Endothelial barrier function is differentially regulated by CEACAM1‐mediated signaling

Abstract

Carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) is known to be crucial to vasculogenesis and angiogenesis. Recently, CEACAM1 deficiency was shown to result in the formation of aortic plaque-like lesions, indicating a role for CEACAM1 in adult vessels as well. The underlying mechanisms remained largely elusive. Therefore, we aimed to elucidate the role of CEACAM1 in endothelial homeostasis. Here, we show that CEACAM1 deficiency causes subcellular eNOS redistribution in endothelial cells ( i.e., by eNOS depalmitoylation) and alters endothelial glycocalyx that confers antiadhesive properties to the endothelium ( i.e., by repression of glycocalyx-degrading enzymes). Accordingly, our analysis revealed an increased leukocyte-endothelial interaction in CEACAM1-deficient endothelium. In addition, CEACAM1 age dependently modulated basal and TNF-α-mediated endothelial barrier (EB) leakiness. In younger mice, CEACAM1 was protective for EB, whereas in aged mice it promoted EB leakiness. EB function depends on interendothelial adherence junctions formed by β-catenin/vascular endothelial-cadherin complexes. We show here that CEACAM1 influenced basal and TNF-α-mediated phosphorylation of β-catenin and caveolin-1, which are essential players in EB modulation. Both increased adhesiveness to leukocytes and EB modulation due to CEACAM1 deficiency may facilitate inflammatory cell transmigration into the vascular wall and subsequent plaque formation. Collectively, these results identify a crucial role for CEACAM1 in endothelial homeostasis of adult blood vessels.-Ghavampour, S., Kleefeldt, F., Bömmel, H., Volland, J., Paus, A., Horst, A., Pfeiffer, V., Hübner, S., Wagner, N., Rueckschloss, U., Ergün, S. Endothelial barrier function is differentially regulated by CEACAM1-mediated signaling.

Aging‐related carcinoembryonic antigen‐related cell adhesion molecule 1 signaling promotes vascular dysfunction

“…The immunoreaction was detected using peroxidase–antiperoxidase and avidin–biotin complex methods by a modified nickel‐enhanced glucose oxidase technique (Kilic & Ergün, ). Immunoblot experiments were conducted according to a protocol described before (Ghavampour et al., ; Oliveira‐Ferrer et al., ). Primary antibodies used in this study are listed in .…”

“…On the other hand, CEACAM1 was shown to upregulate the endothelial expression of VEGF and VEGFR‐2 (Kilic et al., ). Furthermore, we have previously shown that in the presence of TNF‐α, CEACAM1 recruits Src kinase to intercellular adhesion sites, thereby promoting the phosphorylation of adherens junction proteins and increasing vascular permeability (Ghavampour et al., ).…”

Metastatic cancer cell attachment to endothelium is promoted by endothelial glycocalyx sialic acid degradation

“…GCX covers most mammalian cells. For endothelial cells (ECs), a healthy GCX forms a selective barrier between ECs and their neighboring environment, by blocking adhesion receptors on the endothelium from binding to ligands on cells and certain molecules from the environment (Figure a) . The EC GCX is composed of a variety of sugar chains, glycoproteins, and soluble proteins.…”

Development of a Bioinformatics Framework for Identification and Validation of Genomic Biomarkers and Key Immunopathology Processes and Controllers in Infectious and Non-infectious Severe Inflammatory Response Syndrome

“…RETN (resistin) is an immune-associated entity and a component of neutrophil exocytic granules (155) and inhibits essential neutrophil functions e.g., the oxidative burst (156). CEACAM1 is expressed on a variety of immune cells (42, 157), including neutrophils (158) and is a key receptor involved in binding of these cells to endothelial cells during the process of exvagination from the periphery into tissue locations (159,160). CDADC1 (cytidine and dCMP deaminase domain containing 1) is reportedly a testis-specific protein involved in testis development (161), however it may play a role in regulating the cell cycle and proliferation (162,163).…”