PMID- 33888544
OWN - NLM
STAT- MEDLINE
DCOM- 20210621
LR  - 20220531
IS  - 2052-4897 (Electronic)
IS  - 2052-4897 (Linking)
VI  - 9
IP  - 1
DP  - 2021 Apr
TI  - Orai-vascular endothelial-cadherin signaling complex regulates high-glucose 
      exposure-induced increased permeability of mouse aortic endothelial cells.
LID - 10.1136/bmjdrc-2020-002085 [doi]
LID - e002085
AB  - INTRODUCTION: Diabetes-associated endothelial barrier function impairment might 
      be linked to disturbances in Ca(2+) homeostasis. To study the role and molecular 
      mechanism of Orais-vascular endothelial (VE)-cadherin signaling complex and its 
      downstream signaling pathway in diabetic endothelial injury using mouse aortic 
      endothelial cells (MAECs). RESEARCH DESIGN AND METHODS: The activity of 
      store-operated Ca(2+) entry (SOCE) was detected by calcium imaging after 7 days 
      of high-glucose (HG) or normal-glucose (NG) exposure, the expression levels of 
      Orais after HG treatment was detected by western blot analysis. The effect of HG 
      exposure on the expression of phosphorylated (p)-VE-cadherin and VE-cadherin on 
      cell membrane was observed by immunofluorescence assay. HG-induced 
      transendothelial electrical resistance was examined in vitro after MAECs were 
      cultured in HG medium. FD-20 permeability was tested in monolayer aortic 
      endothelial cells through transwell permeability assay. The interactions between 
      Orais and VE-cadherin were detected by co-immunoprecipitation and 
      immunofluorescence technologies. Immunohistochemical experiment was used to 
      detect the expression changes of Orais, VE-cadherin and p-VE-cadherin in aortic 
      endothelium of mice with diabetes. RESULTS: (1) The expression levels of Orais 
      and activity of SOCE were significantly increased in MAECs cultured in HG for 7 
      days. (2) In MAECs cultured in HG for 7 days, the ratio of p-VE-cadherin to 
      VE-cadherin expressed on the cell membrane and the FD-20 permeability in 
      monolayer endothelial cells increased, indicating that intercellular permeability 
      increased. (3) Orais and VE-cadherin can interact and enhance the interaction 
      ratio through HG stimulation. (4) In MAECs cultured with HG, the SOCE activator 
      ATP enhanced the expression level of p-VE-cadherin, and the SOCE inhibitor BTP2 
      decreased the expression level of p-VE-cadherin. (5) Significantly increased 
      expression of p-VE-cadherin and Orais in the aortic endothelium of mice with 
      diabetes. CONCLUSION: HG exposure stimulated increased expression of Orais in 
      endothelial cells, and increased VE-cadherin phosphorylation through 
      Orais-VE-cadherin complex and a series of downstream signaling pathways, 
      resulting in disruption of endothelial cell junctions and initiation of 
      atherosclerosis.
CI  - (c) Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No 
      commercial re-use. See rights and permissions. Published by BMJ.
FAU - Wei, Yuan
AU  - Wei Y
AD  - School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China.
AD  - Longgang District People's Hospital of Shenzhen & The Third Affiliated Hospital 
      (Provisional) of The Chinese University of Hong Kong, Shenzhen, Guangdong, China.
FAU - Bai, Suwen
AU  - Bai S
AD  - School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China.
FAU - Yao, YanHeng
AU  - Yao Y
AD  - School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China.
FAU - Hou, Wenxuan
AU  - Hou W
AD  - School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China.
FAU - Zhu, Junwei
AU  - Zhu J
AD  - Otolaryngology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 
      Municipal Hospital, Jiangsu, China.
FAU - Fang, Haoshu
AU  - Fang H
AUID- ORCID: 0000-0003-3108-6305
AD  - Department of Pathophysiology, Anhui Medical University, Hefei, Anhui, China.
FAU - Du, Yinan
AU  - Du Y
AD  - School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China.
FAU - He, Wei
AU  - He W
AD  - School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China.
FAU - Shen, Bing
AU  - Shen B
AUID- ORCID: 0000-0001-7263-4748
AD  - School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China.
FAU - Du, Juan
AU  - Du J
AD  - School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China 
      dujuan@cuhk.edu.cn.
AD  - Longgang District People's Hospital of Shenzhen & The Third Affiliated Hospital 
      (Provisional) of The Chinese University of Hong Kong, Shenzhen, Guangdong, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - BMJ Open Diabetes Res Care
JT  - BMJ open diabetes research & care
JID - 101641391
RN  - 0 (Antigens, CD)
RN  - 0 (Cadherins)
RN  - 0 (Calcium Release Activated Calcium Channels)
RN  - 0 (cadherin 5)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Antigens, CD
MH  - *Cadherins
MH  - *Calcium Release Activated Calcium Channels
MH  - Cells, Cultured
MH  - *Endothelial Cells
MH  - Glucose
MH  - Mice
MH  - Permeability
MH  - Signal Transduction
PMC - PMC8070857
OTO - NOTNLM
OT  - atherosclerosis
COIS- Competing interests: None declared.
EDAT- 2021/04/24 06:00
MHDA- 2021/06/22 06:00
PMCR- 2021/04/22
CRDT- 2021/04/23 05:45
PHST- 2020/12/18 00:00 [received]
PHST- 2021/02/12 00:00 [revised]
PHST- 2021/02/22 00:00 [accepted]
PHST- 2021/04/23 05:45 [entrez]
PHST- 2021/04/24 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2021/04/22 00:00 [pmc-release]
AID - 9/1/e002085 [pii]
AID - bmjdrc-2020-002085 [pii]
AID - 10.1136/bmjdrc-2020-002085 [doi]
PST - ppublish
SO  - BMJ Open Diabetes Res Care. 2021 Apr;9(1):e002085. doi: 
      10.1136/bmjdrc-2020-002085.