P-selectin, respectively [16 , 55 56 57 ]. The endothelial deposition of platelet-derived RANTES has been shown to trigger further monocyte arrest on the endothelium under high shear but not on endothelium-adherent platelets [19 ]. Also, the chemokines platelet-activating factor and MIP are secreted by platelets adhered on the endothelium. The deposited platelet chemokines form homophilic as well as heterophilic aggregates, which further stimulate their biological activity. For example, RANTES increases the binding of PF4 to the monocyte surface [58 ]. Subsequently, PF4 drastically enhances RANTES-induced monocyte arrest on EC [58 ], predominantly mediated by CCR1 [59 ]. Thus, platelet adhesion to the EC or ECM and chemokines secreted by platelets greatly contribute to subsequent monocyte adhesion to the vascular wall.


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PMC—FORMATION AND FUNCTIONAL CONSEQUENCES
 
Although a rare event under resting conditions, platelets in the circulation sometimes do get activated. Different mechanisms could be responsible for the activation of circulating platelets, e.g., by turbulent flow, by cytokines associated with systemic thromboembolic or inflammatory events, by released agents from platelets from unstable thrombi [60 ], or by rolling interactions with activated endothelium. Whatever the cause, conditions such as systemic inflammation and acute myocardial infarction increase the number of activated platelets in the circulation. These activated platelets are able to bind to all types of leukocytes, but monocytes seem most proficient in this and are therefore the focus of our review. Comparing monocytes with neutrophils in this respect showed more and initially faster binding of activated platelets to monocytes [61 , 62 ]. The platelet-binding capacity between the different subsets of monocytes is still unknown. In mice, the inflammatory monocyte Ly-6Chi subset, shown to be increased dramatically in hypercholesterolemic mice [63 , 64 ], demonstrates a higher expression of PSGL-1 [65 ]. This could contribute to the role of monocytes in atherogenesis, although so far in human monocyte subsets, no difference in PSGL-1 expression has been detected [66 , 67 ]. Reports about this matter are only few, and contradicting data have also been presented [68 , 69 ]. The link between human monocyte subsets and formation of PMC therefore still needs further clarification.

The extent of PMC formation is mostly dependent on platelet activation [61 ] and to a limited extent, on monocyte activation [70 ]. Platelets bind via P-selectin, expressed on the surface of activated platelets, to its receptor on monocytes, PSGL-1 [61 ]. Antibody inhibition studies indicate that the platelet-monocyte conjugation is abolished by blocking P-selectin and partially inhibited by other blocking antibodies [49 , 61 , 71 , 72 ]. This indicates that platelet P-selectin is the critical ligand initiating PMC formation via binding to PSGL-1, and other ligands play only an additive role.

The in vivo circulation time and clearance of the complexes formed between activated platelets and monocytes are also not yet well-defined. In vivo, P-selectin is expressed upon platelet activation for several hours before it is shed from the surface [73 ]. However, in a study using primates, Michelson et al. [74 ] found that the lifespan of PMC was not related to platelet P-selectin shedding. The increased adhesive capacity of these complexes is likely to have a major influence on their clearance. Huo et al. [16 ] have shown in mice that PMC, formed upon injection of activated platelets, indeed had a short circulation time. These authors also showed that the PMC were cleared by monocyte transmigration. However, in patients with percutaneous coronary intervention, which increases the level of activated platelets, PMC were detected much longer and only returned to baseline after 24 h [74 ]. Finally, fagocytic uptake of the platelets by monocytes might also contribute to a reduction in PMC levels.

Monocyte activation upon platelet interaction
The binding of platelets to monocytes mediated via P-selectin–PSGL-1 interactions induces L-selectin shedding from the monocyte surface [75 ] (Fig. 4 ). Furthermore, this interaction between platelets and monocytes was found to increase expression and activity of the {alpha}4β1 and {alpha}Mβ2-integrins [75 , 76 ]. Similarly, engagement of CD40 with CD40L, but also TREM-1 ligation, results in an increase in monocyte adhesive capacity by up-regulation of β1- and β2-integrins [54 , 77 ]. The presence of the chemokines RANTES and CXCL10, deposited by platelets onto the monocytes, augments β2-integrin avidity upon PSGL-1 cross-linking [78 ].


Figure 4
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  		Figure 4. Monocyte activation upon platelet binding, which to monocytes leads to the deposition of platelet-derived chemokines, such as RANTES and PF4 (1). Intracellular signaling induced upon platelet binding via PSGL-1, for instance, results in L-selectin shedding (2) and increased expression and activation of β1- and β2-integrins (3). Furthermore, monocyte NF-{kappa}B activity (4) and the secretion of several cytokines and TF (5) are induced upon binding of activated platelets. Src, Steroid receptor coactivator; PKC, protein kinase C.

Monocyte binding to activated platelets has also been shown to increase the production of various proinflammatory mediators and TF expression. P-selectin–PSGL-1 interactions are important but not exclusively responsible for these processes. TF expression by the monocytes is reduced by a P-selectin-blocking antibody and by IL-10, but not by a CD40L antibody [52 , 79 80 81 ]. Monocyte expression of chemokines, induced by thrombin-activated platelets, is regulated by NF-{kappa}B activity [82 ]. Ligation of TREM-1 or the ligation of monocyte PSGL-1 together with RANTES, but not PF4, induces NF-{kappa}B activity and subsequently secretion of MCP-1, TNF-{alpha}, and IL-8 [54 , 83 , 84 ], although PF4 has been shown to induce the secretion of TNF-{alpha} by monocytes as well [17 ]. Taken together, platelet-derived chemokines, together with the ligation of various adhesion molecules on the monocyte following the interaction with activated platelets, induce activation of monocytes, resulting in changes in expression of adhesion molecules and secretion of cytokines (Fig. 4) .

PSGL-1 signaling
PSGL-1 plays a major role in the binding of monocytes to activated platelets. PSGL-1, however, is not only an adhesion but also a signaling molecule. PSGL-1 ligation induces production of superoxide anion radicals from monocytes and neutrophils [85 ], activation of GTPase Ras as shown in neutrophils [86 ], and tyrosine phosphorylation of various cytoplasmic proteins, such as pp125 focal adhesion kinase, ERK, Syk, Src kinase, and paxillin, demonstrated in neutrophils, lymphocytes, and various monocytic cellular models [86 87 88 89 ]. Also PKC isoforms are activated, mediating integrin activation, shown in lymphocytes [78 ] (Fig. 4) .

The cytoplasmic tail of PSGL-1 is linked to the actin cytoskeleton through the ezrin-radixin-moesin (ERM) proteins [90 ], which is crucial for leukocyte rolling [91 ]. The ERM proteins also mediate PSGL-1 association with Syk [87 ], which is important for the activation of LFA-1 ({alpha}Lβ2) integrins [92 ] and for the induction of serum response element-dependent transcriptional activity [87 ]. Furthermore, the cytoplasmic tail of PSGL-1 also interacts with Nef-associated factor 1 (Naf1) [89 ]. The Naf1-binding sites in the PSGL-1 cytoplasmic domain are distinct from the residues critical for the recognition of ERM proteins [93 ]. Upon PSGL-1 engagement, Naf1 is phosphorylated via Src kinase, leading to activation of β2-integrins, which results in activation of Akt and mammalian target of rapamycin (mTOR) [89 , 94 ]. The activation of mTOR is essential for the transcription and synthesis of uPAR and Rho kinase 1 [94 , 95 ], which are both involved in adhesion and migration processes. Recently, a novel protein selectin ligand interactor cytoplasmic 1 (SLIC-1), which has no apparent signaling role upon leukocyte adhesion, was found to bind to the cytoplasmic domain of PSGL-1. SLIC-1 serves as a sorting molecule that promotes traffic of PSGL-1 to endosomes [96 ]. These findings emphasize a critical role for intracellular signaling, induced by PSGL-1 in rolling, adhesion, and migration of monocytes during inflammatory responses.


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PMC ADHESION AND TRANSENDOTHELIAL MIGRATION
 
The migration of monocytes across the vascular endothelium is required for immune surveillance and for monocyte recruitment at inflammatory sites. The inflammatory nature of atherosclerosis involves chronic stimulation of the EC by lipids in the intima [1 2 3 ]. Chronic activation of EC results in increased chemoattractant signals and increased expression and activity of various adhesion molecules on the cell surface that mediate adhesion to and migration across the endothelium of inflammatory cells, initiating the atherogenic program. Monocyte extravasation is tightly regulated by a multi-step process of tethering, rolling, activation, adhesion, and transmigration. As described above, platelet binding alters the adhesive and migratory phenotype of monocytes.

Tethering and rolling
Similar to the interactions between platelets and EC under physiological flow, monocyte adhesion to the vessel wall also involves tethering and rolling over the endothelium. Rolling is mediated by monocyte-expressed L-selectin and endothelial-expressed P- and E-selectin, interacting with PSGL-1, CD44, or E-selectin-ligand-1 (ESL-1) [97 ] (Fig. 5 ). PSGL-1 and ESL-1 are primarily responsible for tethering and rolling of leukocytes on the endothelium; CD44 is subsequently important for reducing the rolling velocity of leukocytes after they have tethered through P- or L-selectin [98 ]. Two types of monocyte tethering can be distinguished. Primary tethering occurs directly at the endothelial surface. Secondary tethering represents monocyte adhesion to other already-adhered monocytes [99 , 100 ]. PMC show increased primary and secondary tethering on EC and on already-adhered inflammatory cells [101 , 102 ]. Platelet binding to monocytes also results in shedding of L-selectin from the monocyte surface [75 ], decreasing the rolling velocity of activated monocytes. The increased tethering and rolling, together with the L-selectin shedding, result in more monocyte adhesion upon platelet binding to the monocytes.


Figure 5
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  		Figure 5. Monocyte–EC molecular interactions. The initial interaction of monocytes with the endothelium is by tethering and rolling. This is mediated by the selectins and their ligands. Rolling triggers further expression and activation of monocyte integrins, resulting in firm, stable adhesion to the EC through binding to ICAM-1, VCAM-1, or {alpha}vβ3 via fibronectin.

Monocyte activation and firm adhesion
Low velocities of rolling increase monocyte transit time through inflamed vessels, favoring the probability of monocytes to encounter and to be activated by chemokines or lipid mediators presented on the endothelial surface [103 ]. During this process, chemokines on the luminal-endothelial surface, in cooperation with PSGL-1 ligation to endothelial and platelet ligands, induce a rapid increase in the binding affinity and avidity of β2-integrins of the leukocytes [104 , 105 ]. Moreover, RANTES, IL-8, and MCP-1 secreted by platelets and EC trigger arrest of rolling monocytes on EC [19 , 106 ]. The high-affinity binding of chemokines to specific G-protein-coupled receptors initiates the intracellular signaling cascade from these receptors to phospholipase C signaling, activation of small GTPases (Rap1), and transitional changes in integrin conformation through the association with actin-binding proteins, as shown in lymphocytes and monocytes [107 108 109 ]. On monocytes, the {alpha}4β1 (VLA-4) integrin is known to further slow the selectin ligand-dependent rolling, which leads to stable adhesion [110 ]. Leukocyte arrest is induced further by leukocyte integrins {alpha}Lβ2 (LFA-1) or {alpha}Mβ2 (Mac-1) and VLA-4 ligation by the endothelial Ig superfamily members ICAM-1 and VCAM-1, respectively [107 ] (Fig. 5) . JAM-A also contributes to monocyte adhesion to atherosclerotic endothelium through its binding to LFA-1 [111 ] and indirectly through its homophilic binding to platelet JAM-A, supporting adhesion of PMC. Importantly, PMC have induced integrin expression and activity compared with platelet-free monocytes, increasing monocyte adhesion and transmigration capacity.

Transmigration
Upon binding of monocytes to the vessel wall, chemokines from the underlying intima stimulate them to migrate through the endothelial monolayer into the subendothelial space. The EC participate actively in the transmigration event. During transendothelial migration, the cell–cell junctions disengage transiently and locally to allow the leukocyte to cross [112 , 113 ].

Rolling and adhesion of leukocytes over activated endothelium are accompanied by a complex response from the EC, involving extensive reorganization of the endothelial actin cytoskeleton and the activation of intracellular signaling pathways. One of the results is a pronounced morphological response of the EC by forming "docking structures" [114 ] or "transmigratory cups" [115 ]. In these structures, integrin ligands, such as ICAM-1 and VCAM-1, are concentrated [114 ]. Leukocyte adhesion and ligation of ICAM-1 and VCAM-1 and the subsequent increase in endothelial actin stress-fiber formation and monolayer permeability are controlled by the GTPases RhoA, Rac1, and Rap1 in the EC [112 ].

The junctional adhesion receptors PECAM-1, CD99, and JAMs also actively mediate leukocyte transendothelial migration through homophilic interactions [116 117 118 ]. In addition, adherent monocytes interact, via their β2- and β1-integrins, with JAM family members at the most apical regions of the interendothelial junctions. Bradfield et al. [119 ] discovered a novel role for endothelial JAM-C in mice in regulating monocyte retention in the abluminal compartment after primary transmigration in vivo. Blockade of JAM-B/-C decreased the number of monocytes in the extravascular compartment by allowing multiple reverse-transmigration events. The involvement of the JAMs in endothelial permeability and monocyte adhesion and transmigration suggests a broad relevance for JAMs in vascular inflammation. This is corroborated further by a large number of studies that have established a role for, in particular, JAM-A and JAM-C in various inflammation-related models, revealing a role for these adhesion molecules in leukocyte recruitment, neointimal lesion formation, as well as angiogenesis [110 , 120 ].

PMC show increased transmigration compared with platelet-free monocytes [75 , 121 ]. We have observed that the platelets do not remain attached to the monocyte following transmigration [121 ] but instead, are shed from the monocyte as a result of monocytic PSGL-1 redistribution and mechanical stress. Thus, it can be concluded that platelet binding to monocytes results in increased monocyte adhesion and transmigration and subsequent platelet deposition on the endothelium.


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INTERVENTION POSSIBILITIES
 
A number of therapeutic molecules have been used to investigate the inhibition of PMC, including clopidogrel (inhibition of ADP-mediated platelet activation) and Abciximab (GPIIbIIIa antibody). Clopidogrel greatly reduces PMC in patients with atherosclerotic diseases and has been shown to reduce P-selectin expression and CD40L release [122 123 124 ]. Although some studies suggest otherwise by reporting an increase in the expression of RANTES upon clopidogrel administration [125 ], much evidence points to an efficient inhibition of PMC formation by clopidogrel. In contrast, Abciximab did not significantly reduce the formation of PMC [126 ]. Although Abciximab resulted in vitro in less platelet binding to monocytes and a decrease in TF expression on monocytes, no effects or even an increase in PMC levels are observed [126 , 127 ]. Furthermore, there are some studies with aspirin, another platelet aggregation inhibitor, that show no or very little effect on PMC formation [122 , 124 , 128 ]. As traditional platelet activation inhibitors show varying success in preventing PMC formation, P-selectin and PSGL-1 are logical, potential targets for intervention with antibodies or recombinant proteins. Use of rPSGL-1 in animal models indeed results in reduced platelet and leukocyte adhesion to the endothelium and better vascular function after injury [12 , 13 , 129 ]. Also, targeting CD40L or RANTES may be beneficial. RANTES receptor antagonists inhibit the infiltration of monocytes and limit atherosclerotic plaque formation in proatherogenic mice models [55 , 130 , 131 ]. PMC represent a potential therapeutic target for limiting cardiovascular diseases. Targeting inhibition of proinflammatory platelet activation or interaction, in contrast to targeting platelet aggregation, is a good candidate for a future drug.

Conclusions and future considerations
Atherosclerosis and cardiovascular disease involve multifactorial mechanisms with interactions among coagulation, platelets, monocytes, and EC with multiple adhesion molecules, chemokines, and receptors involved. However, the increased monocyte adhesion to and transmigration across the endothelium seem to be the most important factors in accelerating atherogenesis. Platelets and EC can actively stimulate these processes. Platelet interaction with the monocyte—in the circulation or at the vessel wall itself—results in monocyte activation, which subsequently becomes more adhesive, more migratory, more procoagulant (TF) and proinflammatory, and more prone to differentiate into a macrophage. Additionally, the monocytes and platelets, each individually and also bound in a complex, contribute to an inflammatory phenotype of the endothelium. This results in further increased adhesion of monocytes and platelets and activation of these cells. From these observations, platelet–monocyte conjugates are now considered as proatherogenic.

Many unknowns, however, remain to be investigated in the future. Although we can conclude that platelet activation, much more than monocyte activation, is crucial for PMC formation, the kinetics and lifespan of the complexes, however, are still described insufficiently and are dependent on the conditions investigated. Furthermore, the platelet-dependent activation of monocytes depends on the adhesive interactions with platelets but also on platelet-released agents. The signaling pathways that are switched on will therefore be an aggregate of different systems. The latter will also be a factor determining to what extent this activation is reversible or will lead to transcriptional changes and to a more permanent phenotypic adaptation of the monocyte. Defining the key players in platelet-induced monocyte signaling in the near future will likely enable therapy to focus on preventing the relevant platelet and or monocyte activation pathways and with it, to generate tools to attenuate inflammatory vascular disease. Diverse intervention strategies are being explored and may hold good promise, especially when platelets, monocytes, and EC can be targeted simultaneously. In this respect, although studies in our group have shown that EC also express PSGL-1 [29 ], therapeutic targeting of the latter should receive more attention. The role of PSGL-1, apart from binding activated platelets, namely, might also include EC activation. This represents an important topic for further study and perhaps future therapy.

Received July 6, 2008; revised September 1, 2008; accepted September 2, 2008.


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