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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:e10.)
© 2006 American Heart Association, Inc.

Vascular Biology

Importance of Junctional Adhesion Molecule-A for Neointimal Lesion Formation and Infiltration in Atherosclerosis-Prone Mice

Alma Zernecke; Elisa A. Liehn; Line Fraemohs; Philipp von Hundelshausen; Rory R. Koenen; Monica Corada; Elisabetta Dejana; Christian Weber

From the Department of Molecular Cardiovascular Research (A.Z., E.A.L., L.F., P.v.H., R.R.K., C.W.), RWTH University Hospital, Aachen, Germany; Mario Negri Institute for Pharmacological Research and FIRC Institute of Molecular Oncology (M.C., E.D.); and the Department of Biomolecular and Biotechnological Sciences School of Sciences (E.D.), University of Milan, Italy.

Correspondence to Dr Christian Weber, Kardiovaskuläre Molekularbiologie, Universitätsklinikum Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany. E-mail cweber{at}ukaachen.de

	Abstract

Top Abstract Introduction Methods Results and Discussion References

 
Objective— Although junctional adhesion molecule-A (JAM-A) has recently been implicated in leukocyte recruitment on early atherosclerotic endothelium and after reperfusion injury, its role in neointima formation after arterial injury remains to be elucidated.

Methods and Results— Here we show that the genetic deletion of JAM-A in apolipoprotein E–deficient (apoE^–/–) mice significantly reduced neointimal hyperplasia after wire injury of carotid arteries without altering medial area. This was associated with a significant decrease in neointimal macrophage content, whereas the relative content of smooth muscle cells and endothelial recovery was unaltered in JAM-A^–/–apoE^–/– compared with JAM-A^+/+apoE^–/– lesions. In carotid arteries perfused ex vivo, deficiency in JAM-A significantly impaired the recruitment of monocytes 1 week, but not 1 day, after injury. These effects were paralleled by an attenuation of monocyte arrest and transmigration on activated JAM-A^–/–apoE^–/– versus JAM-A^+/+apoE^–/– endothelial cells under flow conditions in vitro. A mechanism underlying reduced recruitment was implied by findings that the luminal expression of the arrest chemokine RANTES in injured arteries and its endothelial deposition by activated platelets in vitro were diminished by JAM-A deficiency.

Conclusions— Our data provide the first evidence to our knowledge for a crucial role of JAM-A in accelerated lesion formation and monocyte infiltration in atherosclerosis-prone mice.

Key Words: adhesion molecule • atherosclerosis • chemokine • monocytes

	Introduction

Top Abstract Introduction Methods Results and Discussion References

 
Junctional adhesion molecule-A (JAM-A), a member of the IgG superfamily, has been identified to participate in the organization of tight junctions of endothelium and epithelium and in the contact of neighboring cells^1,2. Human JAM-A is widely distributed and also found to be expressed on platelets, erythrocytes, lymphocytes, neutrophils, and monocytes³ and has been implicated in transendothelial migration of neutrophils or mononuclear cells.^1,4,5 Whereas genetic deletion of JAM-A caused few phenotypic changes except increased migration of dendritic cells under physiological conditions,⁶ absence of endothelial JAM-A confirmed a defect in neutrophil recruitment during hepatic and cardiac ischemia-reperfusion injury.^7,8

Inflammatory monocyte recruitment has emerged as the crucial force driving the initiation and progression of atherosclerotic lesion formation and is controlled by the expression of adhesion molecules and pro-inflammatory cytokines.^9,10 Recently, JAM-A has been found to be upregulated on atherosclerotic endothelium in carotid arteries of apolipoprotein E–deficient (apoE^–/–) mice on high-cholesterol diet and to participate in the recruitment of monocytes and T cells to carotid arteries perfused ex vivo.¹¹ In addition, platelet activation and adhesion to activated endothelium can be mediated by homophilic engagement of JAM-A.¹² Neointimal hyperplasia after arterial injury is characterized by endothelial denudation, exposure of extracellular matrix, and adhesion of activated platelets, which contribute to the inflammatory recruitment and accumulation of smooth muscle cells. Given the pro-atherogenic role of mononuclear cell infiltration and activated platelets in exacerbating lesion formation,^13–15 we were prompted to study a functional contribution of JAM-A to accelerated neointima formation after arterial injury by genetic deletion in atherosclerosis-prone apoE^–/– mice.

	Methods

Top Abstract Introduction Methods Results and Discussion References

 
Mouse Model of Vascular Injury
Female 6- to 8-week-old JAM-A^+/+ or JAM-A^–/– mice⁶ were recombined with apoE^–/– mice (C57Bl/6) to obtain JAM-A^+/+apoE^–/– and JAM-A^–/–apoE^–/– mice (second generation C57Bl/6 background). Transluminal wire injury of left common carotid arteries was induced in mice fed a western diet.¹⁵ After 4 weeks, arteries were harvested by in situ perfusion fixation with 4% paraformaldehyde and embedded in paraffin. Animal experiments were approved by local authorities and complied with the German animal protection law.

Immunofluorescence and Morphometry
Neointimal and medial areas were quantified in serial pentachrome stained sections (5 µm) within 500 µm from the bifurcation (11 per mouse) by planimetry (Diskus software; Hilgers).¹⁵ Areas within external elastic lamina, internal elastic lamina, or lumen were determined by computer-assisted planimetry (Diskus software). Neointimal area was defined as internal elastic lamina-lumen, and medial area was defined as external elastic lamina-internal elastic lamina. Staining for Mac-2 (CL8942AP; Cedarlane), smooth muscle cell -actin (clone 1A4; DAKO), CD3 (48-2B), CD31 (clone M20), vascular endothelial (VE)–cadherin (goat polyclonal), or regulated on activation, normal T cell expressed and secreted (RANTES, C-19; all Santa Cruz) was visualized with a fluorescein isothiocyanate-conjugated mAb (Sigma) in 3 sections from each carotid artery, recorded using a Leica DMLB fluorescence microscope, and quantified using Diskus software.¹⁵

Endothelial Cell Isolation and Cell Culture
Mouse aortal endothelial cells (ECs) were cultured as described.¹⁶ Rat tail collagen I (1.5 mg/mL) in DMEM supplemented with 10% fetal calf serum was aliquoted into 24-well plates, allowed to gel at 37°C for 60 minutes, and equilibrated with complete EC medium (RPMI-1640, 20% fetal calf serum, 4 µL/L 2-mercaptoethanol, 10 µg/mL gentamicin, and 50 µg/mL EC growth supplement; BD Biosciences) overnight. Aortas from JAM-A^+/+apoE^–/– or JAM-A^–/–apoE^–/– mice were isolated and cleaned from peri-adventitial fat, cut into rings, opened, and placed endothelial side-down onto the collagen gel. After 2 days, complete medium was added and changed every third day. After 10 days, aortic segments were removed and the gel was digested with 0.3% collagenase H solution. Cells were used between passages 1 and 8. Mono Mac 6 cells were maintained as described.¹⁵

Ex Vivo Perfusion of Carotid Arteries
Carotid arteries from JAM-A^+/+apoE^–/– or JAM-A^–/–apoE^–/– mice were isolated for ex vivo perfusion,¹¹ transferred onto a microscope stage, and perfused with Mono Mac 6 cells (10⁶/mL) labeled with calcein-AM (Molecular Probes) in MOPS-buffered physiological salt solution at 4 µL/min. Adhesive interactions were recorded using stroboscopic epifluorescence illumination (Drelloscop 250; Drello, Mönchengladbach, Germany) and determined after 10 minutes of perfusion.

Monocyte Adhesion Assay, Platelet Perfusion, and Immunofluorescence on Endothelium
For laminar flow assays,^14,15,17 confluent aortal JAM-A^+/+apoE^–/– or JAM-A^–/–apoE^–/– ECs in Petri dishes were activated (100 U/mL tumor necrosis factor-, 200 U/mL IFN-) for 12 hours. Platelets were isolated from platelet-rich plasma by centrifugation of blood from JAM-A^+/+apoE^–/– or JAM-A^–/–apoE^–/– mice and bound to 3-aminopropyl-triethoxysilane-treated glass slides (30 minutes, 37°C)¹⁸ and adherent platelets were activated with thrombin (1 U/mL, 30 minutes, 37°C). Mono Mac 6 cells (0.5x10⁶/mL) were perfused at 1.5 dyn/cm². After 4 minutes, firmly adherent and transmigrated cells were counted in multiple fields recorded by video microscopy. Surface-bound RANTES was detected on interleukin (IL)-1ß (10 ng/mL, 12 hours) activated JAM-A^+/+apoE^–/– aortal ECs on glass cover slides after perfusion with JAM-A^+/+apoE^–/– or JAM-A^–/–apoE^–/– platelets (1.5 dyn/cm², 15 minutes)¹⁷ and quantified using AnalySIS software (Soft-Imaging Systems).¹⁴

Statistical Analysis
Data represent mean±SEM and were analyzed by 2-tailed Student t test or 1-way ANOVA followed by Newman-Keuls post-test when appropriate (InStat software; GraphPad).

	Results and Discussion

Top Abstract Introduction Methods Results and Discussion References

 
To explore the role of JAM-A in accelerated neointimal hyperplasia, carotid arteries of apoE^–/– mice were analyzed 4 weeks after wire-induced injury. As compared with JAM-A^+/+apoE^–/– mice, genetic deletion of JAM-A significantly decreased the neointimal area, whereas the medial area was unaltered (Figure 1A and 1B). Consistently, the intima/media ratio was significantly reduced in JAM-A^–/–apoE^–/– versus JAM-A^+/+apoE^–/– carotid arteries (0.52±0.06 versus 1.37±0.22; P<0.01), whereas no difference in the arterial circumference was seen (882±43 versus 937±77 µm). Quantitative immunofluorescence revealed that the reduction in neointimal area was associated with a significant decrease in the relative content of macrophages in JAM-A^–/–apoE^–/– versus JAM-A^+/+apoE^–/– mice (Figure 1C). In addition, the neointimal content of CD3⁺ T cells was diminished in JAM-A^–/–apoE^–/– versus JAM-A^+/+apoE^–/– mice (Figure 1D), whereas the relative content of smooth muscle cells was slightly but not significantly increased (Figure 1E). Although JAM-A is important for endothelial migration in response to growth factors,¹⁹ luminal VE-cadherin and CD31 staining in carotid arteries²⁰ failed to reveal a significant effect of JAM-A deletion on endothelial recovery at 1, 2, or 4 weeks after injury (not shown).

View larger version (33K): [in this window] [in a new window]   Figure 1. JAM-A deficiency reduces neointimal hyperplasia and monocyte recruitment after injury. Carotid arteries of JAM-A+/+apoE–/– or JAM-A–/–apoE–/– mice (n=6 each) were analyzed 4 weeks after wire injury. A, Representative images of sections stained with pentachrome; scale bars, 100 µm. B, Quantification of neointimal and medial areas by planimetry (*P<0.05 vs JAM-A+/+apoE–/–). The relative content of neointimal macrophages (C), CD3+ T cells (D), and smooth muscle cells (E) was determined by quantifying the area stained positive for Mac-2, CD3, and -SMA by immunofluorescence, respectively (*P<0.05 vs JAM-A+/+apoE–/–).

The recruitment of monocytes to lesions in situ was analyzed in carotid arteries perfused ex vivo. Although no difference in monocyte accumulation to denuded segments was observed 1 day after wire injury, arrest was significantly diminished in JAM-A^–/–apoE^–/– compared with JAM-A^+/+apoE^–/– arteries 1 week after injury (Figure 2A and 2B). After endothelial denudation, activated platelets adhere to the exposed subendothelial matrix and provide a substrate for the initial recruitment of leukocytes.^10,18 The engagement of JAM-A on platelets has been shown to mediate degranulation and aggregation²¹ and to participate in the interactions of platelets or platelet microparticles, with endothelium subsequently supporting leukocyte recruitment.^12,17 To further dissect a platelet-dependent role of JAM-A after injury, monocyte adhesion to activated platelets under flow conditions was analyzed in vitro. As compared with JAM-A^+/+apoE^–/– platelets, shear-resistant arrest of monocytes to activated platelets from JAM-A^–/–apoE^–/– mice was not attenuated (Figure 2C), particularly when adjusting for the number of adherent platelets, which was slightly lower for JAM-A^–/–apoE^–/– platelets (43±7x10³ versus 55±6x10³/mm²). Monocyte–platelet interactions may thus be primarily mediated by Mac-1 and its ligands, consistent with the results in ex vivo perfused arteries, whereas homophilic interactions of JAM-A, as for platelet arrest on activated endothelium, or heterophilic binding of platelet JAM-A by monocyte LFA-1 may serve as adjuvant signals triggering outside-in integrin activation or platelet degranulation.^4,18,22

View larger version (25K): [in this window] [in a new window]   Figure 2. JAM-A participates in the recruitment of monocytes to carotid arteries after injury and activated ECs. Carotid arteries of JAM-A+/+apoE–/– and JAM-A–/–apoE–/– mice were perfused ex vivo with monocytic Mono Mac 6 cells 1 day (A) or 1 week (B) after wire injury (n=3). Mono Mac 6 cells were perfused over thrombin activated platelets (C) or stimulated aortic ECs (D) isolated from JAM-A+/+apoE–/– or JAM-A–/–apoE–/– mice (n=3, *P<0.05 vs JAM-A+/+apoE–/–).

To explore the role of endothelial JAM-A, monocytes were perfused on aortic ECs isolated from JAM-A^–/–apoE^–/– or JAM-A^+/+apoE^–/– mice activated with tumor necrosis factor-/IFN-. Compared with JAM-A^+/+, JAM-A^–/– ECs supported significantly less monocyte adhesion and showed substantially reduced (by 80%) monocytes transmigration under flow conditions (Figure 2D). Previously, soluble JAM-A or JAM-A antibody have been used to establish a contribution of JAM-A to monocyte and T cell arrest on activated or atherosclerotic endothelium in concert with interactions by VLA-4.¹¹ In contrast to blocking antibodies or soluble proteins, the genetic deletion of JAM-A more directly unveils its cooperative role in monocyte adhesion and its importance in transmigration.

The infiltration with mononuclear cells is crucially involved in atherogenesis but also determines the degree of neointimal hyperplasia.^9,10 Accordingly, our data confirm that attenuated neointima formation in JAM-A^–/–apoE^–/– carotid arteries may at least in part be caused by a reduction in inflammatory infiltration with monocytes and T cells after injury.^9,10 These data extend previous findings that JAM-A is upregulated on atherosclerotic endothelium in carotid arteries of apoE^–/– mice, where it cooperates with VLA-4 in the atherogenic recruitment of mononuclear cells.¹¹ The finding that JAM-A mediated monocyte recruitment to carotid arteries 1 week after injury, whereas being less important immediately after denudation may reflect a preferential involvement of JAM-A in emigration on newly reconstituted endothelium versus arrest on adherent platelets, paralleling a differential role in neutrophil transmigration but not adhesion after hepatic reperfusion injury.⁷

Activated platelets can deposit the CC chemokine CCL5/RANTES on the surface of monocytes or atherosclerotic endothelium in a P-selectin–dependent process.¹³ Moreover, microparticles shed from activated platelets can mediate the deposition of RANTES via transient interactions on activated endothelium involving JAM-A–dependent signals.¹⁷ Given the well-established role of RANTES deposited by activated platelets in subsequent monocyte recruitment and plaque formation,^13–15 we analyzed the deposition of RANTES on activated endothelium under flow conditions. Perfusion of JAM-A^+/+apoE^–/– platelets over activated aortal ECs led to a marked deposition of RANTES, whereas endothelial staining was markedly reduced after preperfusion with JAM-A^–/–apoE^–/– platelets (Figure 3A and 3B). This was paralleled by immunofluorescence analysis of RANTES deposition in vivo demonstrating robust staining for RANTES preferentially on the luminal surface but also in neointimal cells in JAM-A^+/+apoE^–/– but not JAM-A^–/–apoE^–/– carotid arteries 1 week but not 1 day after wire injury (Figure 3C and 3D; data not shown). Our findings imply that interactions of platelets with the vessel wall involving engagement of JAM-A are required for the effective deposition of RANTES under flow conditions. In line with data that platelet accumulation after hepatic ischemia reperfusion was unaffected by JAM-A deficiency,⁷ this suggests that transient interactions are sufficient for the role of platelets. With regard to the importance of RANTES in accelerated lesion formation,^13,15 attenuated RANTES delivery may constitute another pivotal mechanisms underlying the reduction in neointima formation in JAM-A^–/–apoE^–/– mice.

View larger version (49K): [in this window] [in a new window]   Figure 3. Luminal RANTES deposition is diminished by JAM-A deficiency. Surface-bound RANTES was detected on aortic JAM-A+/+apoE–/– ECs perfused with platelets isolated from JAM-A+/+apoE–/– or JAM-A–/– apoE–/– mice (A) and RANTES deposition was analyzed and expressed as % control (B) (n=3 each, *P<0.05 vs JAM-A+/+ apoE–/–). Immunofluorescence staining for RANTES was performed in carotid arteries of JAM-A+/+apoE–/– or JAM-A–/–apoE–/– mice 1 week after wire injury (arrows indicate luminal surface; bars=50 µm) (C) and luminal RANTES expression was quantified (D) (n=3, *P<0.05 vs JAM-A+/+apoE–/–).

Taken together, our data indicate that JAM-A plays a crucial role in neointimal lesion formation and infiltration after arterial injury in an atherosclerotic context, which can be ascribed to a direct contribution to monocyte recruitment and deposition of platelet RANTES on activated or recovering endothelium and may be targeted to limit lesion development after injury.

	Acknowledgments

 
This study was supported by DFG, EU, and IZKF Biomat.

Received August 21, 2005; accepted November 2, 2005.

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This Article Abstract Full Text (PDF) All Versions of this Article: 26/2/e10    most recent 01.ATV.0000197852.24529.4fv1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zernecke, A. Articles by Weber, C. Search for Related Content PubMed PubMed Citation Articles by Zernecke, A. Articles by Weber, C. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Medline Plus Health Information Carotid Artery Disease