ORAI1 Ca2+ Channel as a Therapeutic Target in Pathological Vascular Remodelling
In the adult, vascular smooth muscle cells (VSMC) are normally physiologically quiescent, arranged circumferentially in one or more layers within blood vessel walls. Remodelling of native VSMC to a proliferative state for vascular development, adaptation or repair is driven by platelet-derived growt...
Main Authors: | , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Frontiers Media S.A.
2021-04-01
|
Series: | Frontiers in Cell and Developmental Biology |
Subjects: | |
Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.653812/full |
id |
doaj-18b587ef040848e0b8635a4206cc25fe |
---|---|
record_format |
Article |
spelling |
doaj-18b587ef040848e0b8635a4206cc25fe2021-04-15T16:20:28ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-04-01910.3389/fcell.2021.653812653812ORAI1 Ca2+ Channel as a Therapeutic Target in Pathological Vascular RemodellingHeba Shawer0Katherine Norman1Katherine Norman2Chew W. Cheng3Richard Foster4Richard Foster5David J. Beech6Marc A. Bailey7School of Medicine, The Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United KingdomSchool of Medicine, The Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United KingdomSchool of Chemistry, University of Leeds, Leeds, United KingdomSchool of Medicine, The Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United KingdomSchool of Medicine, The Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United KingdomSchool of Chemistry, University of Leeds, Leeds, United KingdomSchool of Medicine, The Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United KingdomSchool of Medicine, The Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United KingdomIn the adult, vascular smooth muscle cells (VSMC) are normally physiologically quiescent, arranged circumferentially in one or more layers within blood vessel walls. Remodelling of native VSMC to a proliferative state for vascular development, adaptation or repair is driven by platelet-derived growth factor (PDGF). A key effector downstream of PDGF receptors is store-operated calcium entry (SOCE) mediated through the plasma membrane calcium ion channel, ORAI1, which is activated by the endoplasmic reticulum (ER) calcium store sensor, stromal interaction molecule-1 (STIM1). This SOCE was shown to play fundamental roles in the pathological remodelling of VSMC. Exciting transgenic lineage-tracing studies have revealed that the contribution of the phenotypically-modulated VSMC in atherosclerotic plaque formation is more significant than previously appreciated, and growing evidence supports the relevance of ORAI1 signalling in this pathologic remodelling. ORAI1 has also emerged as an attractive potential therapeutic target as it is accessible to extracellular compound inhibition. This is further supported by the progression of several ORAI1 inhibitors into clinical trials. Here we discuss the current knowledge of ORAI1-mediated signalling in pathologic vascular remodelling, particularly in the settings of atherosclerotic cardiovascular diseases (CVDs) and neointimal hyperplasia, and the recent developments in our understanding of the mechanisms by which ORAI1 coordinates VSMC phenotypic remodelling, through the activation of key transcription factor, nuclear factor of activated T-cell (NFAT). In addition, we discuss advances in therapeutic strategies aimed at the ORAI1 target.https://www.frontiersin.org/articles/10.3389/fcell.2021.653812/fullORAI1STIM1calciumvascular remodellingstore operated calcium entryvascular smooth muscle |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Heba Shawer Katherine Norman Katherine Norman Chew W. Cheng Richard Foster Richard Foster David J. Beech Marc A. Bailey |
spellingShingle |
Heba Shawer Katherine Norman Katherine Norman Chew W. Cheng Richard Foster Richard Foster David J. Beech Marc A. Bailey ORAI1 Ca2+ Channel as a Therapeutic Target in Pathological Vascular Remodelling Frontiers in Cell and Developmental Biology ORAI1 STIM1 calcium vascular remodelling store operated calcium entry vascular smooth muscle |
author_facet |
Heba Shawer Katherine Norman Katherine Norman Chew W. Cheng Richard Foster Richard Foster David J. Beech Marc A. Bailey |
author_sort |
Heba Shawer |
title |
ORAI1 Ca2+ Channel as a Therapeutic Target in Pathological Vascular Remodelling |
title_short |
ORAI1 Ca2+ Channel as a Therapeutic Target in Pathological Vascular Remodelling |
title_full |
ORAI1 Ca2+ Channel as a Therapeutic Target in Pathological Vascular Remodelling |
title_fullStr |
ORAI1 Ca2+ Channel as a Therapeutic Target in Pathological Vascular Remodelling |
title_full_unstemmed |
ORAI1 Ca2+ Channel as a Therapeutic Target in Pathological Vascular Remodelling |
title_sort |
orai1 ca2+ channel as a therapeutic target in pathological vascular remodelling |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cell and Developmental Biology |
issn |
2296-634X |
publishDate |
2021-04-01 |
description |
In the adult, vascular smooth muscle cells (VSMC) are normally physiologically quiescent, arranged circumferentially in one or more layers within blood vessel walls. Remodelling of native VSMC to a proliferative state for vascular development, adaptation or repair is driven by platelet-derived growth factor (PDGF). A key effector downstream of PDGF receptors is store-operated calcium entry (SOCE) mediated through the plasma membrane calcium ion channel, ORAI1, which is activated by the endoplasmic reticulum (ER) calcium store sensor, stromal interaction molecule-1 (STIM1). This SOCE was shown to play fundamental roles in the pathological remodelling of VSMC. Exciting transgenic lineage-tracing studies have revealed that the contribution of the phenotypically-modulated VSMC in atherosclerotic plaque formation is more significant than previously appreciated, and growing evidence supports the relevance of ORAI1 signalling in this pathologic remodelling. ORAI1 has also emerged as an attractive potential therapeutic target as it is accessible to extracellular compound inhibition. This is further supported by the progression of several ORAI1 inhibitors into clinical trials. Here we discuss the current knowledge of ORAI1-mediated signalling in pathologic vascular remodelling, particularly in the settings of atherosclerotic cardiovascular diseases (CVDs) and neointimal hyperplasia, and the recent developments in our understanding of the mechanisms by which ORAI1 coordinates VSMC phenotypic remodelling, through the activation of key transcription factor, nuclear factor of activated T-cell (NFAT). In addition, we discuss advances in therapeutic strategies aimed at the ORAI1 target. |
topic |
ORAI1 STIM1 calcium vascular remodelling store operated calcium entry vascular smooth muscle |
url |
https://www.frontiersin.org/articles/10.3389/fcell.2021.653812/full |
work_keys_str_mv |
AT hebashawer orai1ca2channelasatherapeutictargetinpathologicalvascularremodelling AT katherinenorman orai1ca2channelasatherapeutictargetinpathologicalvascularremodelling AT katherinenorman orai1ca2channelasatherapeutictargetinpathologicalvascularremodelling AT chewwcheng orai1ca2channelasatherapeutictargetinpathologicalvascularremodelling AT richardfoster orai1ca2channelasatherapeutictargetinpathologicalvascularremodelling AT richardfoster orai1ca2channelasatherapeutictargetinpathologicalvascularremodelling AT davidjbeech orai1ca2channelasatherapeutictargetinpathologicalvascularremodelling AT marcabailey orai1ca2channelasatherapeutictargetinpathologicalvascularremodelling |
_version_ |
1721526194361335808 |