ArticlePloS one2011
Activation of GPR4 by acidosis increases endothelial cell adhesion through the cAMP/Epac pathway.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 90 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
90 citing papers in PubMed, 1 synthesis or guideline pooled it, 148 citations in OpenAlex.
- Endocannabinoid System as a Promising Therapeutic Target in Inflammatory Bowel Disease - A Systematic Review.Frontiers in immunology · 2021Pooled it
- Serum bicarbonate and cardiovascular events in hypertensive adults: results from the Systolic Blood Pressure Intervention Trial.Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2020Trial
- Unveiling the impact of colonic pH and pH-sensing receptors in blood pressure regulation.Gut microbes · 2026Review
- Narciclasine Alleviates Endothelial Inflammation and Atherosclerosis Initiation by Inhibiting Histone Lactylation-Mediated NF-κB Activation.Inflammation · 2026Article
- G Protein-Coupled Receptors in Cerebrovascular Diseases: Signaling Mechanisms and Therapeutic Opportunities.International journal of molecular sciences · 2026Review
- GPR4 regulates temporally dynamic and sex-dependent cocaine-induced locomotor sensitization.Frontiers in molecular neuroscience · 2026Article
- pH sensing and inflammation: linking acidic microenvironments to immune reprogramming.Frontiers in immunology · 2026Review
- Novel small molecule inhibitor of GPR68 attenuates endothelial dysfunction and lung injury caused by bacterial lipopolysaccharide.Scientific reports · 2025Article
- Epac2 Deficiency Compromises Adaptation to Dietary Acidification by Decreasing H+ Transport in the Renal Nephron.Function (Oxford, England) · 2025Article
- Joint Acidosis and Acid-Sensing Receptors and Ion Channels in Osteoarthritis Pathobiology and Therapy.Cells · 2025Review
- Role of exchange proteins directly activated by cAMP signaling in vascular remodeling.Pharmacological reviews · 2025Review
- Metabolic pathways in deep vein thrombosis: a new frontier for therapeutic intervention.Blood · 2025Review
- Molecular mechanism of pH sensing and activation in GPR4 reveals proton-mediated GPCR signaling.Cell discovery · 2025Article
- Proton-Sensing G Protein-Coupled Receptors and Their Potential Role in Exercise Regulation of Arterial Function.Biomolecules · 2025Review
- Structural basis of stepwise proton sensing-mediated GPCR activation.Cell research · 2025Article
- Molecular gene signature of circulating stromal/stem cells.Journal of human genetics · 2025Review
- Inhibition of proton sensor GPR68 suppresses endothelial dysfunction and acute lung injury caused by Staphylococcus aureus bacterial particles.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- The GPR4 antagonist NE-52-QQ57 increases survival, mitigates the hyperinflammatory response and reduces viral load in SARS-CoV-2-infected K18-hACE2 transgenic mice.Frontiers in pharmacology · 2025Article
- GPR68 Mediates Lung Endothelial Dysfunction Caused by Bacterial Inflammation and Tissue Acidification.Cells · 2024Article
- pH-sensing GPR68 inhibits vascular smooth muscle cell proliferation through Rap1A.American journal of physiology. Heart and circulatory physiology · 2024Article
30 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Endothelium-leukocyte interaction is critical for inflammatory responses. Whereas the tissue microenvironments are often acidic at inflammatory sites, the mechanisms by which cells respond to acidosis are not well understood. Using molecular, cellular and biochemical approaches, we demonstrate that activation of GPR4, a proton-sensing G protein-coupled receptor, by isocapnic acidosis increases the adhesiveness of human umbilical vein endothelial cells (HUVECs) that express GPR4 endogenously. Acidosis in combination with GPR4 overexpression further augments HUVEC adhesion with U937 monocytes. In contrast, overexpression of a G protein signaling-defective DRY motif mutant (R115A) of GPR4 does not elicit any increase of HUVEC adhesion, indicating the requirement of G protein signaling. Downregulation of GPR4 expression by RNA interference reduces the acidosis-induced HUVEC adhesion. To delineate downstream pathways, we show that inhibition of adenylate cyclase by inhibitors, 2',5'-dideoxyadenosine (DDA) or SQ 22536, attenuates acidosis/GPR4-induced HUVEC adhesion. Consistently, treatment with a cAMP analog or a G(i) signaling inhibitor increases HUVEC adhesiveness, suggesting a role of the G(s)/cAMP signaling in this process. We further show that the cAMP downstream effector Epac is important for acidosis/GPR4-induced cell adhesion. Moreover, activation of GPR4 by acidosis increases the expression of vascular adhesion molecules E-selectin, VCAM-1 and ICAM-1, which are functionally involved in acidosis/GPR4-mediated HUVEC adhesion. Similarly, hypercapnic acidosis can also activate GPR4 to stimulate HUVEC adhesion molecule expression and adhesiveness. These results suggest that acidosis/GPR4 signaling regulates endothelial cell adhesion mainly through the G(s)/cAMP/Epac pathway and may play a role in the inflammatory response of vascular endothelial cells.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.