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Identification and validation of G protein-coupled receptors modulating flow-dependent signaling pathways in vascular endothelial cells

Vascular endothelial cells are exposed to mechanical forces due to their presence at the interface between the vessel wall and flowing blood. The patterns of these mechanical forces (laminar vs. turbulent) regulate endothelial cell function and play an important role in determining endothelial pheno...

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Autores principales: Qiu, Dike, Xu, Ke, Chung, Namjin, Robbins, Jennifer, Luo, Robert, Lawrence, Michael, He, Aiqing, Yu, Fei, Alt, Andrew, Miller, Michael M., Hangeland, Jon, Feder, John N., Seiffert, Dietmar, Arey, Brian J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10285409/
https://www.ncbi.nlm.nih.gov/pubmed/37363403
http://dx.doi.org/10.3389/fmolb.2023.1198079
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author Qiu, Dike
Xu, Ke
Chung, Namjin
Robbins, Jennifer
Luo, Robert
Lawrence, Michael
He, Aiqing
Yu, Fei
Alt, Andrew
Miller, Michael M.
Hangeland, Jon
Feder, John N.
Seiffert, Dietmar
Arey, Brian J.
author_facet Qiu, Dike
Xu, Ke
Chung, Namjin
Robbins, Jennifer
Luo, Robert
Lawrence, Michael
He, Aiqing
Yu, Fei
Alt, Andrew
Miller, Michael M.
Hangeland, Jon
Feder, John N.
Seiffert, Dietmar
Arey, Brian J.
author_sort Qiu, Dike
collection PubMed
description Vascular endothelial cells are exposed to mechanical forces due to their presence at the interface between the vessel wall and flowing blood. The patterns of these mechanical forces (laminar vs. turbulent) regulate endothelial cell function and play an important role in determining endothelial phenotype and ultimately cardiovascular health. One of the key transcriptional mediators of the positive effects of laminar flow patterns on endothelial cell phenotype is the zinc-finger transcription factor, krüppel-like factor 2 (KLF2). Given its importance in maintaining a healthy endothelium, we sought to identify endothelial regulators of the KLF2 transcriptional program as potential new therapeutic approaches to treating cardiovascular disease. Using an approach that utilized both bioinformatics and targeted gene knockdown, we identified endothelial GPCRs capable of modulating KLF2 expression. Genetic screening using siRNAs directed to these GPCRs identified 12 potential GPCR targets that could modulate the KLF2 program, including a subset capable of regulating flow-induced KLF2 expression in primary endothelial cells. Among these targets, we describe the ability of several GPCRs (GPR116, SSTR3, GPR101, LGR4) to affect KLF2 transcriptional activation. We also identify these targets as potential validated targets for the development of novel treatments targeting the endothelium. Finally, we highlight the initiation of drug discovery efforts for LGR4 and report the identification of the first known synthetic ligands to this receptor as a proof-of-concept for pathway-directed phenotypic screening to identify novel drug targets.
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spelling pubmed-102854092023-06-23 Identification and validation of G protein-coupled receptors modulating flow-dependent signaling pathways in vascular endothelial cells Qiu, Dike Xu, Ke Chung, Namjin Robbins, Jennifer Luo, Robert Lawrence, Michael He, Aiqing Yu, Fei Alt, Andrew Miller, Michael M. Hangeland, Jon Feder, John N. Seiffert, Dietmar Arey, Brian J. Front Mol Biosci Molecular Biosciences Vascular endothelial cells are exposed to mechanical forces due to their presence at the interface between the vessel wall and flowing blood. The patterns of these mechanical forces (laminar vs. turbulent) regulate endothelial cell function and play an important role in determining endothelial phenotype and ultimately cardiovascular health. One of the key transcriptional mediators of the positive effects of laminar flow patterns on endothelial cell phenotype is the zinc-finger transcription factor, krüppel-like factor 2 (KLF2). Given its importance in maintaining a healthy endothelium, we sought to identify endothelial regulators of the KLF2 transcriptional program as potential new therapeutic approaches to treating cardiovascular disease. Using an approach that utilized both bioinformatics and targeted gene knockdown, we identified endothelial GPCRs capable of modulating KLF2 expression. Genetic screening using siRNAs directed to these GPCRs identified 12 potential GPCR targets that could modulate the KLF2 program, including a subset capable of regulating flow-induced KLF2 expression in primary endothelial cells. Among these targets, we describe the ability of several GPCRs (GPR116, SSTR3, GPR101, LGR4) to affect KLF2 transcriptional activation. We also identify these targets as potential validated targets for the development of novel treatments targeting the endothelium. Finally, we highlight the initiation of drug discovery efforts for LGR4 and report the identification of the first known synthetic ligands to this receptor as a proof-of-concept for pathway-directed phenotypic screening to identify novel drug targets. Frontiers Media S.A. 2023-06-08 /pmc/articles/PMC10285409/ /pubmed/37363403 http://dx.doi.org/10.3389/fmolb.2023.1198079 Text en Copyright © 2023 Qiu, Xu, Chung, Robbins, Luo, Lawrence, He, Yu, Alt, Miller, Hangeland, Feder, Seiffert and Arey. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Qiu, Dike
Xu, Ke
Chung, Namjin
Robbins, Jennifer
Luo, Robert
Lawrence, Michael
He, Aiqing
Yu, Fei
Alt, Andrew
Miller, Michael M.
Hangeland, Jon
Feder, John N.
Seiffert, Dietmar
Arey, Brian J.
Identification and validation of G protein-coupled receptors modulating flow-dependent signaling pathways in vascular endothelial cells
title Identification and validation of G protein-coupled receptors modulating flow-dependent signaling pathways in vascular endothelial cells
title_full Identification and validation of G protein-coupled receptors modulating flow-dependent signaling pathways in vascular endothelial cells
title_fullStr Identification and validation of G protein-coupled receptors modulating flow-dependent signaling pathways in vascular endothelial cells
title_full_unstemmed Identification and validation of G protein-coupled receptors modulating flow-dependent signaling pathways in vascular endothelial cells
title_short Identification and validation of G protein-coupled receptors modulating flow-dependent signaling pathways in vascular endothelial cells
title_sort identification and validation of g protein-coupled receptors modulating flow-dependent signaling pathways in vascular endothelial cells
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10285409/
https://www.ncbi.nlm.nih.gov/pubmed/37363403
http://dx.doi.org/10.3389/fmolb.2023.1198079
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