PMID- 36112881 OWN - NLM STAT- MEDLINE DCOM- 20221222 LR - 20230217 IS - 1544-0591 (Electronic) IS - 0022-0345 (Linking) VI - 102 IP - 1 DP - 2023 Jan TI - The Role of Endothelial Barrier Function in the Fibrosis of Salivary Gland. PG - 82-92 LID - 10.1177/00220345221118508 [doi] AB - In the salivary glands, fibrosis occurs in many pathological conditions. Endothelial tight junction (TJ)-based barrier function plays a vital role in maintaining the homeostasis of the salivary glands. However, whether endothelial barrier function is changed and involved in the pathogenesis of glandular fibrosis is unknown. Here, by using a mouse model in which the main excretory duct of the submandibular gland (SMG) was ligated to induce inflammation and fibrosis, endothelial barrier function and TJ protein expression and distribution were examined. Both 4-kDa and 70-kDa fluorescence-labeled dextrans permeated more in the 1-, 3-, and 7-d ligated SMGs. Meanwhile, the mRNA level of claudin-5 was increased with an obvious redistribution from apicolateral membranes to lateral membranes and cytoplasm in the fibrotic glands. Notably, the TJ sealer AT1001 significantly attenuated the disrupted endothelial barrier function and thereby ameliorated the glandular fibrosis. Cytokine array detection showed that monocyte chemoattractant protein-1 (MCP-1) was highly enriched in the 3-d ligated SMGs, and MCP-1 directly impaired barrier function, increased claudin-5 expression, induced the relocalization of claudin-5, and activated p-ERK1/2 in cultured human endothelial cells. Furthermore, the upregulation and disorganization of claudin-5 as well as the elevation of MCP-1 and p-ERK1/2 signaling were also confirmed in fibrotic SMGs from patients with chronic sialadenitis and immunoglobulin G4-related sialadenitis. Altogether, our findings revealed that disrupted endothelial barrier function contributed to the progression of glandular fibrosis, and targeting endothelial TJs might be a promising approach to alleviate salivary gland fibrosis-related diseases. FAU - Mao, X D AU - Mao XD AD - Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, P.R. China. FAU - Min, S N AU - Min SN AD - Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, P.R. China. FAU - Zhu, M Q AU - Zhu MQ AD - Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, P.R. China. FAU - He, L AU - He L AD - Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, P.R. China. FAU - Zhang, Y AU - Zhang Y AD - Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, P.R. China. FAU - Li, J W AU - Li JW AD - Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, P.R. China. FAU - Tian, Y X AU - Tian YX AD - Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, P.R. China. FAU - Yu, G Y AU - Yu GY AD - Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, P.R. China. FAU - Wu, L L AU - Wu LL AD - Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, P.R. China. FAU - Cong, X AU - Cong X AD - Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, P.R. China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220912 PL - United States TA - J Dent Res JT - Journal of dental research JID - 0354343 RN - 0 (Claudin-5) RN - 0 (Tight Junction Proteins) SB - IM MH - Humans MH - Claudin-5/metabolism MH - *Endothelial Cells MH - Salivary Glands/metabolism MH - Submandibular Gland/metabolism MH - Tight Junction Proteins/metabolism MH - *Sialadenitis MH - Tight Junctions/metabolism OTO - NOTNLM OT - AT1001 OT - claudin-5 OT - endothelium OT - fibrogenesis OT - monocyte chemoattractant protein-1 OT - submandibular gland EDAT- 2022/09/17 06:00 MHDA- 2022/12/23 06:00 CRDT- 2022/09/16 15:34 PHST- 2022/09/17 06:00 [pubmed] PHST- 2022/12/23 06:00 [medline] PHST- 2022/09/16 15:34 [entrez] AID - 10.1177/00220345221118508 [doi] PST - ppublish SO - J Dent Res. 2023 Jan;102(1):82-92. doi: 10.1177/00220345221118508. Epub 2022 Sep 12.