Expression Of Junctional Adhesion molecule-C Research Articles

The role of junctional adhesion molecule-C in trophoblast differentiation and function during normal pregnancy and preeclampsia.

Junctional adhesion molecule-C (JAM-C) is an important regulator of many physiological processes, ranging from maintenance of tight junction integrity of epithelia to regulation of cell migration, homing and proliferation. Preeclampsia (PE) is a trophoblast-related syndrome with abnormal placentation and insufficient trophoblast invasion. However, the role of JAM-C in normal pregnancy and PE pathogenesis is unknown. The expression and location of JAM-C in placentas were determined by quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry. The expression of differentiation and invasion markers were detected by qRT-PCR or western blot. The effects of JAM-C on migration and invasion of trophoblasts were examined using wound-healing and invasion assays. Additionally, a mouse model was established by injection of JAM-C-positive adenovirus to explore the effects of JAM-C in vivo. In normal pregnancy, JAM-C was preferentially expressed on cytotrophoblast (CTB) progenitors and progressively decreased when acquiring invasion properties with gestation advance. However, in PE patients, the expression of JAM-C was upregulated in extravillous trophoblasts (EVTs) and syncytiotrophoblasts (SynTs) of placentas. It was also demonstrated that JAM-C suppressed the differentiation of CTBs into EVTs in vitro. Consistently, JAM-C inhibited the migration and invasion capacities of EVTs through GSK3β/β-catenin signaling pathway. Importantly, Ad-JAMC-infected mouse model mimicked the phenotype of human PE. JAM-C plays an important role in normal placentation and upregulated JAM-C in placentas contributes to PE development.

The Role of Junctional Adhesion Molecule-C in Trophoblast Differentiation and Function During Pregnancy and Preeclampsia

Background: Junctional adhesion molecule-C (JAM-C) is an important regulator of many physiological processes, ranging from the maintenance of tight junction integrity of epithelia to regulation of cell migration, homing and proliferation. Preeclampsia (PE) is a trophoblast-related syndrome with abnormal implantation and insufficient trophoblast invasion of spiral arteries. What’s the role of JAM-C in trophoblasts differentiation and migration in normal pregnancy and PE pathogenesis? Methods: The expression and location of JAM-C in the placental tissues were determined by qRT-PCR, western blot and immunohistochemistry. RNA-sequencing was used to characterize the role of JAM-C in primary CTBs. The effects of JAM-C on migration and invasion of trophoblasts were determined using wound-healing and Matrigel invasion assays. The expression of differentiated and invasion markers were detected by qRT-PCR or western blot. Additionally, twenty pregnant mice were included. Fetal resorption rate, systolic blood pressure (SBP) and urinary protein level were measured and smooth muscle cell (SMC) coverage were analyzed by immunostaining. Findings: In normal pregnancy, JAM-C was preferentially expressed on cytotrophoblast (CTB) progenitors and progressively decreased when acquiring invasion properties with gestational advance. As RNA-seq analysis demonstrated that JAM-C inhibited the differentiation, migration and invasion of trophoblasts. However, in PE patients, the expression of JAM-C is up-regulated in extravillous trophoblasts (EVTs) and syncytiotrophoblasts (SynTs) of placentas. Over-expression of JAM-C in human trophoblast stem cells (hTSCs) negatively regulated the differentiation potentiality. In HTR-8/SV neo cells, JAM-C inhibits migration and invasion through GSK3β/β-catenin signaling pathway . Importantly, the mouse model induced by JAM-C mimics the human PE phenomenon and impaired spiral arteries remodeling. Interpretation: JAM-C plays an important role in normal placentation and that its abnormal increase in placentas contributes to PE development. Funding Statement: This study was funded by grants from National Key R&D Program of China (2018YFC1004404), Jiangsu Provincial Key Medical Center (YXZXB2016004), National Natural Science Foundation of China (82071666, 81701474, 81701475, 81801470), and Jiangsu Biobank of Clinical Resources (BM2015004). Declaration of Interests: The authors have no conflicts of interest to declare. Ethics Approval Statement: This study was reviewed and approved by the Ethics Committee (2018-034-01) of Affiliated Drum Tower Hospital, Nanjing University Medical School. Written informed consent was obtained from all participants before surgery.

Junctional Adhesion Molecule-C Mediates the Recruitment of Embryonic-Endothelial Progenitor Cells to the Perivascular Niche during Tumor Angiogenesis.

The homing of Endothelial Progenitor Cells (EPCs) to tumor angiogenic sites has been described as a multistep process, involving adhesion, migration, incorporation and sprouting, for which the underlying molecular and cellular mechanisms are yet to be fully defined. Here, we studied the expression of Junctional Adhesion Molecule-C (JAM-C) by EPCs and its role in EPC homing to tumor angiogenic vessels. For this, we used mouse embryonic-Endothelial Progenitor Cells (e-EPCs), intravital multi-fluorescence microscopy techniques and the dorsal skin-fold chamber model. JAM-C was found to be expressed by e-EPCs and endothelial cells. Blocking JAM-C did not affect adhesion of e-EPCs to endothelial monolayers in vitro but, interestingly, it did reduce their adhesion to tumor endothelium in vivo. The most striking effect of JAM-C blocking was on tube formation on matrigel in vitro and the incorporation and sprouting of e-EPCs to tumor endothelium in vivo. Our results demonstrate that JAM-C mediates e-EPC recruitment to tumor angiogenic sites, i.e., coordinated homing of EPCs to the perivascular niche, where they cluster and interact with tumor blood vessels. This suggests that JAM-C plays a critical role in the process of vascular assembly and may represent a potential therapeutic target to control tumor angiogenesis.

Neuronal Expression of Junctional Adhesion Molecule-C is Essential for Retinal Thickness and Photoreceptor Survival.

Photoreceptor cell death is a key pathology of retinal degeneration diseases. To date, the molecular mechanisms for this pathological process remain largely unclear. Junctional adhesion molecule-c (Jam-c) has been shown to play important roles in different biological events. However, its effect on retinal neuronal cells is unknown. To determine the effect of Jam-c on adult mouse eyes, particularly, on retinal structure, vasculature and photoreceptor cells, in order to explore potential important target molecules for ocular diseases. Jam-c global knockout mice, endothelial-specific and neuronal-specific Jam-c conditional knockout mice using Tie2-Cre and Nestin-Cre mice respectively were used in this study. Mouse eyes were harvested from the different groups and eye size examined. Cryosections of the eyes were made and stained with Hematoxylin and Eosin (H&E) and the thicknesses of retinal layers measured. Retinal blood vessels and cone and rod photoreceptors were analyzed using isolectin B4, peanut agglutinin and rhodopsin as markers respectively. In vivo Jam-c knockdown in mouse eyes was performed by intravitreal injection of Jam-c shRNA. Jam-c expression in the retinae was quantified by real-time PCR. Global Jam-c gene deletion in mice resulted in smaller eyes and decreased the diameters of lens and iris. Jam-c-/- mice display marked thinning of the outer nuclear layer (ONL), less numbers of photoreceptor cells, and abnormal retinal vasculature. Importantly, neuronal-specific Jam-c deletion led to similar phenotype, whereas no obvious defect was observed in endothelial-specific Jam-c knockout mice. Moreover, Jam-c knockdown by shRNA also decreased ONL thickness and photoreceptor numbers. We found that Jam-c is critically required for the normal size and retinal structure. Particularly, Jam-c plays important roles in maintaining the normal retinal thickness, vasculature and photoreceptor numbers. Jam-c thus may therefore have important roles in various ocular diseases.

Dachengqi Decoction Attenuates Intestinal Vascular Endothelial Injury in Severe Acute Pancreatitis in Vitro and in Vivo

Background/Aims: Dachengqi decoction (DCQD) is a well-known traditional Chinese herbal drug with strong anti-inflammatory effects. Angiopoietin-1 (Ang-1) plays a vital role in maintaining the stability and integrity of the vascular wall and prevents vascular leakage due to inflammatory mediators. Our previous work found that DCQD protects against pancreatic injury in rats with severe acute pancreatitis (SAP). This study aims to investigate the effects of DCQD on intestinal endothelial damage in both damaged human umbilical vein endothelial cells (HUVECs) and SAP rats. Methods: HUVECs were randomly divided into four groups: control group, TNF-α group, TNF-α plus Ang-1 group (Ang-1 group), and TNF-α plus DCQD group (DCQD group). Cells were incubated for 6 h, 12 h, and 24 h, before collection. The treatment concentration of DCQD was decided based on a Cell Counting Kit-8 (CCK-8) assay. The monolayer permeability of the HUVECs was assessed by measuring the transendothelial electrical resistance (TEER). Apoptosis was analyzed by flow cytometry. mRNA and protein expression of aquaporin 1 (AQP-1), matrix metalloproteinase 9 (MMP9), and junctional adhesion molecule-C (JAM-C) was evaluated by RT-PCR, immunocytofluorescence, and western blot. Forty male Sprague-Dawley rats were randomized into a control group, SAP group, SAP plus Ang-1 group (Ang-1 group), and SAP plus DCQD group (DCQD group). SAP was induced by intraperitoneal injection of cerulein and lipopolysaccharide (LPS), while the control group received 0.9% saline solution. Evans blue was injected through the penile vein and the rats were then sacrificed 12 h after modeling. Levels of serum amylase, TNF-α, IL-1β, IL-2, and IL-6 were determined by using ELISA. Intestinal tissue was analysed by histology, and capillary permeability in the tissues was evaluated by Evans blue extravasation assay. Protein and mRNA expression of AQP-1, MMP9, and JAM-C were assessed by immunohistofluorescence, western blot, and RT-PCR. Results: DCQD reduced the permeability of HUVEC induced by TNF-α in vitro. Furthermore, DCQD altered the mRNA and protein levels of JAM-C, MMP9, and AQP-1 in HUVECs after TNF-α induction. SAP intestinal injury induced by cerulein combined with lipopolysaccharides was concomitant with increased expression of JAM-C and MMP9, and reduced expression of AQP-1 in intestinal tissue. Pretreatment with DCQD attenuated SAP intestinal injury and lowered the levels of serum amylase, TNF–α, IL-1β, IL-2, and IL-6 effectively. Our study demonstrated that DCQD decreased the expression of JAM-C and MMP9 and increased the expression of AQP-1 both in vitro and in vivo. Conclusion: DCQD can reduce capillary endothelial damage in acute pancreatitis-associated intestinal injury and the mechanism may be associated with the regulation of endothelial barrier function-associated proteins AQP-1, MMP9, and JAM-C.

JAM-C promotes lymphangiogenesis and nodal metastasis in non-small cell lung cancer

This study aims to investigate lymphatic metastasis-related genes in non-small cell lung carcinomas (NSCLC). NSCLC tissue was analyzed for expression of junctional adhesion molecule-C (JAM-C) protein. Our data revealed novel associations between JAM-C overexpression in primary tumors and lymphatic microvessel density (LMVD), lymph node metastasis, and poorer overall survival and recurrence-free survival. We used the highly metastatic human lung adenocarcinoma cell line Anip973 and its parental line AGZY83-a, which has a low metastatic capacity, in vivo and vitro. We found that JAM-C played an important role in different metastasis capacity of lymph node. JAM-C affected tumor growth, LNM, JAM-C, VEGF-C, vasculature, and ERK1/2 phosphorylation (p-ERK1/2). β1 integrin was involved in lymph node metastasis. Moreover, JAM-C knockdown in highly metastatic Anip973 decreased cell migration in scratch-wound assays. The JAM-C knockdown in Anip973 cells and JAM-C cDNA in AGZY83-a cells regulated the vascular endothelial growth factor C (VEGF-C) expression. Immunofluorescence showed that blocked VEGF-C expression in JAM-C shRNA Anip973 cells were restored after JAM-C treatment. JAM-C-induced VEGF-C in JAM-C cDNA AGZY83-a cells was also effectively inhibited by treatment with an antibody specifically against JAM-C. Use of media from Anip973 cells, AGZY83-a, and A549cells lung cancer cells that overexpressed or downregulated JAM-C was demonstrated to affect activity of VEGF-C-induced β1 integrin subunit or ERK activity in human dermal lymphatic endothelial cells (HDLEC) treated with VEGF-C or inhibitory antibody to JAM-C. Overall, these results indicate that JAM-C could mediate metastasis as it contributes to VEGF-C expression in cancer cells. JAM-C affects β1and ERK activation in HDLEC, thus promoting lymphangiogenesis and nodal metastasis. Our findings indicate that JAM-C may be a therapeutic target for preventing and treating lymphatic metastases.

SAT0050 A novel function of junctional adhesion molecule-C in regulation of trans-endothelial migration of murine synovial fibroblasts

BackgroundRecent studies demonstrated the potential of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) to emigrate from affected joints and migrate via the bloodstream toward distant healthy cartilage in the SCID mouse model...

Maturing EPCs into endothelial cells: may the force be with the EPCs. Focus on “Fluid shear stress induces differentiation of circulating phenotype endothelial progenitor cells”

endothelial progenitor cells (EPCs) are a unique cell type found circulating in the peripheral blood with the capacity to become mature endothelial cells. EPCs can be released from many sources including the bone marrow, adipose tissue, the vessel wall, as well as potentially the spleen, liver, and

Targeting of Junctional Adhesion Molecule-C Inhibits Experimental Choroidal Neovascularization

To identify the expression of junctional adhesion molecule-C (JAM-C) in choroidal neovascularization (CNV) and evaluate the effect of JAM-C targeting on CNV formation and on cellular functions relevant to CNV in vitro, such as macrophage transmigration, human retinal pigment epithelial (hRPE) cell migration, and monolayer RPE permeability. JAM-C expression in CNV was analyzed by real-time PCR, immunoblot analysis, and immunofluorescence staining. CNV area and blood vessel leakage were quantified using isolectin B4 staining and fluorescein angiography, respectively, 1 week after laser treatment. Macrophage infiltration within the CNV area was measured by immunofluorescence, and transmigration through monolayer RPE was analyzed using a transepithelial migration assay. After JAM-C shRNA transfection, human RPE cell migration was quantified using a transwell assay, and monolayer RPE permeability was determined by measuring the apical-to-basolateral movements of sodium fluorescein. JAM-C expression was upregulated during CNV formation after laser treatment in a time-dependent manner. However, no change in JAM-C expression was found in the retina up to 14 days after laser treatment. JAM-C targeting by intravitreal injection of JAM-C Fc chimera inhibited CNV, blood vessel leakage, and macrophage infiltration. JAM-C Fc chimera inhibited basolateral-to-apical transmigration in vitro through a monolayer of hRPE of macrophages from patients with wet AMD. In addition, shRNA-mediated JAM-C knockdown inhibited hRPE cell migration and hRPE permeability. JAM-C blockade may prove useful for CNV suppression by inhibiting macrophage transmigration, RPE cell migration, and monolayer RPE barrier malfunction.

The trans-endothelial migration of murine synovial fibroblasts of hTNF transgenic mice is controlled by JAM-C

Background and objectivesRecent studies demonstrated the potential of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) to migrate long distances via the bloodstream and invade distant cartilage in the SCID mouse model of...

Expression of Junctional Adhesion Molecule-C on the Surface of Platelets Supports Adhesion, but not Differentiation, of Human CD34+ Cells in Vitro

Background: CD34⁺ progenitor cells play an important role in haematopoiesis and vascular homeostasis. The aim of the present study was to investigate the role of platelet-derived junctional adhesion molecule-C (JAM-C) in adhesion and differentiation of human CD34⁺ cells in vitro, as well as its association with platelet-derived P-selectin in patients with coronary artery disease. Methods and Results: Using flow cytometry we observed that JAM-C expression on the surface of washed platelets is increased after activation with thrombin receptor activating peptide-6 in vitro and correlated with platelet-derived P-selectin expression in patients with coronary artery disease (r=0.326, P=0.007). The role of JAM-C and its counter receptor Mac-1 in adhesion of human CD34⁺ cells over immobilized platelets was investigated by using a neutralizing soluble protein (sJAM-C-Fc) and a monoclonal antibody against JAM-C or integrin Mac-1 (CD11b/CD18). Treatment with soluble JAM-C-Fc or anti-JAM-C or anti-Mac-1, but not with control-Fc or IgG1, resulted in a significantly decreased adhesion of human CD34⁺ cells to platelets under static conditions (P<0.05). In order to validate our findings under high shear stress we performed flow chamber experiments. In a similar manner, inhibiting JAM-C interaction with Mac-1 resulted in a significantly decreased adhesion of CD34⁺ cells over immobilized platelets under high shear stress (P<0.05). Colony forming unit assays and coculture assays revealed that inhibition of JAM-C/Mac-1 axis did not influence the platelet-mediated differentiation of CD34⁺ cells to endothelial cells or to macrophages/foam cells. Conclusions: Taken together a platelet-derived JAM-C supports CD34⁺ cell adhesion, a mechanism potentially involved in homing as well as domiciliation of human CD34⁺ cells.

Schwann cell‐specific JAM‐C‐deficient mice reveal novel expression and functions for JAM‐C in peripheral nerves

Junctional adhesion molecule-C (JAM-C) is an adhesion molecule expressed at junctions between adjacent endothelial and epithelial cells and implicated in multiple inflammatory and vascular responses. In addition, we recently reported on the expression of JAM-C in Schwann cells (SCs) and its importance for the integrity and function of peripheral nerves. To investigate the role of JAM-C in neuronal functions further, mice with a specific deletion of JAM-C in SCs (JAM-C SC KO) were generated. Compared to wild-type (WT) controls, JAM-C SC KO mice showed electrophysiological defects, muscular weakness, and hypersensitivity to mechanical stimuli. In addressing the underlying cause of these defects, nerves from JAM-C SC KO mice were found to have morphological defects in the paranodal region, exhibiting increased nodal length as compared to WTs. The study also reports on previously undetected expressions of JAM-C, namely on perineural cells, and in line with nociception defects of the JAM-C SC KO animals, on finely myelinated sensory nerve fibers. Collectively, the generation and characterization of JAM-C SC KO mice has provided unequivocal evidence for the involvement of SC JAM-C in the fine organization of peripheral nerves and in modulating multiple neuronal responses.—Colom, B., Poitelon, Y., Huang, W., Woodfin, A., Averill, S., Del Carro, U., Zambroni, D., Brain, S. D., Perretti, M., Ahluwalia, A., Priestley, J. V., Chavakis, T., Imhof, B. A., Feltri, M. L., Nourshargh, S. Schwann cell-specific JAM-C-deficient mice reveal novel expression and functions for JAM-C in peripheral nerves.

Junctional Adhesion Molecule C (JAM-C) Constitutes a New Marker for the Differential Diagnosis of B Cell Lymphomas.

Abstract 3940Poster Board III-876 IntroductionDifferentiation of naïve B cells into plasma cells or memory cells occurs in the germinal centres (GC) of lymph follicles or alternatively in the marginal zone via a GC- and T cell independent pathway. It is currently assumed that B cell lymphomas correspond to normal B cell differentiation stages, but the precise correlation of several B cell lymphomas to these two pathways remains controversial. We have previously shown that junctional adhesion molecule C (JAM-C) originally identified at the cell-cell border of endothelial cells, constitutes also a marker of B lymphocytes with a tightly regulated expression during B cell differentiation: immature B cells, GC-B cells and plasma cells stain negatively, whereas mature, memory and marginal zone derived B cells stain strongly positive. Here we test the expression of JAM-C on a series of patients with B cell lymphomas. MethodsB lymphocytes from the peripheral blood of 158 untreated patients were analyzed using flow cytometry with standard antibody panels (CD5, CD10, CD11c, CD22, CD23, CD25, CD38, CD103, FMC7, sIg). Diagnosis of a B cell lymphoma was established according to WHO guidelines, using additionally RT-PCR, karyotyping, or FISH, if necessary. Expression of JAM-C was studied by flow cytometry with a polyclonal antibody obtained from a rabbit immunized with the soluble JAM-C molecule. ResultsALL CASES: 158JAM-C pos%CLL7/42 cases17MCL12/18 cases67HCL4/6 cases67FL1/8 cases13DLBCL (+ Burkitt lymphoma)3/15 cases20MM1/7 cases14B-ALL0/5 cases0MZBL24/31 cases77LPL4/13 cases31plasmablastic lymphoma1/1 case100MCL, HCL and MZBL with a supposed origin in the marginal zone stained mostly positive, whereas CLL and FL with a supposed origin in the germinal centre showed mostly a negative staining. No correlation was found in CLL between JAM-C expression and staining for ZAP70 or CD38. In 12 cases routine work-up was not able to precisely establish a diagnosis of CLL or MZBL, and CLL or MCL. In these cases the presence of JAM-C was considered a strong argument against a GC-origin of the malignant B cells. Addition of JAM-C to antibodies used in the Matutes score increased the sensitivity and specificity of this score for the diagnosis of CLL. Furthermore, it may help differentiating MZBL from LPL which otherwise display overlapping immunophenotypes. ConclusionJAM-C constitutes a new diagnostic marker for the differential diagnosis of B cell lymphomas, and is particularly useful for the distinction between CLL and LPL (negative staining) on the one hand and mantle cell and marginal zone B cell lymphomas (positive staining) on the other hand. Disclosures:No relevant conflicts of interest to declare.

Expression, Localization, and Function of Junctional Adhesion Molecule-C (JAM-C) in Human Retinal Pigment Epithelium

To determine the localization of JAM-C in human RPE and characterize its functions. Immunofluorescence, Western blot, and PCR was used to identify the localization and expression of JAM-C, ZO-1, N-cadherin, and ezrin in cultures of human fetal RPE (hfRPE) with or without si-RNA mediated JAM-C knockdown and in adult native RPE wholemounts. A transepithelial migration assay was used to study the migration of leukocytes through the hfRPE monolayer. JAM-C localized at the tight junctions of cultured hfRPE cells and adult native RPE. During initial junction formation JAM-C was recruited to the primordial cell-cell contacts and after JAM-C knockdown, the organization of N-cadherin and ZO-1 at those contacts was disrupted. JAM-C knockdown caused a delay in the hfRPE cell polarization, as shown by reduced apical staining of ezrin. JAM-C inhibition significantly decreased the chemokine-induced transmigration of granulocytes but not monocytes through the hfRPE monolayer. JAM-C localizes specifically in the tight junctions of hfRPE and adult native RPE. It is important for tight junction formation in hfRPE, possibly by regulating the recruitment of N-cadherin and ZO-1 at the cell-cell contacts, and has a role in the polarization of hfRPE cells. Finally, JAM-C promotes the basal-to-apical transmigration of granulocytes but not monocytes through the hfRPE monolayer.

Junctional adhesion molecule C (JAM-C) distinguishes CD27+ germinal center B lymphocytes from non-germinal center cells and constitutes a new diagnostic tool for B-cell malignancies

Differentiation of naïve B cells into plasma cells or memory cells occurs in the germinal centers (GCs) of lymph follicles or alternatively via a GC- and T-cell-independent pathway. It is currently assumed that B-cell lymphomas correlate to normal B-cell differentiation stages, but the precise correlation of several B-cell lymphomas to these two pathways remains controversial. In the present report, we describe the junctional adhesion molecule C (JAM-C), currently identified at the cell-cell border of endothelial cells, as a new B-cell marker with a tightly regulated expression during B-cell differentiation. Expression of JAM-C in tonsils allows distinction between two CD27+ B-cell subpopulations: JAM-C- GC B cells and JAM-C+ non-germinal B cells. The expression of JAM-C in different B-cell lymphomas reveals a disease-specific pattern and allows a clear distinction between JAM-C- lymphoproliferative syndromes (chronic lymphocytic leukemia, mantle cell lymphoma and follicular lymphoma) and JAM-C+ ones (hairy cell leukemia, marginal zone B-cell lymphoma). Therefore, we propose JAM-C as a new identification tool in B-cell lymphoma diagnosis.

The role of junctional adhesion molecule‐C (JAM‐C) in oxidized LDL‐mediated leukocyte recruitment

The junctional adhesion molecule-C (JAM-C) was recently shown to be a counter receptor for the leukocyte beta2-integrin Mac-1 (CD11b/CD18), thereby mediating interactions between vascular cells, particularly in inflammatory cell recruitment. Here, we investigated the role of JAM-C in oxidized low-density lipoprotein (LDL)-mediated leukocyte recruitment. As compared with normal arteries, immunostaining of atherosclerotic vessels revealed a high expression of JAM-C in association with neointimal smooth muscle cells and the endothelium. Moreover, JAM-C was strongly up-regulated in the spontaneous early lesions in ApoE -/- mice. In vitro, cultured human arterial smooth muscle cells (HASMC) were found to express JAM-C, and oxLDL, as well as enzymatically modified LDL (eLDL) significantly up-regulated JAM-C on both HASMC and endothelial cells in a time- and dose-dependent manner. Although under quiescent conditions, JAM-C predominantly localized to interendothelial cell-cell contacts in close proximity to zonula occludens-1 (ZO-1), oxLDL treatment induced a disorganization of JAM-C localization that was no more restricted to the interendothelial junctions. JAM-C thereby mediated both leukocyte adhesion and leukocyte transendothelial migration upon oxLDL treatment of endothelial cells, whereas JAM-C on quiescent endothelial cells only mediates leukocyte transmigration. Thus, upon oxLDL stimulation endothelial JAM-C functions as both an adhesion, as well as a transmigration receptor for leukocytes. Taken together, JAM-C is up-regulated by oxLDL and may thereby contribute to increased inflammatory cell recruitment during atherosclerosis. JAM-C may therefore provide a novel molecular target for antagonizing interactions between vascular cells in atherosclerosis.