GPR68 senses flow and is essential for vascular physiology
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE111784 | GEO | 2018/04/19
REPOSITORIES: GEO
Similar Datasets
Project description:GPR68 senses flow and is essential for vascular physiology
| PRJNA438129 | ENA
Project description:Mechanotransduction plays a crucial role in vascular biology. One example of this is the local regulation of vascular resistance via flow-mediated dilation (FMD). Impairment of this process is a hallmark of endothelial dysfunction and a precursor to a wide array of vascular diseases, such as hypertension and atherosclerosis. Yet the molecules responsible for sensing flow (shear stress) within endothelial cells remain largely unknown. We designed a 384-well screening system that applies shear stress on cultured cells. We identified a mechanosensitive cell line that exhibits shear stress-activated calcium transients, screened a focused RNAi library, and identified GPR68 as necessary and sufficient for shear stress responses. GPR68 is expressed in endothelial cells of small-diameter (resistance) arteries. Importantly, Gpr68-deficient mice display markedly impaired acute FMD and chronic flow-mediated outward remodeling in mesenteric arterioles. Therefore, GPR68 is an essential flow sensor in arteriolar endothelium and is a critical signaling component in cardiovascular pathophysiology.
| S-EPMC5951615 | biostudies-literature
Project description:Endothelin-1 (ET-1), an endothelium-derived vasoconstrictor peptide, plays a role in the pathophysiology of cardiovascular disease. Transgenic mice that overexpress human preproET-1 selectively in the endothelium (eET-1) exhibit endothelial dysfunction, hypertrophic remodeling and vascular inflammation of resistance-size arteries in the absence of blood pressure elevation. To understand the mechanisms whereby ET-1 induces vascular damage, vascular gene expression using DNA microarrays was employed. RNA from mesenteric arteries of female and male young (6-7 weeks) and mature (6-8 months) eET-1 and wild type (WT) mice was isolated and changes in gene expression were determined by genome-wide expression profiling using Illumina microarray. This study revealed a set of genes potentially regulated by ET-1, which might be implicated in ET-1 induced-vascular damage.
2010-09-01 | GSE19624 | GEO
Project description:Fate decisions of haematopoietic stem cells (HSCs) to self-renew or differentiate in response to various demands are finely tuned by specialized microenvironments called “niches” in the bone marrow. Recent studies suggest that arterioles and sinusoids accompanied with distinct stromal cells marked by nerve/glial antigen 2 (NG2) and leptin receptor (LepR), compose distinct niches regulating quiescence and proliferation of HSCs, respectively. However, it remains unknown how the distinct niche cells differentially regulate the HSC functions. Here we show that effects of cytokines regulating HSC functions are dependent on the producing cell sources. Deletion of chemokine C-X-C motif ligand 12 (CXCL12) in NG2-cre targeted cells, which exclusively overlap with Nestin-GFP (Nes-GFP)+ stromal cells associated with arterioles and sinusoids, resulted in a robust reductions of HSCs in the bone marrow and massive mobilization. Deletion of CXCL12 from arteriolar NG2+ vascular smooth muscle cells caused a significant decrease of HSCs and altered HSC location in the marrow, while CXCL12 depletion from sinusoidal LepR+ cells did not reduce HSC numbers in the bone marrow. By contrast, deletion of stem cell factor (SCF) in LepR+ cells led to significant reductions in HSC numbers whereas SCF deletion in arteriolar NG2+ cells showed no effect on HSC numbers in the marrow. These results uncover the distinct contributions of cytokines derived from perivascular cells in separate vascular niches for HSC maintenance and mobilization. We sought to obtain comprehensive understanding of differences between peri-arteriolar and peri-sinusoidal niche cells by the present RNA-seq analysis.
2017-02-19 | GSE89811 | GEO
Project description:Both sensory and metabolic processes guide food intake. Olfactory inputs help coordinate food appreciation and selection, but their role in food consumption and post-feeding physiology remains poorly understood. In this study, using Drosophila melanogaster as a model system, we investigated the effects of olfactory sensory neurons (OSNs) on food consumption, metabolism, and stress responses. We found that dysfunction of OSNs affects diverse processes, including decreased food consumption, increased triacylglycerol level, enhanced stress resistance to starvation or desiccation, and decreased cold resistance. Decreased neuropeptide F receptor (NPFR) level or increased insulin activity in OSNs inhibited food consumption, while impaired NPF signaling or insulin signaling in OSNs increased resistance to starvation and desiccation. These studies provide insights into the function of the olfactory system in control of feeding behaviors and physiology.
| S-EPMC9011337 | biostudies-literature
Project description:High laminar shear stress (HLSS), as observed in straight parts of arteries, assures a quiescent non-activated endothelium through the induction of the Krüppel-like transcription factors KLF2 and KLF4. Cx40-mediated gap junctional communication contributes to a healthy endothelium by propagating adenosine-evoked anti-inflammatory signals between endothelial cells. As the promoter of the Cx40 gene contains KLF consensus binding sites, we hypothesize that HLSS through the modulation of KLF4, may affect Cx40 expression in ECs, which may affect the quiescent non-activated state of the endothelium.
2019-10-24 | GSE118717 | GEO
Project description:Brain acid signaling plays important roles in both physiological and disease conditions. One key neuronal metabotropic proton receptor in the brain is GPR68, which contributes to hippocampal long-term potentiation (LTP) and mediates neuroprotection in acidotic and ischemic conditions. Here, to gain greater understanding of GPR68 function in the brain, we performed mRNA-Seq analysis in mice. First, we studied sham-operated animals to determine baseline expression. Compared to wild type (WT), GPR68−/− (KO) brain downregulated genes that are enriched in Gene Ontology (GO) terms of misfolding protein binding, response to organic cyclic compounds, and endoplasmic reticulum chaperone complex. Next, we examined the expression profile following transient middle cerebral artery occlusion (tMCAO). tMCAO-upregulated genes cluster to cytokine/chemokine-related functions and immune responses, while tMCAO-downregulated genes cluster to channel activities and synaptic signaling. For proton-sensitive receptors, tMCAO downregulated ASIC1a and upregulated GPR4 and GPR65, but had no effect on ASIC2, PAC, or GPR68. GPR68 deletion did not alter the expression of these proton receptors, either at baseline or after ischemia. Lastly, we performed GeneVenn analysis of differential genes at baseline and post-tMCAO. Ischemia upregulated the expression of three hemoglobin genes, along with H2-Aa, Ppbp, Siglece, and Tagln, in WT but not in KO. Immunostaining showed that tMCAO-induced hemoglobin localized to neurons. Western blot analysis further showed that hemoglobin induction is GPR68-dependent. Together, these data suggest that GPR68 deletion at baseline disrupts chaperone functions and cellular signaling responses and imply a contribution of hemoglobin-mediated antioxidant mechanism to GPR68-dependent neuroprotection in ischemia.
2025-07-26 | GSE303321 | GEO
Project description:Targeted deletion of TRAF7 revealed that it is a crucial part of shear stress-responsive MEKK3-MEK5-ERK5 signaling pathway induced in endothelial cells by blood flow. Similarly, to Mekk3-, Mek5- or Erk5-deficient mice, Traf7-deficient embryos died in utero around midgestation due to impaired endothelial cell integrity. They displayed significantly lower expression of transcription factor Klf2, an essential regulator of vascular hemodynamic forces downstream of the MEKK3-MEK-ERK5 signaling pathway. Deletion of Traf7 in endothelial cells of postnatal mice was also associated with severe cerebral hemorrhage. Here, we show that besides MEKK3 and MEK5, TRAF7 associates with a planar cell polarity protein SCRIB. SCRIB binds with an N-terminal region of TRAF7, while MEKK3 associates with the C-terminal WD40 domain. Downregulation of TRAF7 as well as SCRIB inhibited fluid shear stress-induced phosphorylation of ERK5 in cultured endothelial cells. These findings suggest that TRAF7 and SCRIB may comprise an upstream part of the MEKK3-MEK5-ERK5 signaling pathway. Objective: to present first in vivo experimental evidence of TRAF7 function by using global and endothelium-specific TRAF7 knockout mice and comparing transcriptomes of developing embryos.
2023-06-01 | GSE229698 | GEO
Project description:LOR is associated with worse progression-free survival (PFS) while alprazolam (ALP) is associated with improved PFS, in pancreatic cancer patients receiving chemotherapy. LOR promotes desmoplasia (fibrosis and extracellular matrix protein deposition), inflammatory signaling, and ischemic necrosis. GPR68 is preferentially expressed on human PDAC CAFs, and n-unsubstituted BZDs, such as LOR, significantly increase IL-6 expression and secretion in CAFs in a pH and GPR68-dependent manner. Conversely, ALP, and other GPR68 n-substituted BZDs decrease IL-6 in human CAFs in a pH and GPR68-independent manner. Across many cancer types, LOR is associated with worse survival outcomes relative to ALP and patients not receiving BZDs. We demonstrate that LOR stimulates fibrosis and inflammatory signaling, promotes desmoplasia and ischemic necrosis, and is associated with decreased pancreatic cancer patient survival.
2023-07-19 | GSE237649 | GEO
Project description:Endothelin-1 (ET-1), an endothelium-derived vasoconstrictor peptide, plays a role in the pathophysiology of cardiovascular disease. Transgenic mice that overexpress human preproET-1 selectively in the endothelium (eET-1) exhibit endothelial dysfunction, hypertrophic remodeling and vascular inflammation of resistance-size arteries in the absence of blood pressure elevation. To understand the mechanisms whereby ET-1 induces vascular damage, vascular gene expression using DNA microarrays was employed. RNA from mesenteric arteries of female and male young (6-7 weeks) and mature (6-8 months) eET-1 and wild type (WT) mice was isolated and changes in gene expression were determined by genome-wide expression profiling using Illumina microarray. This study revealed a set of genes potentially regulated by ET-1, which might be implicated in ET-1 induced-vascular damage. Samples 1-8: Total RNA obtained from the entire mesenteric arterial tree of young (6-7 weeks) female preproendothelin-1 overexpressing mice compared to age and sex matched wild type littermate controls. Samples 9-16: Total RNA obtained from the entire mesenteric arterial tree of mature (6-8 months) female preproendothelin-1 overexpressing mice compared to age and sex matched wild type littermate controls. Samples 17-24: Total RNA obtained from the entire mesenteric arterial tree of young (6-7 weeks) male preproendothelin-1 overexpressing mice compared to age and sex matched wild type littermate controls. Samples 25-32: Total RNA obtained from the entire mesenteric arterial tree of mature (6-8 months) male preproendothelin-1 overexpressing mice compared to age and sex matched wild type littermate controls.
2010-09-01 | E-GEOD-19624 | biostudies-arrayexpress