The Role of Nitric Oxide Signaling in the Pathogenesis of Necrotizing Enterocolitis
David J. Hackam in Necrotizing Enterocolitis, 2021
Endothelial barrier function: Endothelium forms a blood–tissue barrier that allows transfer of solutes but not macromolecules, which is important for tissue homeostasis. As a part of an inflammatory response, endothelial barrier permeability increases, allowing passage of macromolecules and increasing blood–tissue exchange (127). NO plays important roles in both endothelial homeostasis and inflammatory hyperpermeability. Low levels of eNOS-derived NO strengthen the endothelial barrier via cGMP (128, 129), countering the barrier-weakening effect of vascular endothelial growth factor (VEGF) (130), endothelin 1 (131), and inflammatory cytokines (132). eNOS deficiency predisposes mice to NEC, pointing to the protective role of eNOS-NO-dependent homeostasis (38, 133). By contrast, high levels of NO dramatically increase endothelial barrier permeability via protein S-nitrosylation and/or peroxynitrite (134, 135). Targets of S-nitrosylation in this response include VASP (136), adherens junction proteins β-catein, and p120 catenin (137–139). Peroxynitrite acts by nitrating tyrosine in β-catenin (140), protein phosphatase 2A (PP2A) (141), and promoting internalization and lysosomal degradation of the tight junction protein claudin-5 (142).
The blood–brain and gut–vascular barriers: from the perspective of claudins
Published in Tissue Barriers, 2021
Anna Agata Scalise, Nikolaos Kakogiannos, Federica Zanardi, Fabio Iannelli, Monica Giannotta
Due to the endothelial cell heterogeneity between and within tissues with different functions, the vasculature of two segments of the intestine (i.e., colon, small intestine) has been compared to the brain vessels.3 Exploiting the single-cell transcriptome dataset from Carmeliet and colleagues, we provide here evidence that in the adherens junctions of the brain, colon and small intestine endothelial cells, the gene expression levels are similar for VE-cadherin (Cdh5), α-catenin (Ctnna1), β-catenin (Ctnnb1), p120 (Ctnnd1) and plakoglobin (Jup). Similarly, in the tight junctions, the expression levels of junctional adhesion molecule-A (F11r), junctional adhesion molecule-B (Jam-2), endothelial cell adhesion molecule (Esam), zonula occludens-1 (Tjp1) and zonula occludens-2 (Tjp2) are comparable (Figure 2(a)). Instead, the expression levels for occludin (Ocln) and claudin-5 (Cldn5) are remarkably high in the brain. In addition, a number of the claudins, including claudins-7, −12, −15 and −34c1, show differential expression between the brain and the intestine (Figure 2(b)). Interestingly, these data on claudins distributions suggested that the diverse barrier functions of endothelial tissues reflect the use of the different claudins and indicate that claudin expression patterns might indeed be responsible for the known variations in permeability.
Clinical characteristics and mutation spectrum in 33 Chinese families with familial exudative vitreoretinopathy
Published in Annals of Medicine, 2022
Jianbo Mao, Yijing Chen, Yuyan Fang, Yirun Shao, Ziyi Xiang, Hanxiao Li, Shixin Zhao, Yiqi Chen, Lijun Shen
LRP5, which was present in 38.1% of cases in our study, was the most frequently occurring of the five genes with variants associated with FEVR, while ZNF408 had no pathogenic variants, concordant with previous studies [21]. The gene mutation detection rates in FEVR seem to vary from study to study. Rao et al. [21] reported variants in LRP5, FZD4, TSPAN12, NDP and KIF11 that accounted for 38.7% of patients with FEVR from 31 family pedigrees. Wang et al. [26] showed that up to 51.2% of the families had identifiable variants. It is possible that numerous uncharacterized pathogenic genes for FEVR remain undiscovered. LRP5, FZD4, TSPAN12, NDP, LRP6 and CTNNB1 have been identified as components of the Norrin/β-catenin signalling pathway. This pathway is highly conserved in biological evolution, playing a significant role in retinal angiogenesis. Recent studies have suggested that RCBTB1, CTNND1, CTNNA1, ILK and DLG1 also participate in the regulation of the Norrin/β-catenin signalling pathway, resulting in abnormal growth of retinal blood vessels. Additionally, Notch ligand JAG1 was reported to be a novel candidate gene for FEVR. These findings indicate that the pathogenesis of FEVR involves multiple signalling pathways.
Critical roles of adherens junctions in diseases of the oral mucosa
Published in Tissue Barriers, 2023
Christina Kingsley, Antonis Kourtidis
In addition to Non-Syndromic Cleft Lip and Palate, genes that cause Syndromic Cleft Lip and Palate SCL/P can be caused by syndromes, such as Van der Woude syndrome, Ectodermal dysplasia, and Blepharocheilodontic syndrome. Blepharocheilodontic syndrome presents at birth with not solely cleft lip and palate, but also with dental and eyelid anomalies. Mutations of the CDH1 gene, which encodes E-cadherin, and in the CTNND1 gene, which encodes p120, have also been linked to Blepharocheilodontic syndrome.105 These mutations disrupt formation of the AJs and cause overall impairment of cell–cell adhesion, resulting in numerous clinical manifestations, such as cancer progression, as well as congenital abnormalities such as neural tube defects or orofacial clefting.106 The above demonstrate the critical roles of AJ components in oral diseases and offer opportunities for further investigation and for the development of new genetic tests for congenital diseases.
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