Role of Junctional Adhesion Molecule-C in the Regulation of Inner Endothelial Blood-Retinal Barrier Function

Abstract

Although JAM-C is abundantly expressed in the retinae and upregulated in choroidal neovascularization (CNV), it remains thus far poorly understood whether it plays a role in the blood-retinal barrier, which is critical to maintain the normal functions of the eye. Here, we report that JAM-C is highly expressed in retinal capillary endothelial cells (RCECs), and VEGF or PDGF-C treatment induced JAM-C translocation from the cytoplasm to the cytomembrane. Moreover, JAM-C knockdown in RCECs inhibited the adhesion and transmigration of macrophages from wet age-related macular degeneration (wAMD) patients to and through RCECs, whereas JAM-C overexpression in RCECs increased the adhesion and transmigration of macrophages from both wAMD patients and healthy controls. Importantly, the JAM-C overexpression-induced transmigration of macrophages from wAMD patients was abolished by the administration of the protein kinase C (PKC) inhibitor GF109203X. Of note, we found that the serum levels of soluble JAM-C were more than twofold higher in wAMD patients than in healthy controls. Mechanistically, we show that JAM-C overexpression or knockdown in RCECs decreased or increased cytosolic Ca2+ concentrations, respectively. Our findings suggest that the dynamic translocation of JAM-C induced by vasoactive molecules might be one of the mechanisms underlying inner endothelial BRB malfunction, and inhibition of JAM-C or PKC in RCECs may help maintain the normal function of the inner BRB. In addition, increased serum soluble JAM-C levels might serve as a molecular marker for wAMD, and modulating JAM-C activity may have potential therapeutic value for the treatment of BRB malfunction-related ocular diseases.

Junctional Adhesion Molecules: Potential Proteins in Atherosclerosis

“…In mouse retinal vascular, JAM-C deficiency increased the spreading of fibronectin and consequently enhanced endothelial cell sprouting and vessel normalization in vitro , dependent on β1-integrin and the small GTPase Rap1 activation ( 149 ). Consistently, VEGF or PDGF-C induced JAM-C translocating from cytoplasm to the cytomembrane to maintain the normal function of the human iBRB, while increased serum sJAM-C was identified as a potential marker of wet age-related macular degeneration (wAMD) ( 150 ). Besides, JAM-A, JAM-B, and especially JAM-C have readily been detected in liver sinusoidal endothelial cells (LSECs), as a part of special mixed-type intercellular junctions ( 151 ).…”

Increased Circulating Soluble Junctional Adhesion Molecules in Systemic Sclerosis: Association with Peripheral Microvascular Impairment

“…Interestingly, increased sJAM levels have been described in other different pathologic conditions. In particular, sJAM-A was found to be higher in patients with coronary artery disease, arterial hypertension, renal insufficiency, and multiple myeloma [19,23,24,26,56], while sJAM-C was shown to be augmented in rheumatoid arthritis and macular degeneration [21,25]. Consistent with our previously published results [7], we herein confirm in a larger sample that both sJAM-A and sJAM-C are predominantly higher in patients with early/active NVC patterns, which are characterized by an ongoing dysregulated angiogenic response resulting in microhemorrhages and immature and unstable giant microvessels, suggesting that an increase in sJAMs might not only reflect but possibly also actively contribute to the derangement of peripheral microcirculation in SSc patients.…”

“…In addition, we not only validated the previously reported association between higher circulating levels of both sJAMs and SSc-related DUs, but, through logistic regression, also uncovered sJAM-C as a better biomarker for more severe peripheral vasculopathy characterized by the development of ischemic DUs. Strikingly, the potential of serum sJAM-C levels as a biomarker was also suggested for wet, age-related macular degeneration, which is characterized by vascular abnormalities into the macula [25].…”

“…Since JAMs may also modulate cell adhesion, migration, and neovascularization, they have been implicated in several pathologic conditions, including cancer, hypertension, rheumatoid arthritis, and inflammatory bowel disease [18][19][20][21]. The soluble forms of these adhesion molecules have also been quantified in the circulation of patients affected by different pathologies, with their levels often correlating with disease severity [19,[21][22][23][24][25][26]. As far as SSc is concerned, an abnormal expression of both JAM-A and JAM-C has been reported in the skin and blood of patients [7,27,28].…”

Tight Junctions of the Neurovascular Unit

“…JAM-A is the predominant isoform in the brain and retinal endothelium regulating permeability changes (Aurrand-Lions et al, 2001;Tomi and Hosoya, 2004). Furthermore, JAM-A and JAM-C have been implicated in leukocyte trafficking as well as junction integrity (Woodfin et al, 2007(Woodfin et al, , 2011Williams et al, 2015;Hou et al, 2021). JAM-C has been shown to play a specific role in regulating microvascular permeability during inflammation by targeting the adherens junction protein vascular endothelial cadherin which can regulate claudin-5 expression via a β-catenin and FoxO1 dependent pathway (Taddei et al, 2008).…”