Adhesion molecules and their role in vascular disease

AJH

2001; 14:44S–54S

Adhesion Molecules and Their Role in Vascular Disease Christian F. Krieglstein and D. Neil Granger A variety of recently discovered glycoproteins have been implicated in cell– cell interactions that are critical for normal hemostasis, immune surveillance, and vascular wall integrity. These cell adhesion molecules (CAM) are known to mediate blood cell (leukocyte, platelet)– endothelial cell interactions that can occur in all segments of the microvasculature under certain physiological (eg, hemostasis) and pathological (eg, inflammation) conditions. The multistep process of leukocyte recruitment illustrates how the coordinated and regulated expression of structurally and functionally distinct families of CAM can elicit a highly reproducible vascular response to inflammation. Selectins mediate the initial, low-affinity leukocyte– endothelial cell interaction that is manifested as leukocyte rolling. This transient binding results in further leukocyte activation and subsequent firm adhesion and transendothelial migration of leukocytes, both of which are mediated by interactions between members of the integrin and immunoglobulin superfamily of CAM. This CAM-regulated process of leukocyte recruitment often results in

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endothelial cell dysfunction, which can be manifested as either impaired endothelium-dependent vasorelaxation in arterioles, excess fluid filtration in capillaries, and enhanced protein extravasation in venules. Consequently, CAM have been implicated in a variety of vascular disorders (eg, ischemia/reperfusion, atherosclerosis, allograft dysfunction, and vasculitis) and an enhanced expression of these CAM has been invoked to explain the exaggerated microvascular dysfunction associated with some of the risk factors (hypertension, hypercholesterolemia, diabetes) for cardiovascular disease. Monoclonal antibodies and genetically engineered mice have proven to be valuable tools for defining the contribution of CAM to disease progression and provide hope for new diagnostic and therapeutic strategies for cardiovascular diseases. Am J Hypertens 2001;14: 44S–54S © 2001 American Journal of Hypertension, Ltd. Key Words: Endothelial cells, hypertension, inflammation, ischemia/reperfusion, microcirculation.

uring the past two decades, our understanding of the molecular basis for cell– cell interactions in blood vessels has achieved an unprecedented level. There is now a clear appreciation for the role of specific glycoproteins that enable 1) vascular smooth muscle cells to maintain the close apposition necessary for cell– cell communication,1 2) endothelial cells to maintain a highly restrictive barrier that prevents excess fluid and protein loss into the interstitium,2 and 3) circulating blood cells to bind to the vessel wall and promote important processes such as thrombogenesis (platelets) and inflammation (leukocytes).3 These cell adhesion molecules (CAM) have received much attention, not only for their participation in normal physiologic processes, but also for their potential roles as

modulators of uncontrolled cell– cell interactions that contribute to the vascular dysfunction and tissue injury that is associated with different vascular diseases (Table 1). This review focuses on CAM that mediate interactions between circulating leukocytes and the blood vessel wall in health and disease. Different families of relevant leukocyte and endothelial CAM are discussed, followed by an evaluation of the role of CAM in the microvascular dysfunction that is elicited by ischemia and reperfusion (I/R) under otherwise normal conditions and in the presence of one of the major risk factors for cardiovascular disease. Finally, some of the scientific evidence that implicates CAM in the initiation and progression of different vascular diseases is summarized.

Received February 26, 2001. Accepted March 6, 2001. From the Department of Molecular and Cellular Physiology (CFK, DNG), Louisiana State University Health Sciences Center, Shreveport, Louisiana and Department of Surgery (CFK), Westfalian Wilhelm’sUniversity, Mu¨nster, Germany. Some of the work summarized in this article is supported by a grant

from the National Heart Lung and Blood Institute (HL26441).

0895-7061/01/$20.00 PII S0895-7061(01)02069-6

Address correspondence and reprint requests to Dr. D. Neil Granger, Department of Molecular and Cellular Physiology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA; e-mail: dgrang@ lsuhsc.edu © 2001 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.

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Table 1.

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Vascular pathologies that involve a role for adhesion molecules

Vascular Condition

Adhesion Molecules

Allograft rejection

CD11a and CD11b/CD18 CD49d/CD29 ICAM-1/VCAM-1 ICAM-1/VCAM-1 CD18 ICAM-1/VCAM-1/PECAM-1 CD11a/CD18 ICAM-1 E-selectin/P-selectin ICAM-1/VCAM-1 P-selectin CD11b/CD18 ICAM-1/VCAM-1 E-selectin CD11a, CD11b and CD11c/CD18 ICAM-1 CD18 ICAM-1 E-selectin/P-selectin CD11/CD18 ICAM-1/VCAM-1/MAdCAM-1 E-selectin ICAM-1 E-selectin CD11a/CD18 CD49d/CD29 VCAM-1 E-selectin CD11a, CD11b and CD11c/CD18 CD49d/CD29 ICAM-1/VCAM-1 CD11a and CD11b/CD18 ICAM-1/VCAM-1

Atherosclerosis Diabetic vasculopathy Giant cell arteritis Glomerulopathies Hypercholesterolemia Hypersensitivity vasculitis Hypertension Ischemia/reperfusion Microscopic polyangiitis Polyarteritis nodosa

Systemic lupus erythematosus

Wegener’s granulomatosis

Molecular Determinants of Leukocyte–Endothelial Cell Adhesion

structure,8 L-selectin may also serve as a ligand for P- and E-selectin.9

Selectins The selectins are lectinlike molecules that are expressed on leukocytes (L-selectin), endothelial cells (E-selectin, P-selectin), and platelets (P-selectin) (Table 2).4 These CAM are known to mediate leukocyte rolling on endothelial cells (L-, P-, and E-selectin) and platelet–leukocyte aggregation. Soluble circulating forms of the selectins can be detected in plasma, where elevated levels have been reported in serum of animals and patients with inflammatory diseases,5 P-selectin is stored in specific granules that are present in platelets (␣-granules) and endothelial cells (Weibel-Palade bodies) from where it can be rapidly mobilized to the cell surface after stimulation.6 Although there is no preformed (storage) pool of E-selectin in endothelial cells, increased cell surface expression can occur in response to transcription-dependent protein synthesis.7 Cytokines, bacterial toxins, and oxidants are known to promote the synthesis of E- and P-selectin in endothelial cells. The major ligands for all three selectins are cell surface glycans that possess a specific sialyl-LewisX-type

Integrins The integrin family of CAM includes heterodimeric proteins that are composed of noncovalently bound ␣ and ␤ subunits (Table 2). At present, 15 ␣- and 8 ␤-chains are known. The ␤1-integrins consist of the common ␤-subunit CD29, which is linked to an immunologically distinct ␣-subunit entitled very late antigen (VLA) because the first glycoproteins identified (VLA-1 and VLA-2) were only expressed at a late stage after T-cell activation. The ␣4␤1-integrin (VLA-4) is involved in the adhesion of eosinophils, lymphocytes, monocytes, and natural killer cells to cytokine-activated endothelial cells.10 –12 VLA-4 is the major ␤1-integrin expressed on resting T- and Blymphocytes.13 The ␤2-integrins consist of a common ␤-subunit CD18, that is linked to one of the four ␣-subunits designated as CD11a, CD11b, CD11c, or CD11d (Table 2). ␤2-Integrins are exclusively expressed on leukocytes; however, the distribution of ␤2-integrin subclasses can vary among leukocyte subpopulations. All

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Table 2.

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Adhesion molecules involved in leukocyte endothelial cell adhesion

Adhesion Molecule

Alternative Designation

Localization

Ligand

Function

Selectin Family L-selectin P-selectin E-selectin

CD62L LAM-1 LECAM-1 CD62P PADGEM GMP-140 CD62E ELAM-1

All leukocytes Endothelial cells ⫹ platelets Endothelial cells

P-/E-selectin GlyCAM, CD14 MAdCAM-1 L-selectin PSGL-1 120kD PSL L-selectin CLA, SSEA-1 250kD ESL

Rolling Rolling Rolling

Integrin Family CD11a/CD18 CD11b/CD18 CD11c/CD18 CD11d/CD18

LFA-1 ␣L␤2 Mac-1 ␣M␤2 p150,95 ␣x␤2 ␣d␤2

CD49d/CD29

VLA-4 ␣4␤1

CD49d/␤7

␣4␤7

All leukocytes Granulocytes ⫹ monocytes Granulocytes ⫹ monocytes Myelomonocytic cell lines ⫹ macrophages Lymphocytes, monocytes, eosinophils ⫹ basophils Lymphocytes

ICAM-1 ICAM-2 ICAM-1 iC3b; Fb iC3b; Fb?

Adherence/emigration

ICAM-3 ICAM-1

Adherence/emigration?

VCAM-1 extracellular matrix molecules

Adherence

VCAM-1 MAdCAM-1 fibronectin

Adherence

Adherence/emigration Adherence/emigration?

Ig-Supergene Family ICAM-1

CD54a

ICAM-2 VCAM-1 PECAM-1

CD102 CD106 CD31

MAdCAM-1

Endothelium ⫹ monocytes Endothelium Endothelium Endothelium, leukos ⫹ platelets Endothelium (intestine)

CD11a/CD18 CD11b/CD18 CD11a/CD18 CD49d/CD29 PECAM-1

Adherence/emigration

L-selectin CD49d/␤7

Adherence/emigration

Adherence/emigration Adherence Adherence/emigration

CAM ⫽ cell adhesion molecule; CLA ⫽ cutaneous lymphocyte antigen; (E)LAM ⫽ (endothelial) leukocyte adhesion molecule; ESL ⫽ E-selectin ligand; GMP ⫽ granule membrane protein; ICAM ⫽ intercellular CAM; LECAM ⫽ lymphocyte-endothelial CAM; LFA ⫽ lymphocyte functionassociated antigen; MAdCAM ⫽ mucosal addressin CAM; PADGEM ⫽ platelet activation-dependent granule external membrane protein; PECAM ⫽ platelet endothelial CAM; PSGL ⫽ P-selectin glycoprotein ligand; SSEA ⫽ sialyl stage-specific embryonic antigen; VCAM ⫽ vascular endothelial CAM; VLA ⫽ very late antigen.

␤2-integrins (CD11a/CD18, CD11b/CD18, CD11c/CD18, CD11d/CD18) are expressed by neutrophils, monocytes, and natural killer cells, whereas CD11a/CD18 is primarily expressed on peripheral blood lymphocytes. CD11d/CD18 is moderately expressed on myelomonocytic cell lines and more strongly on tissue-compartmentalized cells such as foam cells.14 Most of CD11b/CD18 is stored in leukocyte granules, where they can be rapidly (within minutes) mobilized to the cell surface after stimulation with inflammatory mediators.15 Members of the ␤7 subfamily of inte-

grins, ␣E␤7 and ␣4␤7, and their counterreceptors are believed to play key roles in directing lymphocyte traffic to and retention in mucosal organs.16 Ligand specificity of the integrins is largely determined by the ␣-subunits and falls into two groups: cell surface molecules of the immunoglobulin supergene family (ICAM-1,13 ICAM-2,17 VCAM-1,18 and MAdCAM-119) and a variety of large extracellular matrix proteins (fibronectin,20 thrombospondin,21 vitronectin, fibrinogen, and complement component iC3b22,23).

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FIG. 1. Schematic of the multistep paradigm of leukocyte recruitment. In the dormant state, leukocytes and endothelial cells (left) do not interact. Selectin-binding sites (ligands) are present on leukocytes but dormant endothelial cells do not express selectins. Endothelial cell activation results in selectin expression and causes leukocyte-rolling. Subsequent leukocyte activation allows the leukocyte integrins to bind with Ig-supergene family glycoproteins such as ICAM-1 and VCAM-1, permitting firm adhesion. Transendothelial migration (right) is mediated by additional Ig-supergene family members like endothelial PECAM-1.

Immunoglobulin Superfamily The immunoglobulin (Ig) superfamily includes a broad range of molecules with multiple Ig-like domains (Table 2). Some members of this family that are of relevance to vascular diseases include intercellular cell adhesion molecules-1 and -2 (ICAM-1, ICAM-2), vascular cell adhesion molecule-1 (VCAM-1), platelet-endothelial cell adhesion molecule (PECAM)-1, and the mucosal addressin cell adhesion molecule-1 (MAdCAM-1). ICAM-1 is basally expressed on many cell types, but its expression is regulated on endothelial cells,24,25 where it exhibits remarkable heterogeneity between vascular beds.26,27 Organs with a relatively high constitutive expression of ICAM-1 (eg, lung) exhibit smaller increments in ICAM-1 expression after cytokine stimulation than those organs with a low constitutive expression (eg, heart).26,27 A soluble isoform of ICAM-1 can be detected in normal serum, with significantly elevated levels noted in various disease states.28,29 ICAM-2 is a truncated form of ICAM-1 that is basally expressed on endothelial cells,30 but in contrast to ICAM-1, ICAM-2 expression is not increased on activated endothelial cells.31 VCAM-1, which exhibits low to negligible expression on unstimulated endothelial cells, can be profoundly upregulated after cytokine challenge. This CAM mediates the adhesion of lymphocytes and monocytes in inflamed vascular beds. PECAM-1 is constitutively expressed on platelets, most leukocytes, and endothelial cells.32 PE-

CAM-1 can mediate adhesion through either homophilic or heterophilic interactions.33 Because cytokine stimulation does not alter PECAM-1 expression in regional vascular beds, its density has been used as an index of vascular surface area.27 The mucosal addressin MAdCAM-1 is mainly expressed on high endothelial venules of Peyer’s patches, on venules in small intestinal lamina propria, on the marginal sinus of the spleen, and on high endothelial venules of embryonic lymph nodes.34 The ligands for these members of the immunoglobulin superfamily are listed in Table 2.

Physiologic Functions of CAM Although endothelial cells in all segments (arteries, capillaries, and veins) of the vasculature can express CAM, the primary focus of inflammatory responses is postcapillary venules, probably because the density of endothelial CAM expression is greatest in this vascular segment. In vivo observations of the behavior of leukocytes in venules has led to a model of leukocyte– endothelial cell interactions that predicts three sequential and coordinated steps for leukocyte recruitment: rolling, firm adhesion (adherence), and emigration of leukocytes (Fig. 1). To establish an adhesive interaction with endothelial cells, circulating leukocytes must first move from the central stream of flowing blood toward the vessel wall.35 It is now well accepted that selectins and their ligands mediate

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the weak (low-affinity) adhesive interactions that are manifested as leukocyte rolling.36 Although other CAM (eg, VLA-4, VCAM-1, MadCAM-1, and members of the ␤7 subfamily of integrins) have also been implicated in leukocyte, transiently binding (tethering) and rolling their quantitative significance remains unclear.35 The tethered leukocytes are then exposed to low concentrations of chemoattractants/ inflammatory mediators that result in leukocyte activation and subsequently elicit integrin-Ig-dependent leukocyte adherence, with a simultaneous downregulation (shedding) of L-selectin. Leukocyte activation is also associated with an increased avidity of the integrins, which can be elicited by chemokines, bacterial peptides, platelet activating factor (PAF), and leukotriene B4.37 The transendothelial migration of leukocytes begins with locomotion of adherent leukocytes toward the endothelial cell– cell junctions. During this process the cell steadily establishes new adhesive contacts at the migration front, while reducing adhesive interactions at the tail (Fig. 1). Recent studies reporting E- and P-selectindependent leukocyte rolling in mouse aorta demonstrate that the model of leukocyte– endothelial cell interactions also applies to larger vessels upstream from postcapillary venules.38

Regulation of Endothelial CAM Expression The coordinated recruitment of leukocytes to sites of inflammation is largely governed by the time-course and magnitude of endothelial CAM expression. The rapid recruitment of rolling leukocytes can result from L-selectin activation on leukocytes and rapid mobilization of preformed P-selectin to the endothelial cell surface. Leukocyte adherence can also occur quickly as a result of ␤2integrin expression or activation on rolling leukocytes, which enables the cells to attach to basally expressed ICAM-1 on endothelial cells. However, the high density of endothelial CAM that is needed to sustain the large number of leukocytes that infiltrate inflamed tissue is dependent on de novo protein synthesis. A variety of bacterial toxins, cytokines, and oxidants are known to induce transcription-dependent synthesis of different endothelial CAM, including ICAM-1, VCAM-1, MAdCAM-1, E-selectin, and P-selectin. Maximal expression of these CAM is noted between 3 and 6 h after initial exposure to the inflammatory stimulus. Two transcription factors have been implicated in the regulation of endothelial CAM expression, NF-␬B and AP-1.39,40 Binding sites for NF-␬B have been identified in the promoter regions of the genes for E-selectin, VCAM-1, and ICAM-1, whereas a binding site for AP-1 has been localized on the promoter region of the ICAM-1 and E-selectin gene.41 Inhibitors of NF-␬B and AP-1 activation or nuclear translocation have been shown to attenuate cytokine, lipopoly saccharide (LPS), or oxidantinduced CAM expression both in vitro and in vivo.40 These findings provide the rationale for manipulation of

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NF-␬B system or AP-1 as a mean of controlling transcription-dependent cellular events that lead to leukocyte recruitment.

Adhesion Molecules and I/R-Induced Microvascular Dysfunction Cell adhesion molecule-mediated leukocyte– endothelial cell adhesion has been implicated in the pathogenesis of I/R injury, particularly the microvascular dysfunction associated with this regional vascular disorder. Although all endothelial cells are exposed to the same deleterious effects in postischemic tissues, it appears that different segments of the microvasculature respond to this insult in a site-specific manner (ie, the resultant endothelial cell dysfunction is manifested differently in arterioles, capillaries, and venules). In arterioles, the endothelium-dependent vasodilatory response to acetylcholine is attenuated,42,43 whereas capillaries exhibit an impaired endothelial barrier function that results in interstitial edema.44 Furthermore, leukocyte– capillary plugging reduces the number of perfused capillaries and further aggravates tissue hypoxia. However, the reperfused postcapillary venules bear the brunt of the vascular responses to I/R, as illustrated by the enhanced leukocyte– endothelial cell adhesion, platelet– leukocyte aggregation, excessive albumin extravasation, and increased oxidant production.45,46 Macrophages, mast cells, and other auxiliary cells that lie in the interstitial spaces immediately adjacent to the microvasculature are also activated in response to I/R and amplify the inflammatory response through the release of cytokines, oxidants, and other proinflammatory substances.46 – 48 The impaired endothelium-dependent vasodilation induced by I/R is not present in mice that are genetically deficient in leukocyte (CD11/CD18) or endothelial CAMs (P-selectin, ICAM-1), when compared to control (wild type) mice. This observation is consistent with the view that activated and adherent leukocytes represent an important source of superoxide, which inactivates endotheliumderived nitric oxide after I/R.42 Evidence supporting a role for CAM in the capillary and venular dysfunction after I/R is provided in reports demonstrating that I/R-induced venular albumin leakage is tightly coupled to CAM-dependent leukocyte– endothelial cell adhesion45 and the improvement of capillary perfusion, related to diminished leukocyte– capillary plugging, in mice that are genetically deficient in either P-selectin, CD11/CD18, or ICAM-1.49 Studies of posthypoxic endothelial cell monolayers in vitro and postischemic venules in vivo suggest that the exaggerated trafficking of leukocytes observed in this segment of the microcirculation after I/R results from an increased expression or avidity of CAM on the surface of both endothelial cells and leukocytes.50 This hypothesis is further supported by data showing that I/R elicits a rapid increase (10 to 30 min) in P-selectin expression in the

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intestinal vasculature that is followed by a larger increase at 5 h after reperfusion.51 Measurements of P-selectin mRNA in the same tissues suggest that the early increase in P-selectin expression may represent mobilization from its preformed pool (Weibel-Palade bodies), whereas the later increase could be a transcription-related event.51 Eselectin expression is also increased after I/R, reaching peak levels of expression in the gut vasculature at approximately 5 h after reperfusion. The elevated E-selectin expression in postischemic mouse intestine is preceded by NF-␬B activation, and proteasome inhibitors, which prevent the inactivation of NF-␬B by I␬B, attenuate the I/R-induced E-selectin expression. The contributions of P-selectin, E-selectin, ICAM-1, and CD11/CD18 in I/Rmediated leukocyte recruitment and the subsequent microvascular injury have been defined using either neutralizing monoclonal antibodies or mice that are genetically deficient in the specific CAM.

Risk Factors for Cardiovascular Disease and I/R-Induced Microvascular Dysfunction Hypertension Conflicting data have been reported concerning the influence of arterial hypertension on the microvascular responses to I/R. Although it is clear that chronic arterial hypertension is associated with immune dysfunction, it remains unclear whether hypertension exacerbates or attenuates the responses elicited by I/R.3 Studies supporting the potential for exacerbation of the inflammatory response describe a higher total leukocyte count, with an elevated number of spontaneously activated granulocytes in the blood of spontaneously hypertensive rats (SHR), compared with their normotensive counterparts, that is, Wistar-Kyoto (WKY) rats.52 An enhanced production of xanthine oxidase-derived oxygen radicals in the microvasculature of SHR53 and hypertensive Dahl salt-sensitive rats, compared with their normotensive controls, has also been reported.54 However, these findings contrast with reports describing an impaired leukocyte– endothelial cell interaction in mesenteric venules of SHR relative to WKY exposed to different inflammatory stimuli.55,56 Another study showed comparable increases in leukocyte adherence/emigration and the formation of platelet aggregates in mesenteric postcapillary venules of both SHR and WKY in response to I/R. However, albumin extravasation was enhanced after I/R in SHR, but not in WKY. Monoclonal antibodies directed against CD18, P-selectin, or ICAM-1 showed similar protection against the I/R-induced inflammatory responses in both SHR and WKY rats. The enhanced albumin extravasation noted in postischemic venules of SHR was prevented by immunoneutralization of either CD18 on leukocytes or ICAM-1 on endothelial cells.57 These findings suggest that, whereas

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long-term arterial hypertension does not significantly modify the leukocyte and platelet recruitment normally elicited in venules by I/R, it does result in a more vulnerable endothelial barrier that responds with exaggerated albumin leakage that is dependent on adhesive interactions between ␤2-integrins on leukocytes and ICAM-1 on endothelial cells. Hypercholesterolemia Elevated plasma cholesterol concentrations appear to contribute to both the initiation of ischemia as well as the subsequent propagation of ischemic damages.58,59 Because both hypercholesterolemia60 and I/R42 are independently associated with increased superoxide formation, diminished NO bioavailability, impaired endothelium-dependent vasodilation, and leukocyte recruitment, one would expect that the combination of I/R and hypercholesterolemia would lead to exaggerated vascular dysfunction. This prediction is supported by several reports, including studies describing profound leukocyte infiltration and platelet–leukocyte aggregation in postischemic venules of hypercholesterolemic animals. Indeed, an exaggerated production of superoxide has also been demonstrated in arterial endothelial cells of hypercholesterolemic rabbits.61 Albumin leakage from postcapillary venules in response to I/R is also exaggerated in low-density lipoprotein deficient (LDL⫺/⫺) mice62 and rats placed on a high cholesterol diet.63 Hypercholesterolemia also enhances the capillary fluid filtration elicited by I/R.44 In hypercholesterolemic rats rendered neutropenic with antineutrophil serum, I/R did not elicit a significant increase in capillary fluid filtration, suggesting that activated neutrophils mediate the exaggerated endothelial barrier dysfunction associated with hypercholesterolemia.44 Studies using CAMspecific monoclonal antibodies indicate that P-selectinand CD11/CD18-dependent heterotypic and GPIIb– GPIIIa-mediated homotypic platelet aggregation contribute to the extravasation of both leukocytes and albumin in postischemic venules of hypercholesterolemic rats.63 The mechanisms underlying the exaggerated inflammatory responses to I/R in hypercholesterolemic animals remain poorly defined; however, there is growing evidence that implicates an imbalance between the production of superoxide and nitric oxide by the vessel wall. Diabetes Mellitus Diabetes mellitus is also known to exaggerate I/R-induced leukocyte recruitment, albumin leakage, and oxidant production.64 – 66 Leukocyte adhesion and emigration in response to I/R has been shown to be critically dependent on interactions between leukocyte ␤2-integrins and ICAM-1 both in diabetic64,65 and in nondiabetic animal models,45 because treatment with blocking monoclonal antibodies against CD18 or ICAM-1 markedly decreases leukocyte adhesion and emigration at reperfusion. It was shown that increased numbers of neutrophils are activated in human

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diabetic subjects,67 and that activation of neutrophils is usually associated with increased ␤2-integrin expression.22 In addition, an elevated expression of ICAM-1 has been demonstrated in choroidal and retinal blood vessels of diabetic patients,68 and elevated levels of soluble ICAM-1 have been detected in serum of patients with insulin-dependent diabetes.69 Experimental studies demonstrate that ICAM-1 is rapidly increased in diabetic, but not in control, animals exposed to I/R.70 Acute hyperglycemia in control rats does not elicit the microvascular alterations noted in diabetic rats nor does it enhance the I/R-induced leukocyte– endothelial cell adhesion and albumin leakage in diabetic rats; therefore, hyperglycemia alone cannot explain the altered inflammatory responses observed in diabetic animals.64 Studies suggest that the enhanced inflammatory response to I/R in diabetic rats may involve lipid mediators such as PAF and leukotrienes, as treatment with either a PAF receptor antagonist or leukotriene synthesis inhibitor could prevent leukocyte adhesion and emigration.65 Like in hypertensive and hypercholesterolemic63 rats (discussed previously), administration of monoclonal antibodies against CAM completely prevents leukocyte recruitment in diabetic rats. But in contrast to the other risk factors, albumin leakage is not influenced by immunoneutralization of CAM in diabetic rats.68 This suggests that the exaggerated albumin leakage in response to I/R in diabetes be mediated by mechanisms that are independent of leukocyte recruitment and activation.

CAM and Vascular Diseases Atherosclerosis Atherosclerosis, as manifested by coronary, cerebral, and peripheral arterial vascular diseases, is the leading cause of mortality and morbidity in the United States. Experimental data and pathologic observations support a role for CAMmediated leukocyte adhesion in the development of the early lesions (fatty streaks and fibrous plaques) in atherosclerosis. The predominance of T-lymphocytes and monocytes at the site of these fatty streaks underscores the importance of CAM that are specific to these cell types.71 In various atherogenic models the accumulation of Tlymphocytes and monocytes at sites of vascular inflammation was demonstrated to be VCAM-1 dependent.72,73 A role for ICAM-1 in plaque formation is suggested by reports of an increased immunoreactivity for ICAM-1 at the luminal surface of atherosclerotic lesions.74,75 The expression of E-selectin, ICAM-1, and VCAM-1 is more prevalent on the intimal neovasculature than on arterial luminal endothelium of atherosclerotic plaques. Furthermore, the presence of VCAM-1 and ICAM-1 on neovasculature and nonendothelial cells is associated with increased intimal leukocyte accumulation, suggesting that adhesion molecule-mediated leukocyte recruitment or activation of intimal neovasculature may play a critical role in the pathogenesis of human atherosclerosis.76 Shedding of CAM like ICAM-1 from the surface of activated endothelium and macrophages results in measur-

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able plasma levels of soluble cell CAM in patients with atherosclerosis and may provide a useful marker of the endothelial cell activation that is associated with atherogenesis.77 Overall, the available evidence suggests that CAM are essential mediators of the complex cellular interactions that contribute to the atherogenic process.78 As a result, some effort is now directed toward the development of therapeutic strategies that focus on preventing early lesion development by interfering with CAM function. Renal Disease Cell adhesion molecule-mediated leukocyte adhesion also appears to contribute to different kidney diseases, including glomerulonephritis, tubulointerstitial nephritis, allograft rejection, and renal I/R injury. In addition, leukocyte adhesion promotes interactions between emigrated leukocytes and resident glomerular cells that facilitates leukocyte activation, antigen presentation, free radical generation, cytokine production, as well as functional and structural glomerular injury.79 – 81 Selectins are not expressed on renal endothelial cells under physiologic conditions; however, increased expression of P-selectin82,83 and E-selectin82– 84 has been reported in human and experimental glomerulonephritis. Low constitutive levels of ICAM-185 and VCAM-186 have been detected at different sites in the healthy kidney and inflammatory renal disorders are associated with marked upregulation of ICAM-185 and VCAM-1,86 with highest expression detected in areas of active inflammation. Consequently, CAM have emerged as an attractive target for therapeutic intervention in a variety of renal disorders. Monoclonal antibodies that block interactions of leukocyte integrins with Ig-like molecules on endothelium attenuate renal injury in many experimental models of glomerulonephritis; however, clinical use has been limited because of their antigenicity and need for parenteral administration.87 Transplantation Despite major advances in organ transplantation, allograft rejection (either acute or chronic) remains the major determinant of allograft survival. Leukocytes play a critical role in the immune response to transplantation. For an antigen to be recognized as foreign, it must be presented to the leukocyte (T-cell) population by antigen-presenting cells. Leukocyte CAM can work as accessory molecules to the T-cell receptor and major histocompatibility proteins to achieve adequate recognition of self and foreign antigens. In addition, T-cell activation can also be mediated through leukocyte CAM like the T-cell integrins CD11a/ CD18 and CD49/CD29.23 Because CAM are important in the initiation of the allogenic T-cell responses, they have become potential therapeutic targets for induction of tolerance and prevention of rejection.88 Indeed, clinical and experimental studies have demonstrated a reduction in acute rejection and improved graft survival after renal89

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and cardiac transplantation90 after treatment with monoclonal antibodies against CD11a/CD18 or ICAM-1. In contrast to acute rejection, the role of leukocyte CAM in chronic rejection has not been sufficiently addressed. Nonetheless, VCAM-1 has been linked to the development of chronic rejection in human cardiac transplantation.91 It also appears that CAM like ICAM-192 are involved in the pathogenesis of the accelerated transplant-associated atherosclerosis, which is a characteristic feature of chronic rejection.93 Ischemia and reperfusion injury after organ transplantation is linked to both acute and chronic rejection and a number of studies using neutralizing monoclonal antibodies suggest a direct pathologic role of ICAM-1,94 CD11a,95 and CD11b95 in renal I/R injury. Recent reports strongly implicate selectin-mediated recruitment of leukocytes after both cold and warm ischemia.96 Increased circulating levels of CAM have been described after immune activation.5 Whether or not the measurement of soluble CAM in peripheral blood5 or in fluids directly draining the allografts, such as urine in kidney transplants,97 or bile in liver transplants98 provide an alternative method for monitoring graft function is under investigation.

some vasculitic diseases to identify disease activity.108 –110 However, conflicting results were reported and it remains to be determined whether an increase in a particular soluble adhesion molecule can predict disease activity. ICAM-1 antibodies, which have been used to treat patients with rheumatoid arthritis, have produced some amelioration of disease.111

Vasculitis

References

The role of CAM in the development of vasculitic diseases has only recently been addressed, and a limited number of CAM have been studied. For example, in patients with Wegener’s granulomatosis99 increased expression of ICAM-1 and VCAM-1, but not E-selectin, has been detected on renal capillaries and small renal vessels.100,101 On endothelium from patients with panarteritis nodosa,102 both VCAM-1 and E-selectin were upregulated, whereas ICAM-1, ICAM-2, P-selectin, and PECAM-1 expression were unchanged from controls.103 In giant cell arteritis, ICAM-1 expression is upregulated on temporal arteries in both early and advanced lesions, whereas the majority of lesion infiltrating T-cells were found to express CD11a/ CD18.104 Expression of ICAM-1 was also detected on macrophages, giant cells, intimal myofibroblasts, and epithelioid cells in granulomatous lesions,104 suggesting that CD11a/CD18 –ICAM-1 interactions mediate both lymphocyte and monocyte adhesion, as well as lymphocyte activation in giant cell lesions. Inflammation-induced angiogenesis was shown to be the main site of adhesion molecule-mediated leukocyte– endothelial cell interactions leading to the development of inflammatory infiltrates in giant cell arteritis.105 Circulating neutrophils from patients with active systemic lupus erythematosus exhibit elevated CD11b and lymphocytes increased VLA-4, CD11a/CD18, and CD11c/CD18 expression.106 The finding that ICAM-1, VCAM-1, and E-selectin show increased expression in nonlesional skin biopsies of patients with systemic lupus supports the hypothesis that cellular activation may lead to the initiation of vasculitic lesions.107 The measurement of serum levels of soluble CAM has been used in

1.

Conclusion Scientific evidence is rapidly accumulating to support the view that leukocyte- and endothelial cell-associated CAM are critical participants in the vascular dysfunction and tissue injury that is associated with a wide variety of inflammatory and cardiovascular diseases. Advancements in this field of investigation have largely resulted from the marriage of novel immunologic and molecular biological approaches to traditional experimental strategies in cardiovascular physiology. This effort has led to a new appreciation of the difficulties in distinguishing cardiovascular from inflammatory diseases, and it has provided hope that therapeutic interventions, which target CAM, may be of some benefit in the treatment of inflammatory as well as cardiovascular diseases.

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