PMID- 35284541 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220315 IS - 2305-5839 (Print) IS - 2305-5847 (Electronic) IS - 2305-5839 (Linking) VI - 10 IP - 3 DP - 2022 Feb TI - Sphingosine 1-phosphate receptor 1 governs endothelial barrier function and angiogenesis by upregulating endoglin signaling. PG - 136 LID - 10.21037/atm-21-6679 [doi] LID - 136 AB - BACKGROUND: The sphingosine 1-phosphate (S1P)/S1P receptor (S1pr) 1 signaling plays an essential role in regulating vascular integrity and angiogenesis. We have previously shown that cell-surface expression of endoglin (Eng) is sustained by S1P/S1pr1 signaling in endothelial cells (ECs). However, whether S1pr1 mediates Eng signaling, or vice versa, remains unknown. METHODS: S1pr1 inhibitors were used to study whether pharmacological inhibition induces basal vascular leakage in vivo. An acute respiratory distress syndrome (ARDS) model was used to study whether S1pr1 inhibition evoked greater inflammation in lungs. A S1pr1 inhibitor, a bone morphogenetic protein 9 (BMP9) blocking antibody, or lentivirus-mediated expression of soluble extracellular domain of Eng (sEng) were used to test whether blocking both S1P/S1pr1 and BMP9/Eng signaling axes would impose any interaction in retinal angiogenesis. To clarify whether S1P and BMP9 function in a linear pathway, a study of trans-endothelial electrical resistance (TEER) measurement was carried out using a mouse islet EC line MS1; time course studies were executed to exam downstream effectors of S1P and BMP9 signaling pathways in ECs; two stable MS1 cell lines were generated, one with overexpression of human S1PR1 and the other with knockdown of Eng, to validate S1pr1 and Eng were the key players for the crosstalk. Inhibitor of extracellular regulated protein kinases (ERK) was used to check whether this signaling was involved in S1P-induced cell-surface localization of Eng. RESULTS: The present study elucidated that S1pr1 and Eng are both pivotal for angiogenesis in the postnatal mouse retina, and that the activation of S1pr1 or Eng increases vascular barrier function. Activation of S1pr1 enhanced the phosphorylation of Smad family members 1, 5, and 8 (pSmad1/5/8), while the inhibition of S1pr1 reduced the levels of pSma1/5/8 induced by BMP9 treatment. Activation or loss of Eng did not affect S1pr1 signaling. Moreover, activation of ERK was involved in promoting EC-surface expression of Eng by S1pr1. CONCLUSIONS: Our data demonstrates for the first time that there exists a linear pathway of S1pr1-Eng signaling axis in ECs, which governs vascular homeostasis. Functional BMP9/Eng signaling requires S1P/S1pr1 activation, and S1pr1 signaling acts as a vascular protection mechanism upstream of Eng. CI - 2022 Annals of Translational Medicine. All rights reserved. FAU - Wang, Beibei AU - Wang B AD - Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Dong, Nian AU - Dong N AD - Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Wu, Dengmin AU - Wu D AD - The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Fang, Ya AU - Fang Y AD - Department of Radiotherapy Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Chen, Junjie AU - Chen J AD - Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Lin, Yuting AU - Lin Y AD - Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Bellusci, Saverio AU - Bellusci S AD - Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. AD - Cardio-Pulmonary Institute and Department of Pulmonary and Critical Care Medicine and Infectious Diseases, Universities of Giessen and Marburg Lung Center (UGMLC), the German Center for Lung Research (DZL), Justus-Liebig University Giessen, Giessen, Germany. FAU - Zhang, Jin-San AU - Zhang JS AD - Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. AD - International Collaborative Center on Growth Factor Research and School of Pharmaceutical Sciences, Wenzhou Medical University; Institute of Life Sciences, Wenzhou University, Wenzhou, China. FAU - Dai, Kezhi AU - Dai K AD - Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. AD - School of Mental Health, Wenzhou Medical University, Wenzhou, China. FAU - Chen, Chengshui AU - Chen C AD - Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. AD - The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China. LA - eng PT - Journal Article PL - China TA - Ann Transl Med JT - Annals of translational medicine JID - 101617978 PMC - PMC8904984 OTO - NOTNLM OT - S1pr1 OT - angiogenesis OT - endoglin (Eng) OT - endothelial cells (ECs) OT - vascular integrity COIS- Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-21-6679/coif). The authors have no conflicts of interest to declare. EDAT- 2022/03/15 06:00 MHDA- 2022/03/15 06:01 PMCR- 2022/02/01 CRDT- 2022/03/14 06:00 PHST- 2021/11/16 00:00 [received] PHST- 2022/01/11 00:00 [accepted] PHST- 2022/03/14 06:00 [entrez] PHST- 2022/03/15 06:00 [pubmed] PHST- 2022/03/15 06:01 [medline] PHST- 2022/02/01 00:00 [pmc-release] AID - atm-10-03-136 [pii] AID - 10.21037/atm-21-6679 [doi] PST - ppublish SO - Ann Transl Med. 2022 Feb;10(3):136. doi: 10.21037/atm-21-6679.