Published online before print August 2, 2007, doi: 10.1161/ATVBAHA.107.149179
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2007 American Heart Association, Inc.
Brief Reviews |
Vascular Adhesion Molecules in Atherosclerosis
From the Department of Biomedical Engineering and Robert M. Berne Cardiovascular Research Center, University of Virginia, Health Sciences Center, Charlottesville, Va.
Correspondence to Klaus Ley, Robert M. Berne Cardiovascular Research Center, University of Virginia, P.O. Box 801394, Charlottesville, VA 22908. E-mail klausley{at}virginia.edu
Series Editor: Dietmar Vestweber Previous Brief Reviews in this Series:
•van Buul JD, Kanters E, and Hordijk PL. Endothelial signaling by Ig-like cell adhesion molecules. Atheroscler Thromb Vasc Biol. 2007;27:1870–1876.
•Bradfield PF, Nourshargh S, Aurrand-Lions M, Imhof BA. JAM family and related proteins in leukocyte migration. Atheroscler Thromb Vasc Biol. 2007;27:2104–2112.
 |
Abstract |
|---|
Top
Abstract
IntroductionNumerous reports document the role of vascular adhesion molecules in the development and progression of atherosclerosis. Recent novel findings in the field of adhesion molecules require an updated summary of current research. In this review, we highlight the role of vascular adhesion molecules including selectins, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule1 (ICAM-1), PECAM-1, JAMs, and connexins in atherosclerosis. The immune system is important in atherosclerosis, and significant efforts are under way to understand the vascular adhesion molecule–dependent mechanisms of immune cell trafficking into healthy and atherosclerosis-prone arterial walls. This review focuses on the role of vascular adhesion molecules in the regulation of immune cell homing during atherosclerosis and discusses future directions that will lead to better understanding of this disease.
Leukocyte and endothelial adhesion molecules play key roles in the development and progression of atherosclerosis. In animal models, blocking or eliminating P-selectin, VCAM-1 or 
4β1 integrin reduces atherosclerotic lesion formation by more than 50%. Smaller effects are seen by manipulating E-selectin, ICAM-1 or the JAM family of adhesion molecules.
Key Words: atherosclerosis • pathophysiology • lymphocyte • leukocyte • monocyte • macrophages • trafficking
|
Introduction |
|---|
Atherosclerosis results in cardiovascular death of approximately 16.7 million people around the world each year (WHO Health Report, 2003). Atherosclerosis is a chronic inflammatory process that is characterized by the formation of plaques consisting of foam cells, immune cells, vascular endothelial cells (ECs), smooth muscle cells (SMCs), platelets, extracellular matrix, and a lipid-rich core with extensive necrosis and fibrosis of surrounding tissues.1,2 Accumulating evidence suggests the involvement of the innate and adaptive immune systems in atherosclerosis.3–6 The first evidence that immune cells are involved in atherosclerosis came from a study that showed regional accumulation of T cells and macrophages (M
) in human atherosclerotic plaques.7 Most of the T cells within the atherosclerotic plaque are effector or memory T cells8 with a prevalence of CD4+ lymphocytes expressing βT cell receptors.9 
T cells were detected in atherosclerotic vessels, but their numbers are quite small.8 CD3+ T cells are also found within the aortic adventitia of normal/noninflamed vessels of C57BL/6 mice.10 There is some evidence that not only proatherogenic but also antiinflammatory players of the immune system are present within the aortas. Expression of the fork-head transcription factor Foxp-3 that is necessary for the development and function of T regulatory (Treg) cells was detected within human atherosclerotic plaques,11 suggesting a potential involvement of Treg in atherosclerosis. Recently discovered Th17 cells are implicated in numerous autoimmune and inflammatory conditions including multiple sclerosis, inflammatory bowel disease, and arthritis.12 To date, there are no data indicating Th17 presence within atherosclerotic vessels. Further studies will shed light on a potential role of Th17 cells in the regulation of the immune response that accompanies atherosclerosis.
B cells are detected within the atherosclerotic adventitia,13 and CD22+ B cells are found in early and advanced atherosclerotic plaques of apolipoprotein-E–deficient (Apoe–/–) mice.14 Recently, it has been shown that B cells reside within the adventitia of healthy aortas and form, together with T cells, tertiary lymphoid structures on atherosclerosis induction.10,15 Because T and B cells were found in normal/noninflamed as well as in atherosclerotic aortas, it was proposed that lymphocytes actively migrate to the aortas and likely use adhesion molecules for their trafficking.
Numerous reports indicate that monocytes play a crucial role in atherosclerosis (reviewed in1). In response to disturbed or oscillatory flow patterns, the recruitment of monocytes preferentially occurs at the lesser curvature of healthy aortas of C57BL/6 mice.16 Interestingly, in parallel to this migration, accumulation of CD68+/CD11c– macrophages (M) is detected within the adventitia of the lesser curvature of the aortic arch of healthy mice.16 The recruitment of monocytes/macrophages into the atherosclerosis-prone aortic wall has been studied in some detail (review in17,18), however very little is known about monocyte homing into healthy aortas. During the first stage of atherosclerosis (fatty streaks), monocytes actively accumulate within the intima and further differentiate to M and dendritic cells (DCs).
There are at least 2 major subsets of monocytes. Inflammatory monocytes are Ly6Chigh/Gr-1+/CCR2+/CX3CR1+ and a second population, sometimes called resident monocytes, is Ly6Clow/Gr-1low/ CCR2–/CX3CR1high.19 A recent study suggests that the percentage of Ly6Chigh circulating blood monocytes is elevated in atherosclerotic mice, and these Ly6Chigh monocytes preferentially migrate into the aortic wall and become lesional macrophages.20 Vascular DCs are detected at bifurcations and curvature sites of normal arteries21 and throughout atherosclerotic arteries.22,23 There is some evidence that Ly6Clow/CCR2– blood monocytes become CD11c+ dendritic-like cells after entering the aortic vessel wall.24 Detailed mechanisms underlying monocyte migration into the normal and atherosclerosis-prone vessels remain to be determined; however, it is already established that CCR5, CX3CR1, and CCR2 chemokine receptors are involved in monocyte recruitment into aortic wall.24
The role of vascular adhesion molecules in atherosclerosis has been reviewed before.25–28 In this review, we will focus on the new aspects of the role of atherogenic factors in the regulation of the expression of adhesion molecules and the impact of vascular adhesion molecules on the recruitment of the immune cells into the walls of arteries.
|
Four Major Steps That Direct Leukocyte Recruitment |
|---|
Trafficking of lymphocytes through secondary lymphoid organs and leukocyte recruitment into sites of inflammation are tightly regulated processes. Adhesion molecules and chemokines play crucial roles in these events.29,30 There are several steps in leukocyte recruitment into vascular tissues: (1) initial selectin-dependent tethering and rolling, (2) triggering of adhesion via chemokines and their receptors or through selectin binding to P-selectin glycoprotein ligand-1 (PSGL-1),31,32 (3) integrin-dependent adhesion and adhesion strengthening by integrin clustering, (4) transmigration across endothelium.33,30 Details of the adhesion cascade have been reviewed29,33,30; therefore, this review will specifically focus on the mechanisms of the adhesion cascade that recruit immune cells into the normal or atherosclerotic aortic wall.
|
Selectins and Atherosclerosis |
|---|
L-, P-, and E-selectins are C-type lectins that bind sialylated and fucosylated carbohydrate ligands presented by sialomucins and mediate initial capture, tethering, and rolling along endothelium.34 L-selectin is expressed on most circulating leukocytes and mediates lymphocyte rolling in high endothelial venules (HEV) of secondary lymphoid organs and at sites of chronic inflammation, where HEV-like vessels are formed.35 L-selectin also participates in secondary capture, defined as leukocyte capture by adherent leukocytes.36,37 P-selectin is stored in Weibel-Palade bodies of endothelial cells and in intracellular
-granules of platelets and quickly released to the plasma membrane on endothelial cell activation.34 P- and E-selectins are expressed in acute as well as in chronically inflamed endothelium and serve as rolling molecules for monocytes, neutrophils, effector T cells, B cells, and natural killer cells.34 P-selectin binds PSGL-1 that is expressed by all neutrophils, monocytes, and lymphocytes.38 E-selectin is not constitutively expressed under noninflamed conditions, but is synthesized during inflammation. E-selectin binds PSGL-1,39 CD44,40 E-selectin ligand-1(ESL-1)31,41 on myeloid cells and CD43 on T-helper1 lymphocytes.42–44 |
L-Selectin |
|---|
Lymphocytes constitutively home into the normal/noninflamed aortic wall10 and reside within the adventitia.10,15 This trafficking of T and B lymphocyte is partially dependent on L-selectin, since L-selectin (encoded by the Sell gene)-deficient lymphocytes show about 50% reduced migration into the aorta compared with wild-type lymphocytes.10 Interestingly, lymphocyte migration into the atherosclerotic aorta is also regulated by L-selectin, suggesting that L-selectin ligands are constitutively expressed within the normal and atherosclerosis-prone aortic wall.10 L-selectin ligands are carbohydrate-containing molecules. PSGL-1 is an L-selectin ligand that can support secondary capture, the process by which free flowing leukocytes interact with rolling leukocytes on the endothelium.36,45 The involvement of L-selectin in leukocyte recruitment into the aorta may depend on its ability to mediate secondary capture through L-selectin/PSGL-1 interaction.36 Inhibition or absence of L-selectin may prevent leukocyte secondary capture and thus decrease the flux of rolling leukocytes into the atherosclerotic vessels.
L-selectin also binds to incompletely identified endothelial ligands that are collectively named Peripheral Node Addressins (PNAd), characterized by reactivity with monoclonal antibody MECA-79.38,46 Although lymphocyte recruitment into the aortic wall is L-selectin–dependent, aortic luminal endothelial cells and newly formed tertiary lymphoid structures do not express MECA-79, suggesting that other L-selectin ligand(s) may exist in the aortas.10 Our understanding of the role of L-selectin in atherosclerosis is very incomplete. It is not known which ligand(s) L-selectin uses to initiate primary and secondary capture, whether activated T lymphocytes use L-selectin for rolling on the atherosclerotic endothelium, or whether the absence of L-selectin on leukocytes affects the development of atherosclerosis.
|
P-Selectin and E-Selectin |
|---|
Low density lipoprotein (LDL) is a known risk factor for atherosclerosis.47,2 Circulating LDL can be modified, generating oxidized LDL (oxLDL), minimally modified LDL (mmLDL), and other biologically active forms that initiate inflammatory processes.48–50 Although the mechanisms of LDL oxidation are not completely understood, myeloperoxidase, ceruloplasmin, 15-lipoxygenase, nitric oxide synthase, NAD(P)H, and xanthine oxidase have been implicated in the generation of oxLDL.51 Circulating and especially tissue-retained oxLDL52 affects the inflammatory status of the endothelium. oxLDL and mmLDL but not native LDL induce P-selectin expression and monocyte adhesion to activated endothelium.53,54 In vivo, P-selectin is detected on the atherosclerotic endothelium of active plaques but not on the normal/noninflamed endothelium.55 Endothelial expression of P-selectin in rabbits appears after 1 week on atherogenic diet, whereas monocyte accumulation and infiltration of intimal macrophages were observed 2 weeks later.56 HUVECs from newborns with a strong family history of myocardial infarction expressed elevated levels of basal P-selectin.57 These results suggest that increase of P-selectin expression may be the earliest and primary event in the initiation of atherosclerosis. To investigate the importance of P-selectin in the recruitment of monocytes to atherosclerotic lesions, an ex vivo model of isolated carotid arteries was used. In this model, monocyte rolling and attachment on the carotid endothelium from Apoe–/– mice were significantly reduced by blocking P-selectin or its leukocyte ligand, PSGL-1.58 Thus, interaction of endothelial P-selectin with PSGL-1 expressed on monocytes plays a crucial role in the initiation of monocyte adhesion.58 To directly demonstrate the role of P-selectin in atherosclerosis, P-selectin (encoded by the Selp gene)-deficient mice on C57BL/6,59 Apoe–/–,60 and LDLR (encoded by the Ldlr gene)-deficient61 background were generated. In all 3 models of atherosclerosis, Selp–/– mice showed a significant reduction in M
numbers in the plaques and developed smaller fatty streaks at the initial stage of atherosclerosis. There are numerous reports suggesting that circulating activated platelets are a hallmark of cardiovascular diseases. Platelets play an active role in the deposition of proinflammatory stimuli to atherosclerotic endothelium and activation of circulating monocytes. P-selectin is expressed on platelets. Bone marrow transplantation experiments showed that mice receiving Selp–/– platelets developed smaller lesions than those receiving wild-type platelets.62 Even more dramatic findings were obtained in a model of wire-induced artery injury in Selp–/– and Apoe–/– double knockout mice.63 A study with P-selectin (encoded by the Selp gene)-deficient platelets demonstrated that platelets interact with inflamed endothelium through the binding of platelet P-selectin with an endothelial ligand.64 During transient interaction of activated platelets with atherosclerotic endothelium, platelets deposit CCL5 to the endothelium surface that leads to elevated monocyte adhesion.64 Moreover, platelets interact with monocytes and increase affinity and avidity of leukocyte integrins, most likely through the delivery to leukocytes of proinflammatory chemokines.65
E-selectin is found on ECs stimulated by inflammatory cytokines such as tumor necrosis factor (TNF)-, interleukin (IL)-1,66 or platelet factor 4 (PF4), a platelet-specific chemokine released on platelet activation.67 E-selectin is also detected on human atherosclerosis-prone ECs and on the surface of fibrous and lipid-containing human plaques.68 In mice, genetic deficiency of E-selectin (encoded by the Sele gene) leads to reduction in the lesion size although this inhibition is less than that seen for Icam1–/– and Apoe–/– or Selp–/– and Apoe–/– double knockout mice.69 The strongest effects in the inhibition of atherosclerosis have been shown in mice with combined deficiency of E and P-selectins, showing 80% and 40% protection in the early and advanced stages of the disease, respectively.70 These data provide evidence for an overlapping function of selectins in the regulation of atherosclerosis. A summary of the involvement of vascular adhesion molecules in atherosclerosis is shown in the Table.
|
|
Integrins in Atherosclerosis |
|---|
Integrins are a family of 24 cell-surface receptors composed of 18
and 8β subunits that form β heterodimers.71 Integrins mediate cell-cell, cell-extracellular matrix, and cell-pathogen contact. They regulate leukocyte homing, organize the immunologic synapse, participate in costimulation, migration, and phagocytosis. Integrins rapidly change the conformation of their extracellular domain structure (inside-outside signaling)72 and are able to cluster in response to activation.73 In parallel, ligation of integrins leads to a signal cascade from the extracellular domain to the cytoplasm (outside-inside signaling).72 The main integrins that participate in the regulation of leukocyte trafficking are β2 and 4 integrins. All leukocytes constitutively express LFA-1 (CD11a/CD18 or Lβ2),74 a member of the β2 subfamily of integrins. 4β1 (VLA-4) integrin is a member of 4 subfamily and mostly expressed on monocytes and on lymphocytes with extralymphoid homing potential.75 LFA-1 binds 2 endothelial molecules that belong to the immunoglobulin superfamily, intercellular cell adhesion molecule-1, and -2 (ICAMs), which consist of 5 and 2 repeating extracellular Ig-like domains, respectively, a transmembrane region, and short cytoplasmic domain.76 VLA-4 binds to another member of the immunoglobulin superfamily, VCAM-1,77 and to the CS-1 peptide of fibronectin.78 4β7 integrin binds to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), an adhesion molecule expressed in gut associated lymphatic tissues.79 It is not known whether 4β7 integrin is relevant in atherosclerosis. |
4β1 (VLA-4) and VCAM-1
|
|---|
Increased expression of adhesion molecules by the activated endothelium is a critical feature of atherosclerosis. The first evidence came from data showing that the expression of VCAM-1 is induced by arterial endothelial cells in response to accumulation of cholesterol within the intima of aortas.80 Expression of ICAM-1 and VCAM-1 was reported in human coronary arteries.68 Furthermore, the treatment of SMCs with TNF-
led to an increase in both VCAM-1 mRNA and cell surface expression of VCAM-1, suggesting cytokine-dependent expression of aortic VCAM-1.81 Upregulation of endothelial VCAM-1 and ICAM-1 expression in TNF-stimulated HUVECs and subsequent elevated adhesion of monocytes to HUVECs by aldose reductase is another possible mechanism of the regulation of adhesion molecule expression.82
Atherosclerosis is a focal disease affecting discrete regions of the vasculature, such as vessel curvatures and bifurcations.83 These regions are characterized by disturbed oscillatory flow84 that induces upregulation proinflammatory adhesion molecules such as ICAM-1 and VCAM-1.85 An atherogenic diet also rapidly induces VCAM-1 expression in aortic endothelium in rabbit aortic organ cultures in vitro and in vivo as early as 7 days after initiation of an atherogenic diet.86 More evidence that VCAM-1 expression is regulated by proatherogenic factors came from a study that demonstrated oxLDL-induced upregulation of VCAM-1.87 Lipoproteins containing apolipoprotein CIII (apoCIII) increase VCAM-1 and ICAM-1 expression in ECs by activating PKCβ and NF-
B.88 It is noteworthy that VCAM-1 upregulation is detected mainly at atherosclerosis-prone sites of the endothelium.89 In human coronary atherosclerotic plaques, elevated expression of VCAM-1 and ICAM-1 and increased numbers of plaque intimal macrophages and T cells were observed within regions of plaque neovasculazation, but less in the arterial luminal endothelium.90 These results suggest VCAM-1– and ICAM-1–dependent recruitment of immune cells through intimal neovasculature that may participate in atherosclerosis.
Secreted phospholipases A2 (sPLA2s) play an important role in the pathophysiology of atherosclerosis (reviewed in91). One of the SPLA2s, the human group X enzyme, has the highest catalytic activity toward phosphatidylcholine, one of the major phospholipid species of cell membranes and LDL. LDL modified by human group X enzyme increases expression of adhesion molecules on the surface of HUVECs.92 These results link features of metabolic syndrome and atherosclerosis with the regulatory mechanisms controlling the expression of endothelial cell adhesion molecules involved in early atherosclerosis.
The absence of shear stress and flow in some systems is different from the more complicated situation in vivo. Using isolated perfused carotid arteries from Apoe–/– mice, it has been shown that blocking endothelial VCAM-1 with Abs or treating monocytes with the connecting segment-1 (CS-1) peptide reduced adhesion by 75% and increased monocyte rolling velocity on early atherosclerotic endothelium.93 Other evidence that CS-1 is important for monocyte recruitment come from study by Shih et al showing that treatment with mmLDL results in CS-1–dependent, but E- and P-selectin, VCAM-1–, and ICAM-1–independent increased binding of monocytes to human aortic ECs. Thus, CS-1 serves as an alternative ligand for VLA-4 expressed by endothelium in the presence of mmLDL.94 In a model of arterial injury in Apoe–/– mice, VLA-4 also mediates the recruitment of neutrophils and monocyte and thereby promotes neointimal growth.95 Inhibition of VLA-4 by monoclonal antibodies directed at 4 reduced M recruitment to atherosclerotic plaques in Apoe–/– mice.96 Interactions of VCAM-1 and VLA-4 expressed on monocytes are also involved in the regulation of monocyte recruitment97 by the stabilization of rolling interactions and prolongation of monocyte transit time.58 An important role of VCAM-1 in atherosclerosis was confirmed in a study using genetically modified Vcam1D4D/D4DLdlr–/– mice in which the fourth Ig domain of VCAM-1 has been disrupted.97 As a result of this manipulation, VCAM-1 mRNA and protein levels were reduced to 8% of control, but VCAM-1 partial expression allowed incomplete rescue of the lethal phenotype of Vcam1–/– embryos.97,98 Atherosclerosis formation was reduced in Vcam1D4D/D4D mice compared with littermate controls.97 Vcam1D4D/+ heterozygous mice on the Apoe–/– background showed a gene-dosage effect and an intermediate decrease in monocyte adhesion and fatty streak formation.99
|
ICAM-1 and β2 Integrins |
|---|
Another member of the immunoglobulin superfamily, ICAM-1, is also involved in atherosclerosis, presumably through the regulation of monocyte recruitment into atherosclerosis-prone areas. ICAM-1 expression is elevated in atherosclerosis-prone aortas and is regulated by proinflammatory stimuli. As discussed above, oxLDL induces endothelial ICAM-1 upregulation (reviewed in100). However, not only oxLDL but also native LDL increases the expression of ICAM-1 on HUVECs and elevates monocyte adhesion to the activated endothelium.101 In vivo administration of native LDL into Ldlr–/–-recipient mice induces ICAM-1 as well as VCAM-1 expression.102 In agreement with in vitro studies, immunohistochemical studies of human vessels indicate that human atherosclerotic plaques contain SMCs that express ICAM-1 in response to IL-1β.81 Pretreatment of Apoe–/– mice with Abs against ICAM-1 reduced short-term M
homing into atherosclerotic lesions by
70%.96 The absence of ICAM-1 (encoded by the Icam1 gene, Icam1–/– mice) or CD18 (encoded by the Itgb2 gene, Itgb2–/– mice) or both resulted in partial reduction of aortic lesion size, suggesting that ICAM-1 together with CD18 participates in the regulation of monocyte homing.59 In a wire injury model of carotid arteries, Icam1–/– and Apoe–/– double knockout mice showed no significant reduction in lesion size,103 suggesting that ICAM-1 is more important in spontaneous atherosclerosis than in response to injury. Activated T lymphocytes show β1- and β2-integrin–dependent adhesion to SMCs.104 Nothing is known about the role of integrins in recruitment of T and B lymphocytes to the aortic wall. |
Platelet Endothelial Cell Adhesion Molecule-1 |
|---|
Platelet endothelial cell adhesion molecule-1 (PECAM-1), also known as CD31, is a member of the immunoglobulin gene superfamily, a transmembrane glycoprotein with 6 extracellular immunoglobulin (Ig)-like domains.105 PECAM-1 is expressed at high density at the lateral borders of ECs and at lower density on the surface of hematopoietic and immune cells, including M
, neutrophils, monocytes, mast cells, natural killer cells, lymphocytes, and platelets.106 PECAM-1 gene polymorphisms and elevated soluble PECAM-1 levels are associated with severe coronary artery disease.107 In common with other adhesion molecules, PECAM-1 has important signaling properties. Within seconds, acute onset of laminar flow stimulates phosphorylation of the PECAM-1 intracellular domain, which may promote activation of PECAM-1 in atherosclerosis-prone regions of the aortic wall.108 PECAM-1 is a mechanosensitive molecule and serves as a member of a shear stress responsive complex in association with vascular endothelial cadherin (VE-cadherin) and vascular endothelial growth factor receptor 2 (VEGF-R2).109 The important role of this complex is supported by the observation that PECAM-1 (encoded by the Pecam1 gene)-deficient mice show less activation of inflammatory genes such as ICAM-1 in response to disturbed flow.109 PECAM-1 expression has been detected within atherosclerosis-prone aortas on endothelial cells as well as within the neovasculazation regions of the atherosclerotic plaques.110 Pecam1–/– and Apoe–/– mice show a significant reduction in the development of atherosclerosis compared with Apoe–/– controls (Harry B., Lansey M., Sanders J., Bruce A., Schwartz M., Ley K., unpublished data). |
Junctional Adhesion Molecules |
|---|
Under normal/noninflamed conditions, the vascular endothelium limits protein permeability and supports very little leukocyte adhesion and recruitment. In inflammation, the endothelium quickly provides "open gates" for leukocytes to migrate to the inflamed tissues. Transmigration and retention within tissue are regulated by ICAM-1 and VCAM-1 through the interaction of their intracellular domains with moezin and ezrin and formation of endothelial docking structures for adherent leukocytes.111 Diapedesis can be also regulated by CD99, CD99-related antigen (CD99L2), endothelial cell-selective adhesion molecule (ESAM), and junctional adhesion molecules (JAMs), JAM-A, JAM-B, and JAM-C. JAMs are members of the immunoglobulin superfamily, which are localized to intercellular junctions of polarized endothelial and epithelial cells but can also be expressed on circulating leukocytes and platelets.112 JAMs consist of an N-terminal signal peptide, 2 extracellular immunoglobulin-like domains, a transmembrane segment, and a cytoplasmic region.112 These proteins participate in homophilic and heterophilic cell interactions and thus regulate the extravasation of leukocytes into tissues.
|
Junctional Adhesion Molecules in Atherosclerosis |
|---|
An increasing body of evidence suggests that endothelial junctional proteins regulate the processes of leukocyte transmigration through the aortic wall and thus participate in atherosclerosis.
JAM-A is expressed in leukocytes, platelets, and endothelial and epithelial cells113,114 and participates in monocyte transmigration across ECs,115 possibly through the ligation of LFA-1.116 Very high levels of JAM-A were detected in atherosclerotic Apoe–/– mice and in atherosclerotic plaques of cardiovascular patients.117 Using Apoe–/– carotid arteries perfused ex vivo, JAM-A was shown to participate in the recruitment of monocytes and T cells into arteries.118 Deficiency of JAM-A significantly reduced neointimal lesion formation after wire injury of carotid arteries with a decrease in neointimal M content and decreased luminal expression of CCL5 derived from platelets within the injured arteries.119 These findings suggest that interactions of platelets with the aortic wall and efficient deposition of CCL5 are at least partially dependent on JAM-A engagement. In light of the increased understanding of the role of immune cells in atherosclerosis, JAM-A may also play an important role in DC motility and their capacity to migrate to lymph nodes. The absence of JAM-A on DCs results in increased DC migration to lymph nodes and enhanced contact hypersensitivity, reflecting the capacity of JAM-A to regulate activation of adaptive immunity.120 Therefore, it is likely that in the setting of atherosclerosis elevated expression of JAM-A could alter the migration capacity DCs within the different tissues.
JAM-B interacts with a VLA-4 JAM-B-dependent on T cells121 and likely is involved in lymphocyte homing.122 It is tempting to speculate that JAM-B might play an important role in the recruitment of T cells into the aortas through VLA-4/JAM-B dependent mechanism.
JAM-C is expressed on a subset of lymphocytes, platelets, and endothelial cells123–125 and participates in leukocyte-endothelial interactions and mediates leukocyte-platelet and leukocyte-endothelial interactions through Mac-1.126,123 Expression of JAM-C is weak in healthy vessels, but significantly elevated in SMCs in the neointima and in the media of human atherosclerotic vessels.127 It is likely that JAM-C is also involved in early atherosclerotic events, because the expression of JAM-C was detected in early atherosclerotic plaques as well as in the arterial wall underlying the lesions of Apoe–/– mice. Interestingly, oxLDL induces upregulation of JAM-C expression, which may lead to JAM-C–dependent leukocyte adhesion and transmigration.127 JAM-C also increases vascular permeability during inflammation and is involved in angiogenesis.128 Importantly, the disruption of JAM-C function resulted in reduced retina angiogenesis in the model of hypoxia-driven retinal neovascularization,128 suggesting possible implication of JAM-C in the processes of neovascularization in the set of advanced atherosclerosis.
The importance of platelets in thrombosis and atherosclerosis through the contribution to leukocyte adhesion to endothelium and release of multiple secretory products including inflammatory mediators and cytokines has been shown in numerous reports.129 Recently, an important functional role of JAM-C in platelet-dependent DC recruitment into atherosclerotic wall has been discovered.130 Preincubation of DCs with soluble JAM-C significantly reduced their adhesion to platelets. This result suggests that JAM-C may be involved in the regulation of the immune cell recruitment into atherosclerotic aortas.
|
Connexins |
|---|
Although connexins are not adhesion molecules, they are discussed here, because they may be relevant to immune cell recruitment to atherosclerotic lesions. Connexins may regulate leukocyte trafficking into inflamed tissues.131 Connexins form gap junctions that connect adjacent cells and permit intercellular communication.132 Gap junctions may form between leukocytes and leukocytes, or leukocytes and endothelial cells. Three connexins (Cx), Cx37, Cx40, and Cx43, are expressed on vascular endothelial cells. Their expression is upregulated by TNF-
.133 The first evidence of leukocyte communication via gap junctions came from dye transfer experiments that showed that lymphocytes and endothelial cells generate functional gap junction channels during extravasation.134 Blocking of connexins with peptides results in a modest reduction in lymphocyte transmigration across an endothelial cell monolayer.134 |
Connexins in Atherosclerosis |
|---|
The first evidence that atherosclerosis might involve connexins in the regulation of leukocyte migration was generated by a study showing strong expression of messenger RNA of connexins in M
and foam cells in human atherosclerotic carotid arteries, but not in freshly isolated blood monocytes or pure cultures of differentiated monocyte/macrophages.135 Treatment of carotid arteries with lipoprotein-derived phospholipid oxidation products (OxPAPC) alters connexin expression with upregulation of Cx37 and Cx43 in SMCs.136 In contrast to SMCs, endothelial cells treated with OxPAPC showed increased Cx43 expression and diminished expression of Cx37.136 Furthermore, dye transfer between ECs and SMCs was dramatically reduced by OxPAPC. These results provide evidence that atherosclerosis-related products may actively regulate connexin expression, and thus alter the transmigration of inflammatory cells. To shed light on the role of Cx43 in the response to vascular injury, Chadjichristos et al generated heterozygous Cx43+/– (encoded by the Gja1 gene) mice on the Ldlr–/– background to investigate a role of Cx43 in vascular injury.137 Gja1+/–/Ldlr–/– mice fed a high fat diet showed reduced neointimal formation with concurrent decreased M accumulation in the model of balloon injury.137 Because Cx43 is expressed on different cell types, SMC-targeted Gja1–/– (smGja1–/–) mice were made to investigate the role of Cx43 specifically in SMCs.138 In smGja1–/– mice, wire injury models enhanced neointimal formation and adventitial growth.138 This finding contrasts with results obtained from a model of balloon injury using smGja1+/–/Ldlr–/– mice.137 The difference may reflect a specific role of SMCs in smGja1–/– mouse model or the influence of hypercholesterolemia on the response to vascular injury. Reduced levels of Cx43 diminished the development of atherosclerosis in the thoracoabdominal aorta and in the aortic roots of Gja1+/–/Ldlr–/– mice fed a Western diet for 14 weeks.139 Atherosclerotic plaques of Gja1+/–/Ldlr–/– mice were characterized by fewer inflammatory cells and thicker fibrous caps with more collagen and SMCs, suggesting that Cx43 is not only involved in leukocyte recruitment but also in the migration of ECs and SMCs. More evidence that connexins are involved in leukocyte trafficking to atherosclerosis-prone vessels came from a study showing that Cx37 (encoded by the Gja4 gene)-deficient and Apoe–/– double knockout mice developed more aortic lesions compared with controls.140 Adoptive transfer experiments revealed that the absence of Cx37 on leukocytes but not on ECs resulted in elevated monocyte/macrophage recruitment.140 Cx37-dependent ATP release may regulate monocyte adhesion.
|
Vasa Vasorum |
|---|
Recent reports have shown that T and B cells and some M
reside with the aortic adventitia of C57BL/6 and Apoe–/– mice.10,15 Moreover, adoptive transfer experiments using flow cytometry and multiphoton-microscopy suggest that lymphocytes home to the aortas mainly through vasa vasorum.10,141,142 This observation raises a number of questions: which adhesion molecules are expressed by microvessels in vasa vasorum? How does the atherogenic environment affect the inflammatory status of the adventitia? How important are adhesion molecules expressed in the neovasculature in directing leukocyte homing from the blood? Further research is needed to fully investigate these questions. |
Concluding Remarks |
|---|
During the past decade, the important role of vascular adhesion molecules in atherosclerosis has been discovered and is now recognized as a critical factor in disease initiation and progression. Despite considerable progress in our understanding of the factors that regulate the expression of vascular adhesion molecules, many fundamental questions remain to be investigated. To date, it is still unclear what kinds of adhesion molecules are responsible for the homing of DCs and T and B lymphocytes into the arterial wall. Because the aortic adventitia is a major site of lymphocyte accumulation under normal and atherogenic conditions, further studies will have to examine the biology of microvessels that form the network of vasa vasorum. An important but still unanswered question is the role of adhesion molecules in the regulation of transmigration and retention of immune cells within the aortic wall and atherosclerotic plaques. Progress in this area can be expected from novel intravital imaging techniques including multiphoton microscopy.141 Future directions also include the development of blocking agents that might inhibit or reduce harmful recruitment of specific subsets of immune cells into the aortic wall. Although this potential therapeutic approach is very promising, it should be taken into account that inhibiting leukocyte trafficking might lead to significant reduction of host defense. Therefore, it is necessary to identify a key leukocyte subset and crucial adhesion molecules that play critical roles at the different stage of atherosclerosis development for therapeutic targeting that will minimize atherosclerosis without impairing the systemic immune response.
|
Acknowledgments |
|---|
Sources of Funding
This work was supported by NHI HL 58108 and 55798 (to K.L.) and AHA SDG 0730234N (to E.G.).
Disclosures
None.
|
Footnotes |
|---|
Original received June 4, 2007; final version accepted July 20, 2007.
|
References |
|---|
1. Lusis AJ. Atherosclerosis. Nature. 2000; 407: 233–241.[CrossRef][Medline] [Order article via Infotrieve]
2. Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med. 1999; 340: 115–126.
3. Binder CJ, Chang MK, Shaw PX, Miller YI, Hartvigsen K, Dewan A, Witztum JL. Innate and acquired immunity in atherogenesis. Nat Med. 2002; 8: 1218–1226.[CrossRef][Medline] [Order article via Infotrieve]
4. Binder CJ, Hartvigsen K, Chang MK, Miller M, Broide D, Palinski W, Curtiss LK, Corr M, Witztum JL. IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis. J Clin Invest. 2004; 114: 427–437.[CrossRef][Medline] [Order article via Infotrieve]
5. Bjorkbacka H, Kunjathoor VV, Moore KJ, Koehn S, Ordija CM, Lee MA, Means T, Halmen K, Luster AD, Golenbock DT, Freeman MW. Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nat Med. 2004; 10: 416–421.[CrossRef][Medline] [Order article via Infotrieve]
6. Hansson GK, Libby P, Schonbeck U, Yan ZQ. Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res. 2002; 91: 281–291.
7. Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis. 1986; 6: 131–138.[Medline] [Order article via Infotrieve]
8. Stemme S, Holm J, Hansson GK. T lymphocytes in human atherosclerotic plaques are memory cells expressing CD45RO and the integrin VLA-1. Arterioscler Thromb. 1992; 12: 206–211.
9. Frostegard J, Ulfgren AK, Nyberg P, Hedin U, Swedenborg J, Andersson U, Hansson GK. Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis. 1999; 145: 33–43.[CrossRef][Medline] [Order article via Infotrieve]
10. Galkina E, Kadl A, Sanders J, Varughese D, Sarembock IJ, Ley K. Lymphocyte recruitment into the aortic wall before and during development of atherosclerosis is partially L-selectin dependent. J Exp Med. 2006; 203: 1273–1282.
11. Heller EA, Liu E, Tager AM, Yuan Q, Lin AY, Ahluwalia N, Jones K, Koehn SL, Lok VM, Aikawa E, Moore KJ, Luster AD, Gerszten RE. Chemokine CXCL10 promotes atherogenesis by modulating the local balance of effector and regulatory T cells. Circulation. 2006; 113: 2301–2312.
12. Bettelli E, Oukka M, Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 2007; 8: 345–350.[CrossRef][Medline] [Order article via Infotrieve]
13. Parums D, Mitchinson MJ. Demonstration of immunoglobulin in the neighbourhood of advanced atherosclerotic plaques. Atherosclerosis. 1981; 38: 211–216.[CrossRef][Medline] [Order article via Infotrieve]
14. Zhou X, Hansson GK. Detection of B cells and proinflammatory cytokines in atherosclerotic plaques of hypercholesterolaemic apolipoprotein E knockout mice. Scand J Immunol. 1999; 50: 25–30.[CrossRef][Medline] [Order article via Infotrieve]
15. Moos MP, John N, Grabner R, Nossmann S, Gunther B, Vollandt R, Funk CD, Kaiser B, Habenicht AJ. The lamina adventitia is the major site of immune cell accumulation in standard chow-fed apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2005; 25: 2386–2391.
16. Jongstra-Bilen J, Haidari M, Zhu SN, Chen M, Guha D, Cybulsky MI. Low-grade chronic inflammation in regions of the normal mouse arterial intima predisposed to atherosclerosis. J Exp Med. 2006; 203: 2073–2083.
17. Bobryshev YV. Monocyte recruitment and foam cell formation in atherosclerosis. Micron. 2006; 37: 208–222.[CrossRef][Medline] [Order article via Infotrieve]
18. Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol. 2006; 6: 508–519.[CrossRef][Medline] [Order article via Infotrieve]
19. Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity. 2003; 19: 71–82.[CrossRef][Medline] [Order article via Infotrieve]
20. Swirski FK, Libby P, Aikawa E, Alcaide P, Luscinskas FW, Weissleder R, Pittet MJ. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest. 2007; 117: 195–205.[CrossRef][Medline] [Order article via Infotrieve]
21. Wick G, Romen M, Amberger A, Metzler B, Mayr M, Falkensammer G, Xu Q. Atherosclerosis, autoimmunity, and vascular-associated lymphoid tissue. FASEB J. 1997; 11: 1199–1207.[Medline] [Order article via Infotrieve]
22. Bobryshev YV, Lord RS. Ultrastructural recognition of cells with dendritic cell morphology in human aortic intima. Contacting interactions of Vascular Dendritic Cells in athero-resistant and athero-prone areas of the normal aorta. Arch Histol Cytol. 1995; 58: 307–322.[Medline] [Order article via Infotrieve]
23. Yilmaz A, Lochno M, Traeg F, Cicha I, Reiss C, Stumpf C, Raaz D, Anger T, Amann K, Probst T, Ludwig J, Daniel WG, Garlichs CD. Emergence of dendritic cells in rupture-prone regions of vulnerable carotid plaques. Atherosclerosis. 2004; 176: 101–110.[CrossRef][Medline] [Order article via Infotrieve]
24. Tacke F, Alvarez D, Kaplan TJ, Jakubzick C, Spanbroek R, Llodra J, Garin A, Liu J, Mack M, van RN, Lira SA, Habenicht AJ, Randolph GJ. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest. 2007; 117: 185–194.[CrossRef][Medline] [Order article via Infotrieve]
25. Braunersreuther V, Mach F. Leukocyte recruitment in atherosclerosis: potential targets for therapeutic approaches? Cell Mol Life Sci. 2006; 63: 2079–2088.[CrossRef][Medline] [Order article via Infotrieve]
26. Dong ZM, Wagner DD. Leukocyte-endothelium adhesion molecules in atherosclerosis. J Lab Clin Med. 1998; 132: 369–375.[CrossRef][Medline] [Order article via Infotrieve]
27. Eriksson EE. Leukocyte recruitment to atherosclerotic lesions, a complex web of dynamic cellular and molecular interactions. Curr Drug Targets Cardiovasc Haematol Disord. 2003; 3: 309–325.[CrossRef][Medline] [Order article via Infotrieve]
28. Huo Y, Ley K. Adhesion molecules and atherogenesis. Acta Physiol Scand. 2001; 173: 35–43.[CrossRef][Medline] [Order article via Infotrieve]
29. Butcher EC. Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell. 1991; 67: 1033–1036.[CrossRef][Medline] [Order article via Infotrieve]
30. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994; 76: 301–314.[CrossRef][Medline] [Order article via Infotrieve]
31. Hidalgo A, Peired AJ, Wild MK, Vestweber D, Frenette PS. Complete identification of E-selectin ligands on neutrophils reveals distinct functions of PSGL-1, ESL-1, and CD44. Immunity. 2007; 26: 477–489.[CrossRef][Medline] [Order article via Infotrieve]
32. Zarbock A, Lowell CA, Ley K. Spleen Tyrosine Kinase Syk Is Necessary for E-Selectin-Induced alpha(L)beta(2) Integrin-Mediated Rolling on Intercellular Adhesion Molecule-1. Immunity. 2007; 26: 773–783.[CrossRef][Medline] [Order article via Infotrieve]
33. Ley K, Laudanna C, Cybulsky M, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol. 2007.
34. McEver RP. Selectins: lectins that initiate cell adhesion under flow. Curr Opin Cell Biol. 2002; 14: 581–586.[CrossRef][Medline] [Order article via Infotrieve]
35. Bistrup A, Tsay D, Shenoy P, Singer MS, Bangia N, Luther SA, Cyster JG, Ruddle NH, Rosen SD. Detection of a sulfotransferase (HEC-GlcNAc6ST) in high endothelial venules of lymph nodes and in high endothelial venule-like vessels within ectopic lymphoid aggregates: relationship to the MECA-79 epitope. Am J Pathol. 2004; 164: 1635–1644.
36. Eriksson EE, Xie X, Werr J, Thoren P, Lindbom L. Importance of primary capture and L-selectin-dependent secondary capture in leukocyte accumulation in inflammation and atherosclerosis in vivo. J Exp Med. 2001; 194: 205–218.
37. Sperandio M, Smith ML, Forlow SB, Olson TS, Xia L, McEver RP, Ley K. P-selectin glycoprotein ligand-1 mediates L-selectin-dependent leukocyte rolling in venules. J Exp Med. 2003; 197: 1355–1363.
38. Ley K, Kansas GS. Selectins in T-cell recruitment to non-lymphoid tissues and sites of inflammation. Nat Rev Immunol. 2004; 4: 325–335.[CrossRef][Medline] [Order article via Infotrieve]
39. Katayama Y, Hidalgo A, Furie BC, Vestweber D, Furie B, Frenette PS. PSGL-1 participates in E-selectin-mediated progenitor homing to bone marrow: evidence for cooperation between E-selectin ligands and alpha4 integrin. Blood. 2003; 102: 2060–2067.
40. Katayama Y, Hidalgo A, Chang J, Peired A, Frenette PS. CD44 is a physiological E-selectin ligand on neutrophils. J Exp Med. 2005; 201: 1183–1189.
41. Steegmaier M, Levinovitz A, Isenmann S, Borges E, Lenter M, Kocher HP, Kleuser B, Vestweber D. The E-selectin-ligand ESL-1 is a variant of a receptor for fibroblast growth factor. Nature. 1995; 373: 615–620.[CrossRef][Medline] [Order article via Infotrieve]
42. Alcaide P, King SL, Dimitroff CJ, Lim YC, Fuhlbrigge RC, Luscinskas FW. The 130-kDa glycoform of CD43 functions as an E-selectin ligand for activated Th1 cells in vitro and in delayed-type hypersensitivity reactions in vivo. J. Invest Dermatol. 2007; 127: 1964–1972.[CrossRef][Medline] [Order article via Infotrieve]
43. Fuhlbrigge RC, King SL, Sackstein R, Kupper TS. CD43 is a ligand for E-selectin on CLA+ human T cells. Blood. 2006; 107: 1421–1426.
44. Matsumoto M, Atarashi K, Umemoto E, Furukawa Y, Shigeta A, Miyasaka M, Hirata T. CD43 functions as a ligand for E-Selectin on activated T cells. J Immunol. 2005; 175: 8042–8050.
45. Kunkel EJ, Chomas JE, Ley K. Role of primary and secondary capture for leukocyte accumulation in vivo. Circ Res. 1998; 82: 30–38.
46. Uchimura K, Rosen SD. Sulfated L-selectin ligands as a therapeutic target in chronic inflammation. Trends Immunol. 2006; 27: 559–565.[CrossRef][Medline] [Order article via Infotrieve]
47. Brown MS, Goldstein JL. Biomedicine. Lowering LDL–not only how low, but how long? Science. 2006; 311: 1721–1723.
48. Gleissner CA, Leitiniger N, Ley K. Effects of native and modified low-density lipoproteins on monocyte recruitment in atherosclerosis. Hypertension. 2007; 50: 276–283.
49. Leitinger N. Oxidized phospholipids as modulators of inflammation in atherosclerosis. Curr Opin Lipidol. 2003; 14: 421–430.[CrossRef][Medline] [Order article via Infotrieve]
50. Matsuura E, Kobayashi K, Tabuchi M, Lopez LR. Oxidative modification of low-density lipoprotein and immune regulation of atherosclerosis. Prog Lipid Res. 2006; 45: 466–486.[CrossRef][Medline] [Order article via Infotrieve]
51. Carr AC, McCall MR, Frei B. Oxidation of LDL by myeloperoxidase and reactive nitrogen species: reaction pathways and antioxidant protection. Arterioscler Thromb Vasc Biol. 2000; 20: 1716–1723.
52. Skalen K, Gustafsson M, Rydberg EK, Hulten LM, Wiklund O, Innerarity TL, Boren J. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature. 2002; 417: 750–754.[CrossRef][Medline] [Order article via Infotrieve]
53. Chen H, Li D, Saldeen T, Mehta JL. Transforming growth factor-beta(1) modulates oxidatively modified LDL-induced expression of adhesion molecules: role of LOX-1. Circ Res. 2001; 89: 1155–1160.
54. Gebuhrer V, Murphy JF, Bordet JC, Reck MP, McGregor JL. Oxidized low-density lipoprotein induces the expression of P-selectin (GMP140/PADGEM/CD62) on human endothelial cells. Biochem J. 1995; 306 (Pt 1): 293–298.[Medline] [Order article via Infotrieve]
55. Johnson-Tidey RR, McGregor JL, Taylor PR, Poston RN. Increase in the adhesion molecule P-selectin in endothelium overlying atherosclerotic plaques. Coexpression with intercellular adhesion molecule-1. Am J Pathol. 1994; 144: 952–961.[Abstract]
56. Sakai A, Kume N, Nishi E, Tanoue K, Miyasaka M, Kita T. P-selectin and vascular cell adhesion molecule-1 are focally expressed in aortas of hypercholesterolemic rabbits before intimal accumulation of macrophages and T lymphocytes. Arterioscler Thromb Vasc Biol. 1997; 17: 310–316.
57. Paez A, Mendez-Cruz AR, Varela E, Rodriguez E, Guevara J, Flores-Romo L, Montano LF, Masso FA. HUVECs from newborns with a strong family history of myocardial infarction overexpress adhesion molecules and react abnormally to stimulating agents. Clin Exp Immunol. 2005; 141: 449–458.[CrossRef][Medline] [Order article via Infotrieve]
58. Ramos CL, Huo Y, Jung U, Ghosh S, Manka DR, Sarembock IJ, Ley K. Direct demonstration of P-selectin- and VCAM-1-dependent mononuclear cell rolling in early atherosclerotic lesions of apolipoprotein E-deficient mice. Circ Res. 1999; 84: 1237–1244.
59. Nageh MF, Sandberg ET, Marotti KR, Lin AH, Melchior EP, Bullard DC, Beaudet AL. Deficiency of inflammatory cell adhesion molecules protects against atherosclerosis in mice. Arterioscler Thromb Vasc Biol. 1997; 17: 1517–1520.
60. Dong ZM, Brown AA, Wagner DD. Prominent role of P-selectin in the development of advanced atherosclerosis in ApoE-deficient mice. Circulation. 2000; 101: 2290–2295.
61. Johnson RC, Chapman SM, Dong ZM, Ordovas JM, Mayadas TN, Herz J, Hynes RO, Schaefer EJ, Wagner DD. Absence of P-selectin delays fatty streak formation in mice. J Clin Invest. 1997; 99: 1037–1043.[Medline] [Order article via Infotrieve]
62. Burger PC, Wagner DD. Platelet P-selectin facilitates atherosclerotic lesion development. Blood. 2003; 101: 2661–2666.
63. Manka D, Forlow SB, Sanders JM, Hurwitz D, Bennett DK, Green SA, Ley K, Sarembock IJ. Critical role of platelet P-selectin in the response to arterial injury in apolipoprotein-E-deficient mice. Arterioscler Thromb Vasc Biol. 2004; 24: 1124–1129.
64. Huo Y, Schober A, Forlow SB, Smith DF, Hyman MC, Jung S, Littman DR, Weber C, Ley K. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med. 2003; 9: 61–67.[CrossRef][Medline] [Order article via Infotrieve]
65. Huo Y, Ley KF. Role of platelets in the development of atherosclerosis. Trends Cardiovasc Med. 2004; 14: 18–22.[CrossRef][Medline] [Order article via Infotrieve]
66. Stocker CJ, Sugars KL, Harari OA, Landis RC, Morley BJ, Haskard DO. TNF-alpha, IL-4, and IFN-gamma regulate differential expression of P- and E-selectin expression by porcine aortic endothelial cells. J Immunol. 2000; 164: 3309–3315.
67. Yu G, Rux AH, Ma P, Bdeir K, Sachais BS. Endothelial expression of E-selectin is induced by the platelet-specific chemokine platelet factor 4 through LRP in an NF-kappaB-dependent manner. Blood. 2005; 105: 3545–3551.
68. Davies MJ, Gordon JL, Gearing AJ, Pigott R, Woolf N, Katz D, Kyriakopoulos A. The expression of the adhesion molecules ICAM-1, VCAM-1, PECAM, and E-selectin in human atherosclerosis. J Pathol. 1993; 171: 223–229.[CrossRef][Medline] [Order article via Infotrieve]
69. Collins RG, Velji R, Guevara NV, Hicks MJ, Chan L, Beaudet AL. P-Selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice. J Exp Med. 2000; 191: 189–194.
70. Dong ZM, Chapman SM, Brown AA, Frenette PS, Hynes RO, Wagner DD. The combined role of P- and E-selectins in atherosclerosis. J Clin Invest. 1998; 102: 145–152.[Medline] [Order article via Infotrieve]
71. Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell. 2002; 110: 673–687.[CrossRef][Medline] [Order article via Infotrieve]
72. Luo BH, Carman CV, Springer TA. Structural basis of integrin regulation and signaling. Annu Rev Immunol. 2007; 25: 619–647.[CrossRef][Medline] [Order article via Infotrieve]
73. Hogg N, Henderson R, Leitinger B, McDowall A, Porter J, Stanley P. Mechanisms contributing to the activity of integrins on leukocytes. Immunol Rev. 2002; 186: 164–171.[CrossRef][Medline] [Order article via Infotrieve]
74. Kurzinger K, Reynolds T, Germain RN, Davignon D, Martz E, Springer TA. A novel lymphocyte function-associated antigen (LFA-1): cellular distribution, quantitative expression, and structure. J Immunol. 1981; 127: 596–602.[Abstract]
75. Luster AD, Alon R, von Andrian UH. Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol. 2005; 6: 1182–1190.[CrossRef][Medline] [Order article via Infotrieve]
76. Springer TA. Adhesion receptors of the immune system. Nature. 1990; 346: 425–434.[CrossRef][Medline] [Order article via Infotrieve]
77. Elices MJ, Osborn L, Takada Y, Crouse C, Luhowskyj S, Hemler M, and Lobb R. VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site. Cell. 1990; 60: 577–584.[CrossRef][Medline] [Order article via Infotrieve]
78. Guan JL, Hynes RO. Lymphoid cells recognize an alternatively spliced segment of fibronectin via the integrin receptor alpha 4 beta 1. Cell. 1990; 60: 53–61.[CrossRef][Medline] [Order article via Infotrieve]
79. Butcher EC, Williams M, Youngman K, Rott L, Briskin M. Lymphocyte trafficking and regional immunity. Adv Immunol. 1999; 72: 209–253.[Medline] [Order article via Infotrieve]
80. Cybulsky MI, Gimbrone MA Jr. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science. 1991; 251: 788–791.
81. Couffinhal T, Duplaa C, Moreau C, Lamaziere JM, Bonnet J. Regulation of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in human vascular smooth muscle cells. Circ Res. 1994; 74: 225–234.
82. Ramana KV, Bhatnagar A, Srivastava SK. Inhibition of aldose reductase attenuates TNF-alpha-induced expression of adhesion molecules in endothelial cells. FASEB J. 2004; 18: 1209–1218.
83. Garin G, Berk BC. Flow-mediated signaling modulates endothelial cell phenotype. Endothelium. 2006; 13: 375–384.[CrossRef][Medline] [Order article via Infotrieve]
84. VanderLaan PA, Reardon CA, Getz GS. Site specificity of atherosclerosis: site-selective responses to atherosclerotic modulators. Arterioscler Thromb Vasc Biol. 2004; 24: 12–22.
85. Brooks AR, Lelkes PI, Rubanyi GM. Gene expression profiling of human aortic endothelial cells exposed to disturbed flow and steady laminar flow. Physiol Genomics. 2002; 9: 27–41.
86. Li H, Cybulsky MI, Gimbrone MA Jr, Libby P. An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium. Arterioscler Thromb. 1993; 13: 197–204.
87. Khan BV, Parthasarathy SS, Alexander RW, Medford RM. Modified low density lipoprotein and its constituents augment cytokine-activated vascular cell adhesion molecule-1 gene expression in human vascular endothelial cells. J Clin Invest. 1995; 95: 1262–1270.[Medline] [Order article via Infotrieve]
88. Kawakami A, Aikawa M, Alcaide P, Luscinskas FW, Libby P, Sacks FM. Apolipoprotein CIII induces expression of vascular cell adhesion molecule-1 in vascular endothelial cells and increases adhesion of monocytic cells. Circulation. 2006; 114: 681–687.
89. Nakashima Y, Raines EW, Plump AS, Breslow JL, Ross R. Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse. Arterioscler Thromb Vasc Biol. 1998; 18: 842–851.
90. O’Brien KD, McDonald TO, Chait A, Allen MD, Alpers CE. Neovascular expression of E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in human atherosclerosis and their relation to intimal leukocyte content. Circulation. 1996; 93: 672–682.
91. Macphee CH, Nelson JJ, Zalewski A. Lipoprotein-associated phospholipase A2 as a target of therapy. Curr Opin Lipidol. 2005; 16: 442–446.[Medline] [Order article via Infotrieve]
92. Karabina SA, Brocheriou I, Le NG, Agrapart M, Durand H, Gelb M, Lambeau G, Ninio E. Atherogenic properties of LDL particles modified by human group X secreted phospholipase A2 on human endothelial cell function. FASEB J. 2006; 20: 2547–2549.
93. Huo Y, Hafezi-Moghadam A, Ley K. Role of vascular cell adhesion molecule-1 and fibronectin connecting segment-1 in monocyte rolling and adhesion on early atherosclerotic lesions. Circ Res. 2000; 87: 153–159.
94. Shih PT, Elices MJ, Fang ZT, Ugarova TP, Strahl D, Territo MC, Frank JS, Kovach NL, Cabanas C, Berliner JA, Vora DK. Minimally modified low-density lipoprotein induces monocyte adhesion to endothelial connecting segment-1 by activating beta1 integrin. J Clin Invest. 1999; 103: 613–625.[Medline] [Order article via Infotrieve]
95. Barringhaus KG, Phillips JW, Thatte JS, Sanders JM, Czarnik AC, Bennett DK, Ley KF, Sarembock IJ. Alpha4beta1 integrin (VLA-4) blockade attenuates both early and late leukocyte recruitment and neointimal growth following carotid injury in apolipoprotein E–/– mice. J Vasc Res. 2004; 41: 252–260.[CrossRef][Medline] [Order article via Infotrieve]
96. Patel SS, Thiagarajan R, Willerson JT, Yeh ET. Inhibition of alpha4 integrin and ICAM-1 markedly attenuate macrophage homing to atherosclerotic plaques in ApoE-deficient mice. Circulation. 1998; 97: 75–81.
97. Cybulsky MI, Iiyama K, Li H, Zhu S, Chen M, Iiyama M, Davis V, Gutierrez-Ramos JC, Connelly PW, Milstone DS. A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest. 2001; 107: 1255–1262.[Medline] [Order article via Infotrieve]
98. Gurtner GC, Davis V, Li H, McCoy MJ, Sharpe A, Cybulsky MI. Targeted disruption of the murine VCAM1 gene: essential role of VCAM-1 in chorioallantoic fusion and placentation. Genes Dev. 1995; 9: 1–14.[Medline] [Order article via Infotrieve]
99. Dansky HM, Barlow CB, Lominska C, Sikes JL, Kao C, Weinsaft J, Cybulsky MI, Smith JD. Adhesion of monocytes to arterial endothelium and initiation of atherosclerosis are critically dependent on vascular cell adhesion molecule-1 gene dosage. Arterioscler Thromb Vasc Biol. 2001; 21: 1662–1667.
100. Kita T, Kume N, Minami M, Hayashida K, Murayama T, Sano H, Moriwaki H, Kataoka H, Nishi E, Horiuchi H, Arai H, Yokode M. Role of oxidized LDL in atherosclerosis. Ann N Y Acad Sci. 2001; 947: 199–205.[CrossRef][Medline] [Order article via Infotrieve]
101. Smalley DM, Lin JH, Curtis ML, Kobari Y, Stemerman MB, Pritchard KA Jr. Native LDL increases endothelial cell adhesiveness by inducing intercellular adhesion molecule-1. Arterioscler Thromb Vasc Biol. 1996; 16: 585–590.
102. Verna L, Ganda C, Stemerman MB. In vivo low-density lipoprotein exposure induces intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 correlated with activator protein-1 expression. Arterioscler Thromb Vasc Biol. 2006; 26: 1344–1349.
103. Manka D, Collins RG, Ley K, Beaudet AL, Sarembock IJ. Absence of p-selectin, but not intercellular adhesion molecule-1, attenuates neointimal growth after arterial injury in apolipoprotein e-deficient mice. Circulation. 2001; 103: 1000–1005.
104. Stemme S, Patarroyo M, Hansson GK. Adhesion of activated T lymphocytes to vascular smooth muscle cells and dermal fibroblasts is mediated by beta 1- and beta 2-integrins. Scand J Immunol. 1992; 36: 233–242.[CrossRef][Medline] [Order article via Infotrieve]
105. Newman PJ, Berndt MC, Gorski J, White GC, Lyman S, Paddock C, Muller WA. PECAM-1 (CD31) cloning and relation to adhesion molecules of the immunoglobulin gene superfamily. Science. 1990; 247: 1219–1222.
106. Muller WA. Leukocyte-endothelial-cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol. 2003; 24: 327–334.[Medline] [Order article via Infotrieve]
107. Elrayess MA, Webb KE, Flavell DM, Syvanne M, Taskinen MR, Frick MH, Nieminen MS, Kesaniemi YA, Pasternack A, Jukema JW, Kastelein JJ, Zwinderman AH, Humphries SE. A novel functional polymorphism in the PECAM-1 gene (53G>A) is associated with progression of atherosclerosis in the LOCAT and REGRESS studies. Atherosclerosis. 2003; 168: 131–138.[CrossRef][Medline] [Order article via Infotrieve]
108. Newman PJ, Newman DK. Signal transduction pathways mediated by PECAM-1: new roles for an old molecule in platelet and vascular cell biology. Arterioscler Thromb Vasc Biol. 2003; 23: 953–964.
109. Tzima E, Irani-Tehrani M, Kiosses WB, Dejana E, Schultz DA, Engelhardt B, Cao G, DeLisser H, Schwartz MA. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature. 2005; 437: 426–431.[CrossRef][Medline] [Order article via Infotrieve]
110. Li C, Mollahan P, Baguneid MS, McMahon RF, Kumar P, Walker MG, Freemont AJ, Kumar S. A comparative study of neovascularisation in atherosclerotic plaques using CD31, CD105 and transforminggrowthfactor (TGF) beta 1. Pathobiology. 2006; 73: 192–197.[CrossRef][Medline] [Order article via Infotrieve]
111. Barreiro O, Yanez-Mo M, Serrador JM, Montoya MC, Vicente-Manzanares M, Tejedor R, Furthmayr H, Sanchez-Madrid F. Dynamic interaction of VCAM-1 and ICAM-1 with moesin and ezrin in a novel endothelial docking structure for adherent leukocytes. J Cell Biol. 2002; 157: 1233–1245.
112. Mandell KJ, Parkos CA. The JAM family of proteins. Adv Drug Deliv Rev. 2005; 57: 857–867.[CrossRef][Medline] [Order article via Infotrieve]
113. Imhof BA, Aurrand-Lions M. Adhesion mechanisms regulating the migration of monocytes. Nat Rev Immunol. 2004; 4: 432–444.[CrossRef][Medline] [Order article via Infotrieve]
114. Bazzoni G, Dejana E. Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol Rev. 2004; 84: 869–901.
115. Martin-Padura I, Lostaglio S, Schneemann M, Williams L, Romano M, Fruscella P, Panzeri C, Stoppacciaro A, Ruco L, Villa A, Simmons D, Dejana E. Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J Cell Biol. 1998; 142: 117–127.
116. Ostermann G, Weber KS, Zernecke A, Schroder A, Weber C. JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes. Nat Immunol. 2002; 3: 151–158.[CrossRef][Medline] [Order article via Infotrieve]
117. Babinska A, Azari BM, Salifu MO, Liu R, Jiang XC, Sobocka MB, Boo D, Al KG, Deitch JS, Marmur JD, Ehrlich YH, Kornecki E. The F11 receptor (F11R/JAM-A) in atherothrombosis: overexpression of F11R in atherosclerotic plaques. Thromb Haemost. 2007; 97: 272–281.[Medline] [Order article via Infotrieve]
118. Ostermann G, Fraemohs L, Baltus T, Schober A, Lietz M, Zernecke A, Liehn EA, Weber C. Involvement of JAM-A in mononuclear cell recruitment on inflamed or atherosclerotic endothelium: inhibition by soluble JAM-A. Arterioscler Thromb Vasc Biol. 2005; 25: 729–735.
119. Zernecke A, Liehn EA, Fraemohs L, von Hundelshausen P, Koenen RR, Corada M, Dejana E, Weber C. Importance of junctional adhesion molecule-A for neointimal lesion formation and infiltration in atherosclerosis-prone mice. Arterioscler Thromb Vasc Biol. 2006; 26: e10–e13.
120. Cera MR, Del PA, Vecchi A, Corada M, Martin-Padura I, Motoike T, Tonetti P, Bazzoni G, Vermi W, Gentili F, Bernasconi S, Sato TN, Mantovani A, Dejana E. Increased DC trafficking to lymph nodes and contact hypersensitivity in junctional adhesion molecule-A-deficient mice. J Clin Invest. 2004; 114: 729–738.[CrossRef][Medline] [Order article via Infotrieve]
121. Cunningham SA, Rodriguez JM, Arrate MP, Tran TM, Brock TA. JAM2 interacts with alpha4beta1. Facilitation by JAM3. J Biol Chem. 2002; 277: 27589–27592.
122. Palmeri D, van ZA, Huang CC, Hemmerich S, Rosen SD. Vascular endothelial junction-associated molecule, a novel member of the immunoglobulin superfamily, is localized to intercellular boundaries of endothelial cells. J Biol Chem. 2000; 275: 19139–19145.
123. Santoso S, Sachs UJ, Kroll H, Linder M, Ruf A, Preissner KT, Chavakis T. The junctional adhesion molecule 3 (JAM-3) on human platelets is a counterreceptor for the leukocyte integrin Mac-1. J Exp Med. 2002; 196: 679–691.
124. Liang TW, Chiu HH, Gurney A, Sidle A, Tumas DB, Schow P, Foster J, Klassen T, Dennis K, DeMarco RA, Pham T, Frantz G, Fong S. Vascular endothelial-junctional adhesion molecule (VE-JAM)/JAM 2 interacts with T, NK, and dendritic cells through JAM 3. J Immunol. 2002; 168: 1618–1626.
125. Johnson-Leger CA, urrand-Lions M, Beltraminelli N, Fasel N, Imhof BA. Junctional adhesion molecule-2 (JAM-2) promotes lymphocyte transendothelial migration. Blood. 2002; 100: 2479–2486.
126. Chavakis T, Keiper T, Matz-Westphal R, Hersemeyer K, Sachs UJ, Nawroth PP, Preissner KT, Santoso S. The junctional adhesion molecule-C promotes neutrophil transendothelial migration in vitro and in vivo. J Biol Chem. 2004; 279: 55602–55608.
127. Keiper T, Al-Fakhri N, Chavakis E, Athanasopoulos AN, Isermann B, Herzog S, Saffrich R, Hersemeyer K, Bohle RM, Haendeler J, Preissner KT, Santoso S, Chavakis T. The role of junctional adhesion molecule-C (JAM-C) in oxidized LDL-mediated leukocyte recruitment. FASEB J. 2005; 19: 2078–2080.
128. Orlova VV, Economopoulou M, Lupu F, Santoso S, Chavakis T. Junctional adhesion molecule-C regulates vascular endothelial permeability by modulating VE-cadherin-mediated cell-cell contacts. J Exp Med. 2006; 203: 2703–2714.
129. von Hundelshausen P, Weber C. Platelets as immune cells: bridging inflammation and cardiovascular disease. Circ Res. 2007; 100: 27–40.
130. Langer HF, Daub K, Braun G, Schonberger T, May AE, Schaller M, Stein GM, Stellos K, Bueltmann A, Siegel-Axel D, Wendel HP, Aebert H, Roecken M, Seizer P, Santoso S, Wesselborg S, Brossart P, Gawaz M. Platelets recruit human dendritic cells via Mac-1/ JAM-C interaction and modulate dendritic cell function in vitro. Arterioscler Thromb Vasc Biol. 2007; 27: 1463–1470.
131. Wong CW, Christen T, Kwak BR. Connexins in leukocytes: shuttling messages? Cardiovasc Res. 2004; 62: 357–367.
132. Evans WH, Martin PE. Gap junctions: structure and function (Review). Mol Membr Biol. 2002; 19: 121–136.[CrossRef][Medline] [Order article via Infotrieve]
133. van Rijen HVM, van Kempen MJA, Postma S, Jongsma HJ. Tumor 37 necrosis factor alpha alters the expression of connexin 43, connexin 37 and connexin 3, in human umbilical vein endothelial cells. Cytokine. 1998; 10: 258–264.[CrossRef][Medline] [Order article via Infotrieve]
134. Oviedo-Orta E, Errington RJ, Evans WH. Gap junction intercellular communication during lymphocyte transendothelial migration. Cell Biology International. 2002; 26: 253–263.[CrossRef][Medline] [Order article via Infotrieve]
135. Polacek D, Lal R, Volin MV, Davies PF. Gap junctional communication between vascular cells. Induction of connexin43 messenger RNA in macrophage foam cells of atherosclerotic lesions. Am J Pathol. 1993; 142: 593–606.[Abstract]
136. Isakson BE, Kronke G, Kadl A, Leitinger N, Duling BR. Oxidized phospholipids alter vascular connexin expression, phosphorylation, and heterocellular communication. Arterioscler Thromb Vasc Biol. 2006; 26: 2216–2221.
137. Chadjichristos CE, Matter CM, Roth I, Sutter E, Pelli G, Luscher TF, Chanson M, Kwak BR. Reduced connexin43 expression limits neointima formation after balloon distension injury in hypercholesterolemic mice. Circulation. 2006; 113: 2835–2843.
138. Liao Y, Regan CP, Manabe I, Owens GK, Day KH, Damon DN, Duling BR Smooth Muscle-Targeted Knockout of Connexin43 Enhances Neointimal Formation in Response to Vascular Injury. Arterioscler Thromb Vasc Biol. 2007; 27: 1037–1042.
139. Kwak BR, Veillard N, Pelli G, Mulhaupt F, James RW, Chanson M, Mach F. Reduced connexin43 expression inhibits atherosclerotic lesion formation in low-density lipoprotein receptor-deficient mice. Circulation. 2003; 107: 1033–1039.
140. Wong CW, Christen T, Roth I, Chadjichristos CE, Derouette JP, Foglia BF, Chanson M, Goodenough DA, Kwak BR. Connexin37 protects against atherosclerosis by regulating monocyte adhesion. Nat Med. 2006; 12: 950–954.[CrossRef][Medline] [Order article via Infotrieve]
141. Maffia P, Zinselmeyer BH, Ialenti A, Kennedy S, Baker AH, McInnes IB, Brewer JM, Garside P. Images in cardiovascular medicine. Multiphoton microscopy for 3-dimensional imaging of lymphocyte recruitment into apolipoprotein-E-deficient mouse carotid artery. Circulation. 2007; 115: e326–e328.
142. Moulton KS, Vakili K, Zurakowski D, Soliman M, Butterfield C, Sylvin E, Lo KM, Gillies S, Javaherian K, Folkman J. Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis. Proc Natl Acad Sci U S A. 2003; 100: 4736–4741.
This article has been cited by other articles:
 |
|
 |
|
  E. Koltsova and K. Ley Tyrosine Sulfation of Leukocyte Adhesion Molecules and Chemokine Receptors Promotes Atherosclerosis Arterioscler Thromb Vasc Biol, November 1, 2009; 29(11): 1709 - 1711. [Full Text] [PDF]
|
|
|
|
|
|
A. D. Westmuckett and K. L. Moore Lack of Tyrosylprotein Sulfotransferase Activity in Hematopoietic Cells Drastically Attenuates Atherosclerosis in Ldlr-/- Mice Arterioscler Thromb Vasc Biol, November 1, 2009; 29(11): 1730 - 1736. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. K. Swirski, R. Weissleder, and M. J. Pittet Heterogeneous In Vivo Behavior of Monocyte Subsets in Atherosclerosis Arterioscler Thromb Vasc Biol, October 1, 2009; 29(10): 1424 - 1432. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L.-N. Zhang, J. Vincelette, Y. Cheng, U. Mehra, D. Chen, S.-K. Anandan, R. Gless, H. K. Webb, and Y.-X. Wang Inhibition of Soluble Epoxide Hydrolase Attenuated Atherosclerosis, Abdominal Aortic Aneurysm Formation, and Dyslipidemia Arterioscler Thromb Vasc Biol, September 1, 2009; 29(9): 1265 - 1270. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Li, E. J. Barrett, S.-H. Ko, W. Cao, and Z. Liu Insulin and Insulin-Like Growth Factor-I Receptors Differentially Mediate Insulin-Stimulated Adhesion Molecule Production by Endothelial Cells Endocrinology, August 1, 2009; 150(8): 3475 - 3482. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. L. Thurberg, J. T. Fallon, R. Mitchell, T. Aretz, R. E. Gordon, and M. W. O'Callaghan Cardiac Microvascular Pathology in Fabry Disease: Evaluation of Endomyocardial Biopsies Before and After Enzyme Replacement Therapy Circulation, May 19, 2009; 119(19): 2561 - 2567. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. CELLA, F. VIANELLO, F. COZZI, H. MAROTTA, F. TONA, G. SAGGIORATO, O. IQBAL, and J. FAREED Effect of Bosentan on Plasma Markers of Endothelial Cell Activity in Patients with Secondary Pulmonary Hypertension Related to Connective Tissue Diseases J Rheumatol, April 1, 2009; 36(4): 760 - 767. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Nold-Petry, M. F. Nold, J. A. Zepp, S.-H. Kim, N. F. Voelkel, and C. A. Dinarello IL-32-dependent effects of IL-1{beta} on endothelial cell functions PNAS, March 10, 2009; 106(10): 3883 - 3888. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. G. Rajapakse, X.-F. Ming, J. M. Carvas, and Z. Yang The hexosamine biosynthesis inhibitor azaserine prevents endothelial inflammation and dysfunction under hyperglycemic condition through antioxidant effects Am J Physiol Heart Circ Physiol, March 1, 2009; 296(3): H815 - H822. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Goel, B. R. Schrank, S. Arora, B. Boylan, B. Fleming, H. Miura, P. J. Newman, R. C. Molthen, and D. K. Newman Site-Specific Effects of PECAM-1 on Atherosclerosis in LDL Receptor-Deficient Mice Arterioscler Thromb Vasc Biol, November 1, 2008; 28(11): 1996 - 2002. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Gleissner, P. von Hundelshausen, and K. Ley Platelet Chemokines in Vascular Disease Arterioscler Thromb Vasc Biol, November 1, 2008; 28(11): 1920 - 1927. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Smedlund and G. Vazquez Involvement of Native TRPC3 Proteins in ATP-Dependent Expression of VCAM-1 and Monocyte Adherence in Coronary Artery Endothelial Cells Arterioscler Thromb Vasc Biol, November 1, 2008; 28(11): 2049 - 2055. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Kisucka, A. K. Chauhan, I. S. Patten, A. Yesilaltay, C. Neumann, R. A. Van Etten, M. Krieger, and D. D. Wagner Peroxiredoxin1 Prevents Excessive Endothelial Activation and Early Atherosclerosis Circ. Res., September 12, 2008; 103(6): 598 - 605. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Orasanu, O. Ziouzenkova, P. R. Devchand, V. Nehra, O. Hamdy, E. S. Horton, and J. Plutzky The Peroxisome Proliferator-Activated Receptor-{gamma} Agonist Pioglitazone Represses Inflammation in a Peroxisome Proliferator-Activated Receptor-{alpha}-Dependent Manner In Vitro and In Vivo in Mice J. Am. Coll. Cardiol., September 2, 2008; 52(10): 869 - 881. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G. Frank and M. P. Lisanti ICAM-1: role in inflammation and in the regulation of vascular permeability Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H926 - H927. [Full Text] [PDF]
|
|
|
|
|
|
R. M. Mansouri, E. Bauge, B. Staels, and P. Gervois Systemic and Distal Repercussions of Liver-Specific Peroxisome Proliferator-Activated Receptor-{alpha} Control of the Acute-Phase Response Endocrinology, June 1, 2008; 149(6): 3215 - 3223. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Hettema, H. Bootsma, and C. G. M. Kallenberg Macrovascular disease and atherosclerosis in SSc Rheumatology, May 1, 2008; 47(5): 578 - 583. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Montecucco, F. Burger, F. Mach, and S. Steffens CB2 cannabinoid receptor agonist JWH-015 modulates human monocyte migration through defined intracellular signaling pathways Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1145 - H1155. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||