GPR182 is a novel marker for sinusoidal endothelial differentiation with distinct GPCR signaling activity in vitro
Open accessAbstract
Endothelial cells (EC) along the vascular tree exhibit organ-specific angiodiversity. Compared to most other ECs, liver sinusoidal endothelial cells (LSEC) that constitute the organ-specific microvasculature of the liver are morphologically and functionally unique. Previously, we showed that transcription factor Gata4 acts as a master regulator controlling LSEC differentiation. Upon analysis of the molecular signature of LSEC, we identified GPR182 as a potential LSEC-specific orphan G-protein coupled receptor (GPCR). Here, we demonstrate that GPR182 is expressed by LSEC and by EC with sinusoidal differentiation in spleen, lymph node and bone marrow in healthy human tissues. In a tissue microarray analysis of human hepatocellular carcinoma (HCC) samples, endothelial GPR182 expression was significantly reduced in tumor samples compared to peritumoral liver tissue samples (p = 0.0105). Loss of endothelial GPR182 expression was also seen in fibrotic and cirrhotic liver tissues. In vitro, GPR182 differentially regulated canonical GPCR signaling pathways as shown using reporter luciferase assays in HEK293T cells. Whereas ERK and RhoA signaling were inhibited, CREB and Calcium signaling were activated by ectopic GPR182 overexpression. Our data demonstrate that GPR182 is an endothelial subtype-specific marker for human sinusoidal EC of the liver, spleen, lymph node and bone marrow. In addition, we provide evidence for GPR182-dependent downstream signaling via ERK and SRF pathways that may be involved in regulating endothelial subtype-specific sinusoidal differentiation and sinusoidal functions such as permeability.
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The early HSEC transcriptome suggests the activation of sinusoidal function, including endocytosis, antigen presentation, and signaling.
“the early HSEC transcriptome further suggests the activation of sinusoidal function, including endocytosis (Stab2, Colec12, Ehd3, and Lyve1), antigen presentation (Fcgrt, Fcer1g, and Mrc1), and signaling (Gpr182, Bmp2, Dll4, and Efna1)”
From Single-Cell Transcriptomics Reveals Early Emergence of Liver Parenchymal and Non-parenchymal Cell Lineages (2020) · cites this paper as Schmid et al., 2018
The Introduction (page unavailable) identifies GPR182 as an LSEC-associated molecule, and section 3.3 (page unavailable) reports its signaling activity in vitro. This supports the Gpr182 signaling example, but the paper does not report an early HSEC transcriptome or show that the listed endocytosis, antigen-presentation, and other signaling genes are activated in it. (LLM, conf=0.85)
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References 39 · Cited by 33
Research works printed but not linked: 4
- R. Daneman, L. Zhou, D. Agalliu, et al., The mouse blood-brain barrier tran- scriptome: a new resource for understanding the development and function of brain endothelial cells, PLoS One 5 (2010), e13741.
- Y.A. Ghouri, I. Mian, J.H. Rowe, Review of hepatocellular carcinoma: epide- miology, etiology, and carcinogenesis, J. Carcinog. 16 (2017) 1.
- A.L. Martin, M.A. Steurer, R.S. Aronstam, Constitutive activity among orphan class-A G protein coupled receptors, PLoS One 10 (2015), e0138463.
- C. Weinl, S. Castaneda Vega, H. Riehle, et al., Endothelial depletion of murine SRF/MRTF provokes intracerebral hemorrhagic stroke, Proc. Natl. Acad. Sci. U. S. A. 112 (2015) 9914e9919.
- Authors
- Schmid, C. D., Schledzewski, K., Mogler, C., Waldburger, N., Kalna, V., Marx, A., Randi, A. M., Géraud, C., Goerdt, S., & Koch, P.-S.
- Affiliations
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- Imperial College London (GB)
- ORCID
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 497
- Issue
- 1
- Pages
- 32-38
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2792872268
- Cited by
- 33
- References
- 39
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 3 · 2021: 8 · 2020: 5 · 2018: 1
- FWCI
- 2.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion, other-oa)
- Funders
- Deutsche Forschungsgemeinschaft (DFG INST 91027/9-1 FUGG, DFG INST 91027/10-1 FUGG, GRK2099/RTG2099, SFB-TRR209)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- liver sinusoidal endothelial cells, endothelial differentiation, G protein-coupled receptors, orphan G protein-coupled receptor, GATA4, hepatocellular carcinoma, liver fibrosis, ERK signaling, SRF, CREB, calcium signaling, RhoA, endothelial permeability
- MeSH terms
- Cell Differentiation, Cells, Cultured, Humans, Organ Specificity, Signal Transduction, Biomarkers, Neovascularization, Physiologic, Endothelial Cells, Receptors, G-Protein-Coupled
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