Affinage

EDN1

Endothelin-1 · UniProt P05305

Length
212 aa
Mass
24.4 kDa
Annotated
2026-06-09
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EDN1 encodes endothelin-1 (ET-1), a secreted vasoactive peptide that drives vasoconstriction, smooth muscle contractility, and tissue remodeling through G-protein-coupled ETA and ETB receptor signaling (PMID:15838290, PMID:16336267). ET-1 transcription integrates numerous inputs: hypoxia-driven HIF-1α binding to hypoxia response elements (negatively tuned by miR-199) (PMID:19783678), NRF1 promoter binding under hypoxia (repressed by testosterone) (PMID:34257425), aldosterone via mineralocorticoid and glucocorticoid receptors recruiting RNA Pol II to the edn1 promoter (PMID:19638349), TGF-β through the ALK5/Smad3 axis (PMID:17376964), and Ang II via an Oct-1/NOX2/superoxide cascade acting on the promoter (PMID:37381986); NF-κB activates ET-1 and is antagonized by SIRT1 deacetylation (PMID:33095054), while PER1 (PMID:32437627), the DHEA/PI3K-FoxO1 axis (PMID:18718910), and the miR-648 3' UTR interaction (PMID:25403488) provide additional negative control. Once secreted, ET-1 acting through ETA mobilizes intracellular Ca²⁺ via G-protein/IP3 and PLC (PMID:12529247, PMID:14656702), activates PKC (PMID:9486138), and engages the PI3K–RhoA–Rho-kinase–MLC and Src/JAK2/MAPK pathways to produce contraction (PMID:15838290, PMID:12893655), with O-GlcNAcylation reinforcing RhoA-dependent contractile responses (PMID:20978008). These signals drive collagen and CTGF synthesis in fibroblasts (PMID:16336267), COX-2/prostacyclin production (PMID:1324048, PMID:12618423), and downstream transcriptional programs including ets-1 and collagenase (PMID:9486138); extracellular ET-1 also exerts ETB-dependent negative feedback on its own mRNA stability and transcription via ERK and p38 MAPK (PMID:18278064). ET-1 contributes to neuronal sensitization through ETA/PKA-mediated TRPA1 potentiation (PMID:30990108) and to tumor angiogenesis and proliferation via ARHGEF2/EDN1 (PMID:35896520) and EDNRA/β-arrestin/STAT3 feedback loops (PMID:36453252). ET-1 physically engages ETB receptor, which heterodimerizes with the Mas receptor to mediate vasoprotective Ang-(1-7) cross-talk and eNOS/NO signaling (PMID:39633565).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1990 Medium

    Establishing how ET-1 receptors are regulated post-translationally clarified that agonist exposure desensitizes signaling through receptor trafficking rather than PKC.

    Evidence Radioligand binding, internalization kinetics, and crosslinking identifying a 66 kDa ET-1 receptor in C-6 glioma cells

    PMID:2161363

    Open questions at the time
    • Did not assign the 66 kDa receptor to ETA vs ETB
    • Downstream signaling consequences of internalization not resolved
  2. 1992 Medium

    Defining which receptor subtype couples ET-1 to vasoactive mediator release showed ETA selectively triggers prostacyclin output.

    Evidence Rat perfused lung with selective ETA antagonist BQ-123 and radioligand binding

    PMID:1324048

    Open questions at the time
    • Intracellular signaling linking ETA to PGI2 not mapped
    • ETB contribution not separately tested
  3. 1998 Medium

    Ordering the ET-1 contractile/remodeling cascade established a PKC- and Ca²⁺-dependent route to ets-1 and collagenase induction in vascular smooth muscle.

    Evidence RT-PCR with PKC inhibition, Ca²⁺ chelation, and cycloheximide superinduction

    PMID:9486138

    Open questions at the time
    • Receptor subtype driving ets-1 not specified
    • Direct promoter occupancy not demonstrated
  4. 2003 Medium

    Dissecting ETA-coupled signaling across contraction, Ca²⁺ mobilization, and CSD defined parallel Src/JAK2/MAPK, PI3K/RhoA/Rho-kinase, PKC, and PLC/IP3 branches.

    Evidence Isometric tension, Ca²⁺ imaging, and in vivo CSD models with broad pharmacological inhibitor panels

    PMID:12529247 PMID:12618423 PMID:14656702 PMID:15838290

    Open questions at the time
    • Cross-talk hierarchy among branches incompletely resolved
    • Tissue-specific weighting of pathways not generalized
  5. 2003 Medium

    Demonstrating RhoA membrane translocation under combined agonist stimulation explained ET-1's synergistic potentiation of vasoconstriction.

    Evidence Isolated corpus cavernosum contraction with ETA blockade, Rho kinase inhibition, and RhoA membrane fractionation

    PMID:12893655

    Open questions at the time
    • RhoGEF mediating translocation not identified here
    • Generalizability to systemic vasculature untested
  6. 2004 Medium

    Placing ET-1 upstream of TNF-α established its causal role in triggering hepatopulmonary syndrome.

    Evidence ET-1 infusion in portal hypertensive rat models with HPS marker phenotyping

    PMID:14715521

    Open questions at the time
    • Receptor mediating TNF-α induction not defined
    • Cellular source of TNF-α not identified
  7. 2005 Medium

    Mapping the ET-1 fibrotic program identified Gαi/PC-PLC/PLD-dependent collagen I and CTGF induction with ETA-to-ETB receptor switching during chronic stimulation.

    Evidence Pharmacological G-protein/phospholipase inhibition with Western blot and RT-PCR in dermal fibroblasts

    PMID:16336267

    Open questions at the time
    • Trigger for receptor subtype switching unknown
    • Transcriptional mediators of CTGF biphasic kinetics not resolved
  8. 2007 Medium

    Identifying TGF-β/ALK5/Smad3 as an ET-1 inducer revealed an autocrine ET-1 loop mediating TGF-β's anti-migratory effects on endothelium.

    Evidence ALK5 inhibition and ET receptor antagonism in endothelial migration/proliferation assays

    PMID:17376964

    Open questions at the time
    • Direct Smad3 binding to edn1 promoter not shown
    • Receptor subtype for autocrine effect not specified
  9. 2008 Medium

    Characterizing ETB-dependent autoregulation showed extracellular ET-1 suppresses its own mRNA via stability changes and ERK/p38 MAPK, defining a negative feedback loop.

    Evidence mRNA stability assays, RNA Pol II ChIP, and MAPK/receptor antagonists in porcine aortic endothelial cells

    PMID:18278064

    Open questions at the time
    • RNA-binding factors controlling mRNA stability not identified
    • Physiological context where feedback dominates unclear
  10. 2008 Medium

    Defining the DHEA/PI3K-FoxO1 versus MAPK balance established opposing transcriptional control of ET-1 secretion in endothelium.

    Evidence ET-1 promoter luciferase reporter, PKA siRNA, and wortmannin/H89 inhibition with DHEA

    PMID:18718910

    Open questions at the time
    • FoxO1 binding site on edn1 promoter not directly mapped
    • In vivo relevance of DHEA control untested
  11. 2009 High

    Demonstrating HIF-1α occupancy of hypoxia response elements and aldosterone-driven MR/GR promoter binding established direct hypoxic and hormonal transcriptional control of EDN1.

    Evidence ChIP, promoter analysis, miRNA antagonism, and siRNA knockdown in liver endothelial and renal collecting duct cells

    PMID:19638349 PMID:19783678

    Open questions at the time
    • Interaction between hypoxic and hormonal inputs not examined
    • Cell-type specificity of the responses not generalized
  12. 2010 Medium

    Linking ET-1 to vascular O-GlcNAcylation identified OGT-dependent reinforcement of RhoA/Rho-kinase contractile signaling.

    Evidence OGT siRNA and inhibitor with vascular contraction assays and RhoA pathway Western blots

    PMID:20978008

    Open questions at the time
    • O-GlcNAc target proteins driving RhoA activation not identified
    • Reversibility/dynamics not characterized
  13. 2012 Medium

    Showing a shift to VDCC-mediated Ca²⁺ entry after chronic hypoxia revealed pathologic remodeling of ET-1 Ca²⁺ signaling in pulmonary arterial smooth muscle.

    Evidence Fura-2 Ca²⁺ imaging with PKC, Rho kinase, and tyrosine kinase inhibitors

    PMID:22387294

    Open questions at the time
    • Molecular basis for loss of K⁺-channel coupling unknown
    • Specific VDCC subtype not defined
  14. 2014 High

    Identifying miR-648 targeting of the ET-1 3' UTR established a post-transcriptional brake on ET-1, itself under PlGF and PAX5 control.

    Evidence Luciferase 3' UTR reporters with mutant constructs, miRNA mimics, and PAX5 ChIP/gain-loss

    PMID:25403488

    Open questions at the time
    • Physiological context where miR-648 dominates not defined
    • Quantitative contribution versus transcriptional control unclear
  15. 2019 Medium

    Demonstrating ETA/PKA-mediated TRPA1 sensitization extended ET-1 function into nociception and mechanical hyperalgesia.

    Evidence Ca²⁺ imaging, electrophysiology, colocalization, and in vivo behavioral assays in sensory neurons

    PMID:30990108

    Open questions at the time
    • Direct ETA–TRPA1 physical coupling not shown
    • PKA phosphorylation site on TRPA1 not mapped
  16. 2019 Medium

    Showing ET-1 suppresses Ca²⁺-regulated K⁺ currents revealed a PKC-dependent inhibition of melanoma migration.

    Evidence Patch-clamp recording, transwell migration, and pharmacological channel modulation

    PMID:15083534

    Open questions at the time
    • Receptor subtype not specified
    • Channel identity not molecularly defined
  17. 2020 Medium

    Establishing SIRT1 deacetylation of NF-κB and PER1 repression defined negative regulatory nodes controlling ET-1-driven contraction and salt responses.

    Evidence Luciferase reporters, gain/loss-of-function, contraction assays, and in vivo CAS and PER1-KO models

    PMID:32437627 PMID:33095054

    Open questions at the time
    • Interplay between circadian and inflammatory control of EDN1 not integrated
    • NF-κB binding site fine-mapping incomplete
  18. 2021 Medium

    Identifying NRF1 as a direct hypoxic activator of EDN1, repressed by testosterone, added a sex-hormone-modulated transcriptional input.

    Evidence Promoter binding assays with in vivo rat hypoxia and testosterone manipulation

    PMID:34257425

    Open questions at the time
    • NRF1 binding site sequence not resolved
    • Relationship to HIF-1α input under hypoxia unexamined
  19. 2022 Medium

    Linking EDN1 to oncogenic circuits revealed ARHGEF2/EDN1-driven HCC angiogenesis and an EDNRA/β-arrestin/STAT3 positive feedback loop in colorectal cancer.

    Evidence Multi-omics, ChIP, promoter luciferase, and siRNA knockdown in tumor models

    PMID:35896520 PMID:36453252

    Open questions at the time
    • Direct STAT3 versus indirect promoter effects not fully separated
    • Therapeutic generalizability across tumor types untested
  20. 2023 High

    Resolving the Ang II → Oct-1 → NOX2 → superoxide → EDN1 promoter pathway established a redox-dependent transcriptional mechanism validated in vivo.

    Evidence siRNA, promoter deletion, EMSA, SOD treatment, and Nox2-KO mice

    PMID:37381986

    Open questions at the time
    • Superoxide-sensitive transcription factor at the promoter not fully defined
    • Crosstalk with other Ang II effectors not addressed
  21. 2024 High

    Mapping a direct MasR:ETBR physical interaction defined the structural basis for vasoprotective Ang-(1-7)/ET-1 cross-talk and eNOS/NO signaling.

    Evidence Co-IP, peptide array binding mapping, eNOS/vascular contractility assays, and a mouse pulmonary hypertension model

    PMID:39633565

    Open questions at the time
    • Stoichiometry and structural model of the heterodimer not resolved
    • G-protein coupling consequences of dimerization not detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many transcriptional, post-transcriptional, and receptor-level regulatory inputs are integrated within a single cell type to set ET-1 output in physiology versus disease remains unresolved.
  • No unified model reconciling competing HIF-1α, NRF1, MR/GR, NF-κB, and miRNA inputs
  • Receptor heterodimerization dynamics in native tissue uncharacterized
  • Quantitative thresholds linking ET-1 levels to specific phenotypes undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005576 extracellular region 3 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-397014 Muscle contraction 3
Partners
EDNRAEDNRBMAS1
Complex memberships
ETB receptor homo-oligomerMasR:ETBR heterodimer

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 Ethanol-induced ET-1 expression in liver sinusoidal endothelial cells involves NADPH oxidase activation and HIF-1α binding to hypoxia response elements in the ET-1 proximal promoter, as demonstrated by promoter analysis and chromatin immunoprecipitation. miR-199 negatively regulates HIF-1α and ET-1 expression; anti-miR-199 reverses this suppression. Chromatin immunoprecipitation, promoter analysis, miRNA transfection/antagonism Journal of immunology Medium 19783678
2007 TGF-β induces ET-1 expression in endothelial cells preferentially through the ALK5/Smad3 pathway; specific ALK5 inhibition blocked this induction. ET-1 acts in an autocrine manner to mediate a significant portion of TGF-β's anti-migratory and anti-proliferative effects on endothelial cells, as shown by ET receptor antagonism partially reverting TGF-β effects. Pharmacological inhibition of ALK5, ET receptor antagonism, migration/proliferation assays Journal of cell science Medium 17376964
2005 ET-1 induces collagen I synthesis in human dermal fibroblasts via ETA receptor signaling through Gαi, phosphatidylcholine-phospholipase C (PC-PLC), and phospholipase D (PLD), but not phospholipase Cβ. Prolonged ET-1 stimulation causes a switch in receptor subtype expression from ETA to ETB and biphasic induction of connective tissue growth factor (CTGF). Pharmacological inhibition of G-proteins and phospholipases, Western blot, RT-PCR The FEBS journal Medium 16336267
2003 ET-1 stimulates Ca²⁺ mobilization in human brain capillary endothelial cells via G-protein/IP3 pathway; this is dose-dependently inhibited by NO via a guanylyl cyclase/PKG-dependent mechanism. cGMP-dependent protein kinase was shown to colocalize with actin, and NO/cGMP reduced Ca²⁺ mobilization induced by thapsigargin and IP3, with associated alterations in actin/vimentin cytoskeleton. Ca²⁺ imaging, pharmacological inhibitors, immunolocalization American journal of physiology. Cell physiology Medium 12529247
1998 ET-1 induces ets-1 mRNA expression in vascular smooth muscle cells via a PKC-dependent, intracellular Ca²⁺-dependent pathway. Inhibition of PKC (H-7) or chelation of intracellular Ca²⁺ blocked ET-1-induced ets-1 expression. ET-1-induced ets-1 activation subsequently drives collagenase I mRNA expression. RT-PCR, pharmacological inhibition of PKC and Ca²⁺ chelation, cycloheximide superinduction The American journal of physiology Medium 9486138
2009 Aldosterone transcriptionally induces ET-1 (edn1) gene expression in renal collecting duct cells via mineralocorticoid receptor and glucocorticoid receptor binding to hormone response elements in the edn1 promoter. This was demonstrated by ChIP showing nuclear translocation and promoter binding of both receptors, histone modification, and RNA polymerase II recruitment. siRNA knockdown of both receptors corroborated pharmacological studies. Chromatin immunoprecipitation, siRNA knockdown, nuclear translocation assay, hnRNA measurement The Journal of biological chemistry High 19638349
2008 DHEA stimulates phosphorylation and nuclear exclusion of FoxO1 in endothelial cells via PI3-kinase- and PKA-dependent pathways. A constitutively nuclear FoxO1 mutant transactivates the ET-1 promoter; DHEA inhibits this transactivation. PI3K blockade augments ET-1 promoter activity and secretion, while MAPK blockade inhibits them, establishing a balance between PI3K-dependent inhibition and MAPK-dependent stimulation of ET-1 secretion. ET-1 promoter luciferase reporter, siRNA knockdown of PKA, wortmannin/H89 inhibition, DHEA treatment The Journal of biological chemistry Medium 18718910
2010 ET-1 augments vascular O-GlcNAcylation in smooth muscle cells via ETA receptor activation, and this O-GlcNAcylation contributes to increased vascular contractile responses by activating the RhoA/Rho-kinase pathway including phosphorylation of MYPT-1, PKC-potentiated phosphatase inhibitor-17, MLC, and upregulation of RhoGEFs. OGT siRNA or OGT inhibitor abolished ET-1-induced O-GlcNAcylation and RhoA activation. OGT siRNA transfection, OGT inhibitor, vascular contraction assay, Western blot for RhoA pathway components Cardiovascular research Medium 20978008
1992 Both ET-1 and human big-ET-1 release prostacyclin (PGI₂) in rat perfused lungs via selective activation of ET1 (ETA) receptors, as demonstrated by blockade with the selective ETA antagonist BQ-123. Rat perfused lung preparation, selective ETA receptor antagonist BQ-123, radioligand binding British journal of pharmacology Medium 1324048
2003 ET-1 induces cortical spreading depression via ETA receptor and phospholipase C (PLC) activation, but not ETB receptor activation. ETA antagonist BQ-123 completely blocked ET-1-induced CSDs; ETB antagonist BQ-788 had no effect. PLC antagonist U-73122 inhibited CSD; PKC inhibitor Gö-6983 did not. In vivo cortical spreading depression model, selective receptor antagonists, PLC/PKC inhibitors American journal of physiology. Heart and circulatory physiology Medium 14656702
2003 ET-1 regulates COX-2 expression (but not COX-1) in peripheral lung vascular smooth muscle cells via ETA receptor activation and phosphorylation of p38 and p44/42 MAPK. ET-1 also stimulates its own synthesis (ppET-1 expression) via both ETA and ETB receptors. ET-1 signaling increases prostacyclin and PGE₂ release. ET receptor antagonists (BQ-610, BQ-788), MAPK inhibitors (SB-203580, PD-98056), RT-PCR, Western blot, ELISA, GC-MS American journal of physiology. Lung cellular and molecular physiology Medium 12618423
1990 ET-1 receptor down-regulation in C-6 glioma cells occurs via increased endocytosis of the hormone-receptor complex and decreased receptor insertion into the plasma membrane. PKC activation by PMA causes a similar down-regulation by the same mechanism. ET-1-mediated down-regulation does not involve PKC. A 66 kDa protein was identified as the ET-1 receptor by crosslinking. Radioligand binding, internalization kinetics modeling, chemical crosslinking/SDS-PAGE, PKC inhibition Molecular and cellular endocrinology Medium 2161363
2008 Activation of ETB receptors by extracellular ET-1 reduces ET-1 mRNA abundance in porcine aortic endothelial cells by simultaneously decreasing ET-1 mRNA stability and transiently increasing RNA Pol II loading at the ET-1 promoter. This feedback involves receptor endocytosis and both ERK and p38 MAPK pathways: p38 MAPK inhibition prevented ET-1-induced decrease in ET-1 mRNA; ERK1/2 inhibition increased ET-1 mRNA. ETA antagonism had no effect. mRNA stability assay, promoter activity (RNA Pol II ChIP), MAPK inhibitors, selective ET receptor antagonists British journal of pharmacology Medium 18278064
2003 ET-1-induced contraction of rabbit basilar artery proceeds via three signaling pathways: (1) Src-JAK2-PTK-MAPK, (2) PI3K-RhoA-Rho kinase-MLC phosphorylation, and (3) PKC, all acting through the ETA receptor. MAPK is downstream of PTK, Src, and JAK pathways; PI3K is upstream of RhoA activation; Rho kinase inhibition reduces MLC phosphorylation and contraction. Isometric tension measurement, Western blot for MAPK/RhoA, pharmacological inhibitors (PD98059, U0126, genistein, damnacanthal, AG-490, wortmannin, Y-27632) Journal of cardiovascular pharmacology Medium 15838290
2012 Following chronic hypoxia, ET-1-induced Ca²⁺ increase in pulmonary arterial smooth muscle cells occurs via voltage-dependent Ca²⁺ channels (VDCC) activated primarily by PKC, tyrosine kinases, and Rho kinase (>70% reduction by their respective inhibitors), rather than by K⁺ channel inhibition-mediated depolarization that is lost after chronic hypoxia. Fura-2 Ca²⁺ imaging, PKC inhibitors (staurosporine, GF109203X), Rho kinase inhibitors (Y-27632, HA1077), tyrosine kinase inhibitors American journal of physiology. Lung cellular and molecular physiology Medium 22387294
2003 ET-1 activates RhoA-Rho kinase pathway to potentiate synergistic vasoconstriction with phenylephrine in rat corpus cavernosum. ETA receptor blockade reversed the augmented contraction, and Rho kinase inhibitor Y-27632 dose-dependently relaxed tissue. The combined ET-1+PE stimulus produced a fourfold increase of RhoA in membrane fractions compared to either agonist alone. Isolated tissue contraction assay, Western blot for RhoA membrane translocation, ETA receptor antagonist (A-127722), Rho kinase inhibitor (Y-27632) American journal of physiology. Regulatory, integrative and comparative physiology Medium 12893655
2007 The transmembrane segment 1 (amino acids 93-131) of the human endothelin B receptor is a central region required for both ET-1 binding and homodimer (homo-oligomer) formation, as demonstrated by systematic deletion analysis of cell-free produced ETB receptor fragments in pulldown, coelution, and surface plasmon resonance assays. Cell-free expression, pulldown assay, coelution, surface plasmon resonance, single-particle analysis The FEBS journal Medium 17535295
2004 Exogenous ET-1 infusion in portal hypertensive (PVL) rats increases TNF-α levels and triggers the full hepatopulmonary syndrome (HPS) including pulmonary microvascular changes, establishing that ET-1 is upstream of TNF-α in triggering HPS. Biliary cirrhosis uniquely produces both elevated ET-1 and TNF-α, which together induce HPS. Rat models (CBDL, PVL, TAA), ET-1 infusion, molecular and physiological evaluation of HPS markers American journal of physiology. Gastrointestinal and liver physiology Medium 14715521
2019 ET-1 sensitizes TRPA1 channels in primary sensory neurons via the ETA receptor and protein kinase A (PKA) pathway, contributing to mechanical hyperalgesia. ETAR was shown to colocalize with TRPA1 in DRG neurons; pharmacological blocking of ETAR, PKA, or TRPA1 attenuated ET-1-induced mechanical hyperalgesia in vivo. Ca²⁺ imaging, electrophysiology, immunostaining, pharmacological inhibitors, in vivo behavioral assay Molecular pain Medium 30990108
2020 SIRT1 deacetylates NF-κB, which inhibits NF-κB-mediated transcriptional activation of ET-1 and the MLCK/MLC2 pathway in vascular smooth muscle cells. NF-κB was shown to bind to the ET-1 promoter region by luciferase reporter assay. SIRT1 overexpression inhibited VSMC contraction and proliferation in vitro and alleviated coronary artery spasm in vivo. Luciferase reporter assay, Western blot, RT-qPCR, siRNA/overexpression, collagen gel contraction assay, in vivo rat CAS model American journal of physiology. Heart and circulatory physiology Medium 33095054
2014 miR-648 targets the 3' UTR of ET-1 mRNA, as demonstrated by luciferase reporter assays using wild-type and mutant ET-1 3' UTR constructs and miR-648 mimic transfection. PlGF represses miR-648 expression, leading to increased ET-1. miR-648 is cotranscriptionally regulated with MICAL3 via the MICAL3 distal promoter (P1) under positive control by PAX5, as shown by ChIP and PAX5 gain/loss-of-function. Luciferase 3' UTR reporter assay with mutant constructs, miRNA mimic transfection, ChIP for PAX5, PAX5 siRNA/overexpression Molecular and cellular biology High 25403488
2021 Nuclear respiratory factor 1 (NRF1) transcriptionally activates ET-1 by directly binding to the ET-1 promoter region in endothelial cells under hypoxia conditions. Testosterone represses NRF1 expression in vivo and in vitro, thereby reducing ET-1 levels. This was demonstrated by NRF1 promoter binding assays and testosterone supplementation/castration experiments in rats. Promoter binding assay, in vivo rat hypoxia model, testosterone supplementation/castration, RT-PCR, ELISA Hypertension research Medium 34257425
2023 Ang II promotes ET-1 production in human microvascular endothelial cells via a pathway requiring Oct-1 transcription factor-dependent upregulation of NOX2, which increases superoxide anion production. SOD (superoxide dismutase) neutralization of superoxide abolished Ang II-stimulated ET-1 promoter activity, mRNA expression, and ET-1 release. This pathway was also operative in vivo: Nox2-deficient mice failed to increase cardiac ET-1 after high-fat diet. NOX2 siRNA silencing, Oct-1 siRNA, promoter deletion assays, EMSA, SOD treatment, ELISA, Nox2-KO mice, RT-qPCR Arteriosclerosis, thrombosis, and vascular biology High 37381986
2024 Ang-(1-7) and ET-1 engage in cross talk through a physical interaction between the Mas receptor (MasR) and ETB receptor (ETBR) to produce vasoprotective signaling. Co-immunoprecipitation and peptide array experiments demonstrated direct MasR:ETBR interaction; binding sites on MasR (aa 290-314) and ETBR (aa 176-200) were mapped. Disrupting peptides blocked both Ang-(1-7) and ET-1 signaling, and compounds enhancing MasR:ETBR interaction amplified eNOS/NO activity and vasorelaxation. Co-immunoprecipitation, peptide array binding mapping, eNOS activity assay, vascular contractility assay, mouse pulmonary hypertension model Hypertension High 39633565
2022 ARHGEF2 promotes angiogenesis in hepatocellular carcinoma via the EDN1 pathway; ER stress upregulates ARHGEF2 through ZNF263, and elevated ARHGEF2 increases EDN1 expression to accelerate HCC angiogenesis and drug resistance. ARHGEF2 knockdown combined with targeted medicines showed greater HCC cell growth inhibition. RNA-seq, ATAC-seq, ChIP-seq, siRNA knockdown, in vitro and in vivo HCC models Cell death & disease Medium 35896520
2022 The EDN1/EDNRA/β-arrestin axis activates STAT3 phosphorylation in colorectal cancer cells; EDNRA knockdown suppressed STAT3 phosphorylation, and STAT3 directly binds to EDN1 and EDNRA promoters to form a positive feedback loop, as shown by ChIP and promoter luciferase assays. Phosphokinase array, siRNA knockdown, ChIP, promoter luciferase assay, cell proliferation/migration assays International journal of oncology Medium 36453252
2019 ET-1 inhibits B-16 melanoma cell migration by decreasing Ca²⁺-regulated K⁺ currents via a PKC-dependent pathway. Ca²⁺-regulated K⁺ channel blockers mimicked ET-1 inhibition of migration; K⁺ channel opener diclofenac reversed ET-1-induced inhibition of both K⁺ current and migration. Patch-clamp whole-cell recording, transwell migration assay, pharmacological channel blockers/openers Cell motility and the cytoskeleton Medium 15083534
2020 PER1 (circadian clock protein) acts as a negative regulator of ET-1 expression in renal collecting duct cells in response to high-salt/mineralocorticoid treatment; siRNA-mediated knockdown of PER1 in mpkCCDc14 cells increased ET-1 mRNA expression and peptide secretion in response to aldosterone. siRNA knockdown of PER1, RT-PCR, ELISA, PER1 global knockout mice with HS/DOCP treatment Canadian journal of physiology and pharmacology Medium 32437627

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection. Journal of the American College of Cardiology 157 30621952
2009 Ethanol-induced expression of ET-1 and ET-BR in liver sinusoidal endothelial cells and human endothelial cells involves hypoxia-inducible factor-1alpha and microrNA-199. Journal of immunology (Baltimore, Md. : 1950) 121 19783678
1981 The genetic analysis of a reciprocal translocation, eT1(III; V), in Caenorhabditis elegans. Genetics 109 6953041
2014 Autophagy regulates vascular endothelial cell eNOS and ET-1 expression induced by laminar shear stress in an ex vivo perfused system. Annals of biomedical engineering 101 24838486
1991 Chromosomal assignments of the human endothelin family genes: the endothelin-1 gene (EDN1) to 6p23-p24, the endothelin-2 gene (EDN2) to 1p34, and the endothelin-3 gene (EDN3) to 20q13.2-q13.3. American journal of human genetics 94 2018043
2007 The role of shear stress on ET-1, KLF2, and NOS-3 expression in the developing cardiovascular system of chicken embryos in a venous ligation model. Physiology (Bethesda, Md.) 91 18073411
2004 ET-1 and TNF-alpha in HPS: analysis in prehepatic portal hypertension and biliary and nonbiliary cirrhosis in rats. American journal of physiology. Gastrointestinal and liver physiology 90 14715521
2007 Signaling by ALK5 mediates TGF-beta-induced ET-1 expression in endothelial cells: a role for migration and proliferation. Journal of cell science 86 17376964
2005 Signalling and regulation of collagen I synthesis by ET-1 and TGF-beta1. The FEBS journal 76 16336267
2003 ET-1- and NO-mediated signal transduction pathway in human brain capillary endothelial cells. American journal of physiology. Cell physiology 71 12529247
1998 Ets-1 is an early response gene activated by ET-1 and PDGF-BB in vascular smooth muscle cells. The American journal of physiology 71 9486138
2016 Liraglutide prevents and reverses monocrotaline-induced pulmonary arterial hypertension by suppressing ET-1 and enhancing eNOS/sGC/PKG pathways. Scientific reports 66 27581840
2001 Endothelin B receptor deficiency potentiates ET-1 and hypoxic pulmonary vasoconstriction. American journal of physiology. Lung cellular and molecular physiology 65 11290529
2000 The human heart endothelin system: ET-1 synthesis, storage, release and effect. Trends in pharmacological sciences 62 10973089
2008 The genome of Erwinia tasmaniensis strain Et1/99, a non-pathogenic bacterium in the genus Erwinia. Environmental microbiology 61 18462403
2013 ET-1 actions in the kidney: evidence for sex differences. British journal of pharmacology 60 22372527
2015 Inverse Correlation Between Plasma Adropin and ET-1 Levels in Essential Hypertension: A Cross-Sectional Study. Medicine 56 26448026
2010 O-GlcNAcylation contributes to the vascular effects of ET-1 via activation of the RhoA/Rho-kinase pathway. Cardiovascular research 53 20978008
2001 Silencing of HTR1B and reduced expression of EDN1 in human lung cancers, revealed by methylation-sensitive representational difference analysis. Oncogene 53 11709722
2012 ET-1 deletion from endothelial cells protects the kidney during the extension phase of ischemia/reperfusion injury. Biochemical and biophysical research communications 51 22846580
2018 Release of IL-6 After Stroke Contributes to Impaired Cerebral Autoregulation and Hippocampal Neuronal Necrosis Through NMDA Receptor Activation and Upregulation of ET-1 and JNK. Translational stroke research 50 29476447
2009 Aldosterone modulates steroid receptor binding to the endothelin-1 gene (edn1). The Journal of biological chemistry 50 19638349
1992 Human big-endothelin-1 and endothelin-1 release prostacyclin via the activation of ET1 receptors in the rat perfused lung. British journal of pharmacology 49 1324048
2014 Wnt signaling interacts with bmp and edn1 to regulate dorsal-ventral patterning and growth of the craniofacial skeleton. PLoS genetics 47 25058015
2016 Air Pollution-Induced Vascular Dysfunction: Potential Role of Endothelin-1 (ET-1) System. Cardiovascular toxicology 46 26148452
1994 Effects of an ET1-receptor antagonist, FR139317, on regional haemodynamic responses to endothelin-1 and [Ala11,15]Ac-endothelin-1 (6-21) in conscious rats. British journal of pharmacology 44 8075866
2008 Relationships among ET-1, PPARgamma, oxidative stress and endothelial dysfunction in diabetic animals. Journal of smooth muscle research = Nihon Heikatsukin Gakkai kikanshi 42 18552452
2008 Dehydroepiandrosterone stimulates phosphorylation of FoxO1 in vascular endothelial cells via phosphatidylinositol 3-kinase- and protein kinase A-dependent signaling pathways to regulate ET-1 synthesis and secretion. The Journal of biological chemistry 41 18718910
2003 ET-1 induces cortical spreading depression via activation of the ETA receptor/phospholipase C pathway in vivo. American journal of physiology. Heart and circulatory physiology 40 14656702
1993 Effect of hyperosmolality on production and mRNA expression of ET-1 in inner medullary collecting duct. The American journal of physiology 40 8476078
2008 Oxidative stress-induced, poly(ADP-ribose) polymerase-dependent upregulation of ET-1 expression in chronic diabetic complications. Canadian journal of physiology and pharmacology 39 18516100
2007 Functional analysis of cell-free-produced human endothelin B receptor reveals transmembrane segment 1 as an essential area for ET-1 binding and homodimer formation. The FEBS journal 38 17535295
2003 RhoA-Rho kinase mediates synergistic ET-1 and phenylephrine contraction of rat corpus cavernosum. American journal of physiology. Regulatory, integrative and comparative physiology 38 12893655
2001 Upregulation of ET-1 and its receptors and remodeling in small pulmonary veins under hypoxic conditions. American journal of physiology. Lung cellular and molecular physiology 36 11350789
2010 Nuclear membrane receptors for ET-1 in cardiovascular function. American journal of physiology. Regulatory, integrative and comparative physiology 34 21084674
2008 Endothelin (ET)-1 and ET-3 promote expression of c-fos and c-jun in human choriocarcinoma via ET(B) receptor-mediated G(i)- and G(q)-pathways and MAP kinase activation. British journal of pharmacology 33 18362896
2014 ET-1 increases reactive oxygen species following hypoxia and high-salt diet in the mouse glomerulus. Acta physiologica (Oxford, England) 31 25219340
2008 EDN1 Lys198Asn is associated with diabetic retinopathy in type 2 diabetes. Molecular vision 30 18806884
2003 Cyclooxygenase is regulated by ET-1 and MAPKs in peripheral lung microvascular smooth muscle cells. American journal of physiology. Lung cellular and molecular physiology 30 12618423
1990 ET-1 receptors in C-6 cells: homologous down-regulation and modulation by protein kinase C. Molecular and cellular endocrinology 29 2161363
2001 Interactions of lymphotoxin alpha (TNF-beta), angiotensin-converting enzyme (ACE), and endothelin-1 (ET-1) gene polymorphisms in adult periodontitis. Journal of periodontology 28 11210078
2014 Berberine combined with atorvastatin downregulates LOX‑1 expression through the ET‑1 receptor in monocyte/macrophages. International journal of molecular medicine 27 24756769
2013 Sex differences in ET-1 receptor expression and Ca2+ signaling in the IMCD. American journal of physiology. Renal physiology 27 23946290
2001 Benidipine inhibits expression of ET-1 and TGF-beta1 in Dahl salt-sensitive hypertensive rats. Hypertension research : official journal of the Japanese Society of Hypertension 26 11409647
2001 Interactions of Lymphotoxin α (TNF-β), Angiotensin-Converting Enzyme (ACE), and Endothelin-1 (ET-1) Gene Polymorphisms in Adult Periodontitis. Journal of periodontology 26 29537523
1997 In vitro expression of endothelin-1 (ET-1) and the ETA and ETB ET receptors by the prostatic epithelium and stroma. The Journal of clinical endocrinology and metabolism 26 9024245
2022 ARHGEF2/EDN1 pathway participates in ER stress-related drug resistance of hepatocellular carcinoma by promoting angiogenesis and malignant proliferation. Cell death & disease 25 35896520
2021 AGEs/RAGE blockade downregulates Endothenin-1 (ET-1), mitigating Human Umbilical Vein Endothelial Cells (HUVEC) injury in deep vein thrombosis (DVT). Bioengineered 25 33896376
2015 Associations of EDNRA and EDN1 polymorphisms with carotid intima media thickness through interactions with gender, regular exercise, and obesity in subjects in Taiwan: Taichung Community Health Study (TCHS). BioMedicine 25 26040574
2023 Hyperglycemia-induced oxidative stress and epigenetic regulation of ET-1 gene in endothelial cells. Frontiers in genetics 24 37139232
2022 Correlation between hs-CRP, IL-6, IL-10, ET-1, and Chronic Obstructive Pulmonary Disease Combined with Pulmonary Hypertension. Journal of healthcare engineering 24 35186226
2013 Elevated endothelin-1 (ET-1) levels may contribute to hypoadiponectinemia in childhood obesity. The Journal of clinical endocrinology and metabolism 24 23457411
2005 The distribution and density of ET-1 and its receptors are different in human right and left ventricular endocardial endothelial cells. Peptides 24 16042982
2021 ET-1 as a Sex-Specific Mechanism Impacting Age-Related Changes in Vascular Function. Frontiers in aging 23 35822003
2020 Knockout of the circadian clock protein PER1 results in sex-dependent alterations of ET-1 production in mice in response to a high-salt diet plus mineralocorticoid treatment. Canadian journal of physiology and pharmacology 23 32437627
2006 NPY, ET-1, and Ang II nuclear receptors in human endocardial endothelial cells. Canadian journal of physiology and pharmacology 23 16902577
2013 edn1 and hand2 Interact in early regulation of pharyngeal arch outgrowth during zebrafish development. PloS one 22 23826316
2002 Release of preformed Ang II from myocytes mediates angiotensinogen and ET-1 gene overexpression in vivo via AT1 receptor. Journal of molecular and cellular cardiology 22 12431448
2020 SIRT1-mediated deacetylation of NF-κB inhibits the MLCK/MLC2 pathway and the expression of ET-1, thus alleviating the development of coronary artery spasm. American journal of physiology. Heart and circulatory physiology 21 33095054
2019 Endothelins (EDN1, EDN2, EDN3) and their receptors (EDNRA, EDNRB, EDNRB2) in chickens: Functional analysis and tissue distribution. General and comparative endocrinology 21 31351053
2008 Activation of ETB receptors regulates the abundance of ET-1 mRNA in vascular endothelial cells. British journal of pharmacology 21 18278064
2021 Testosterone attenuates hypoxia-induced hypertension by affecting NRF1-mediated transcriptional regulation of ET-1 and ACE. Hypertension research : official journal of the Japanese Society of Hypertension 20 34257425
2018 5-HTT, BMPR2, EDN1, ENG, KCNA5 gene polymorphisms and susceptibility to pulmonary arterial hypertension: A meta-analysis. Gene 20 30218748
2014 Effect of SNP polymorphisms of EDN1, EDNRA, and EDNRB gene on ischemic stroke. Cell biochemistry and biophysics 20 24633486
2012 ROCK cooperated with ET-1 to induce epithelial to mesenchymal transition through SLUG in human ovarian cancer cells. Bioscience, biotechnology, and biochemistry 20 22232246
2010 Teratogenic effects of blue cohosh (Caulophyllum thalictroides) in Japanese medaka (Oryzias latipes) are probably mediated through GATA2/EDN1 signaling pathway. Chemical research in toxicology 20 20707411
2009 Maternal EDN1 G5665T polymorphism influences circulating endothelin-1 levels and plays a role in determination of preeclampsia phenotype. Journal of hypertension 20 19730395
2002 Insulin sensitivity and big ET-1 conversion to ET-1 after ETA- or ETB-receptor blockade in humans. Journal of applied physiology (Bethesda, Md. : 1985) 20 12391119
1993 The human endothelin-1 gene (EDN1) encoding a peptide with potent vasoactive properties maps distal to HLA on chromosome arm 6p in close linkage to D6S89. Cytogenetics and cell genetics 20 8428511
2022 The EDN1/EDNRA/β‑arrestin axis promotes colorectal cancer progression by regulating STAT3 phosphorylation. International journal of oncology 19 36453252
2019 ETAR and protein kinase A pathway mediate ET-1 sensitization of TRPA1 channel: A molecular mechanism of ET-1-induced mechanical hyperalgesia. Molecular pain 19 30990108
2017 Plasma ET-1 Concentrations are Elevated in Patients with Hypertension - Meta-Analysis of Clinical Studies. Kidney & blood pressure research 19 28531898
2016 EDN1 Gene Variant is Associated with Neonatal Persistent Pulmonary Hypertension. Scientific reports 19 27425626
2019 Activation of PERK in ET-1- and thrombin-induced pulmonary fibroblast differentiation: Inhibitory effects of curcumin. Journal of cellular physiology 18 30825198
2019 Impact of ET-1 and sex in glomerular hyperfiltration in humanized sickle cell mice. Clinical science (London, England : 1979) 18 31273050
2014 Over-expression of astrocytic ET-1 attenuates neuropathic pain by inhibition of ERK1/2 and Akt(s) via activation of ETA receptor. Molecular and cellular neurosciences 18 24593954
2012 Kinase-dependent activation of voltage-gated Ca2+ channels by ET-1 in pulmonary arterial myocytes during chronic hypoxia. American journal of physiology. Lung cellular and molecular physiology 18 22387294
1992 No effect of a Taq1 polymorphism in DNA at the endothelin I (EDN1) locus on normal blood pressure level or variability. Clinical genetics 17 1347490
2022 Restoration of miR-648 overcomes 5-FU-resistance through targeting ET-1 in gastric cancer cells in-vitro. Pathology, research and practice 16 36191447
2023 Hypoxic glioma cell-secreted exosomal circ101491 promotes the progression of glioma by regulating miR-125b-5p/EDN1. Brain research bulletin 15 36796652
2010 Endothelin-1 (ET-1) and vein graft failure and the therapeutic potential of ET-1 receptor antagonists. Pharmacological research 15 21056670
2007 Screening of the endothelin1 gene (EDN1) in a cohort of patients with essential left ventricular hypertrophy. Annals of human genetics 15 17335511
1999 Effects of physiological or pathological pressure load in vivo on myocardial expression of ET-1 and receptors. The American journal of physiology 15 10564203
2020 Endothelin-1 (ET-1) promotes a proinflammatory microglia phenotype in diabetic conditions. Canadian journal of physiology and pharmacology 14 32119570
2016 Linagliptin reduces effects of ET-1 and TLR2-mediated cerebrovascular hyperreactivity in diabetes. Life sciences 14 26898123
2004 ET-1 inhibits B-16 murine melanoma cell migration by decreasing K(+) currents. Cell motility and the cytoskeleton 14 15083534
2023 Research progress on the role of ET-1 in diabetic kidney disease. Journal of cellular physiology 13 37063089
2023 Aprocitentan, a dual endothelin-1 (ET-1) antagonist for treating resistant hypertension: Mechanism of action and therapeutic potential. Drug discovery today 13 37742911
2019 Effect of Rho kinase inhibitor fasudil on the expression ET-1 and NO in rats with hypoxic pulmonary hypertension. Clinical hemorheology and microcirculation 13 29660902
2014 MicroRNA 648 Targets ET-1 mRNA and is cotranscriptionally regulated with MICAL3 by PAX5. Molecular and cellular biology 13 25403488
2023 Ang II Promotes ET-1 Production by Regulating NOX2 Activity Through Transcription Factor Oct-1. Arteriosclerosis, thrombosis, and vascular biology 12 37381986
2022 Platelets-Derived miR-200a-3p Modulate the Expression of ET-1 and VEGFA in Endothelial Cells by Targeting MAPK14. Frontiers in physiology 12 35755441
2016 The paternal polymorphism rs5370 in the EDN1 gene decreases the risk of preeclampsia. Pregnancy hypertension 12 27939477
2013 The -974C>A (rs3087459) gene polymorphism in the endothelin gene (EDN1) is associated with risk of developing acute coronary syndrome in Mexican patients. Gene 12 24035903
2011 Identification of gene variants in NOS3, ET-1 and RAS that confer risk and protection against microangiopathy in type 2 diabetic obese subjects. Biochemical and biophysical research communications 12 21406182
2024 Ang-(1-7) and ET-1 Interplay Through Mas and ETB Receptor Interaction Defines a Novel Vasoprotective Mechanism. Hypertension (Dallas, Tex. : 1979) 11 39633565
2018 Dexamethasone downregulates SIRT1 and IL6 and upregulates EDN1 genes in stem cells derived from gingivae via the AGE/RAGE pathway. Biotechnology letters 11 29302812
2016 Endothelin-1 (ET-1) induces resistance to bortezomib in human multiple myeloma cells via a pathway involving the ETB receptor and upregulation of proteasomal activity. Journal of cancer research and clinical oncology 11 27530445
2010 Alcama mediates Edn1 signaling during zebrafish cartilage morphogenesis. Developmental biology 11 21073867
2004 Signal transduction of ET-1 in contraction of cerebral arteries. Journal of cardiovascular pharmacology 11 15838290

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