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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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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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. |
format | Online Article Text |
id | pubmed-10285409 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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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