Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide and encompasses chronic bronchitis and emphysema. It has been shown that vascular wall remodeling and pulmonary hypertension (PH) can occur not only in patients with COPD but also in smokers with normal lung function, suggesting a causal role for vascular alterations in the development of emphysema. Mechanistically, abnormalities in the vasculature, such as inflammation, endothelial dysfunction, imbalances in cellular apoptosis/proliferation, and increased oxidative/nitrosative stress promote development of PH, cor pulmonale, and most probably pulmonary emphysema. Hypoxemia in the pulmonary chamber modulates the activation of key transcription factors and signaling cascades, which propagates inflammation and infiltration of neutrophils, resulting in vascular remodeling. Endothelial progenitor cells have angiogenesis capabilities, resulting in transdifferentiation of the smooth muscle cellsviaaberrant activation of several cytokines, growth factors, and chemokines. The vascular endothelium influences the balance between vaso-constriction and -dilation in the heart. Targeting key players affecting the vasculature might help in the development of new treatment strategies for both PH and COPD. The present review aims to summarize current knowledge about vascular alterations and production of reactive oxygen species in COPD. The present review emphasizes on the importance of the vasculature for the usually parenchyma-focused view of the pathobiology of COPD.

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. FASEB J. 32, 5612–5625 (2018). www.fasebj.org

Aging is an independent risk factor for cardiovascular diseases and therefore of particular interest for the prevention of cardiovascular events. However, the mechanisms underlying vascular aging are not well understood. Since carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) is crucially involved in vascular homeostasis, we sought to identify the role ofCEACAM1 in vascular aging. Using human internal thoracic artery and murine aorta, we show thatCEACAM1 is upregulated in the course of vascular aging. Further analyses demonstrated thatTNF‐α isCEACAM1‐dependently upregulated in the aging vasculature. Vice versa,TNF‐α inducesCEACAM1 expression. This results in a feed‐forward loop in the aging vasculature that maintains a chronic pro‐inflammatory milieu. Furthermore, we demonstrate that age‐associated vascular alterations, that is, increased oxidative stress and vascular fibrosis, due to increased medial collagen deposition crucially depend on the presence ofCEACAM1. Additionally, age‐dependent upregulation of vascularCEACAM1 expression contributes to endothelial barrier impairment, putatively via increasedVEGF/VEGFR‐2 signaling. Consequently, aging‐related upregulation of vascularCEACAM1 expression results in endothelial dysfunction that may promote atherosclerotic plaque formation in the presence of additional risk factors. Our data suggest thatCEACAM1 might represent an attractive target in order to delay physiological aging and therefore the transition to vascular disorders such as atherosclerosis.

The Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), also known as CD66a, is a member of the immunoglobulin superfamily. CEACAM1 was shown to be a prognostic marker in patients suffering from cancer. In this review, we summarize pre-clinical and clinical evidence linking CEACAM1 to tumorigenicity and cancer progression. Furthermore, we discuss potential CEACAM1-based mechanisms that may affect cancer biology.

We previously reported that binding to heparan sulfate (HS) is required for the ability of the placentally secreted pregnancy-specific glycoprotein 1 (PSG1) to induce endothelial tubulogenesis. PSG1 is composed of four immunoglobulin-like domains but which domains of the protein bind to HS remains unknown. To analyze the interaction of PSG1 with HS, we generated several recombinant proteins, including the individual domains, chimeric proteins between two PSG1 domains, and mutants. Using flow cytometric and surface plasmon resonance studies, we determined that the B2 domain of PSG1 binds to HS and that the positively charged amino acids encompassed between amino acids 43–59 are required for this interaction. Furthermore, we showed that the B2 domain of PSG1 is required for the increase in the formation of tubes by endothelial cells (EC) including a human endometrial EC line and two extravillous trophoblast (EVT) cell lines and for the pro-angiogenic activity of PSG1 observed in an aortic ring assay. PSG1 enhanced the migration of ECs while it increased the expression of matrix metalloproteinase-2 in EVTs, indicating that the pro-angiogenic effect of PSG1 on these two cell types may be mediated by different mechanisms. Despite differences in amino acid sequence, we observed that all human PSGs bound to HS proteoglycans and confirmed that at least two other members of the family, PSG6 and PSG9, induce tube formation. These findings contribute to a better understanding of the pro-angiogenic activity of human PSGs and strongly suggest conservation of this function among all PSG family members.

Chronic inflammation with progressive age, called inflammaging, contributes to the pathogenesis of cardiovascular diseases. Previously, we have shown increased vascular expression of the Carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) in aged mice and humans, presumably via mutual upregulation with the pro‐inflammatory cytokine TNF‐α. CEACAM1 is critical for aging‐associated vascular alterations like endothelial dysfunction, fibrosis, oxidative stress, and sustained inflammation and can be regarded as a main contributor to vascular inflammaging. This study was conducted to elucidate the mechanisms underlying endothelial CEACAM1 upregulation by TNF‐α in detail. Using wildtype (WT) and TNF‐α knockout (Tnf^−/−) mice, we confirmed that the aging‐related upregulation of endothelial CEACAM1 critically depends on TNF‐α. The underlying mechanisms were analyzed in an endothelial cell culture model. TNF‐α time‐dependently upregulated CEACAM1 in vitro. In pharmacological experiments, we identified an early NF‐κB‐ and a delayed β‐catenin‐mediated response. Involvement of β‐catenin was further substantiated by siRNA‐mediated knockdown of the β‐catenin‐targeted transcription factor TCF4. Both signaling pathways acted independent from each other. Elucidating the delayed response, co‐immunoprecipitation analysis revealed release of β‐catenin from adherens junctions by TNF‐α. Finally, TNF‐α activated Akt kinase by increasing its Ser⁴⁷³ phosphorylation. Consequently, Akt kinase facilitated β‐catenin signaling by inhibiting its degradation via phosphorylation of GSK3β at Ser⁹ and by increased phosphorylation of β‐catenin at Ser⁵⁵² that augments its transcriptional activity. Taken together, our study provides novel mechanistic insights into the aging‐related, inflammation‐mediated endothelial upregulation of CEACAM1. Beyond the pathogenesis of cardiovascular diseases, these findings may be significant to all fields of inflammaging.