ArticleThe Journal of clinical investigation2006
Chronic activation of the prostaglandin receptor EP4 promotes hyaluronan-mediated neointimal formation in the ductus arteriosus.
Article in The Journal of clinical investigation, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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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.
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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.
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Who cites it
62 citing papers in PubMed, 171 citations in OpenAlex.
- Hox/Meis-dependent gene-regulatory transition underlies cardiopharyngeal neural crest diversification.The EMBO journal · 2026Article
- Perinatal risk factors for hemodynamically significant patent ductus arteriosus in very low birth weight infants.Clinical and experimental pediatrics · 2026Article
- Sphingosine kinase 1 is integral for elastin deficiency-induced arterial hypermuscularization.Nature cardiovascular research · 2026Article
- Hereditary TTP/Upshaw-Schulman syndrome: the ductus arteriosus controls newborn survival.International journal of hematology · 2024Review
- Vav2 promotes ductus arteriosus anatomic closure via the remodeling of smooth muscle cells by Rac1 activation.Journal of molecular medicine (Berlin, Germany) · 2023Article
- A novel role for PGEAmerican journal of physiology. Heart and circulatory physiology · 2023Article
- Multimodality imaging in diagnosis and management of patent ductus arteriosus in an adult: a case report.American journal of cardiovascular disease · 2023Article
- Mouse models of patent ductus arteriosus (PDA) and their relevance for human PDA.Developmental dynamics : an official publication of the American Association of Anatomists · 2022Review
- Ductus Arteriosus of Extremely Preterm Twins is More Resistant to Cyclooxygenase Inhibitors Than Those of Singletons.Pediatric cardiology · 2022Article
- Transcriptome Analysis Reveals Differential Gene Expression between the Closing Ductus Arteriosus and the Patent Ductus Arteriosus in Humans.Journal of cardiovascular development and disease · 2021Article
- Molecular Mechanisms Underlying Remodeling of Ductus Arteriosus: Looking beyond the Prostaglandin Pathway.International journal of molecular sciences · 2021Review
- Vulnerability to shear stress caused by altered peri-endothelial matrix is a key feature of Moyamoya disease.Scientific reports · 2021Article
- Fibulin-1 Integrates Subendothelial Extracellular Matrices and Contributes to Anatomical Closure of the Ductus Arteriosus.Arteriosclerosis, thrombosis, and vascular biology · 2020Article
- EPAC in Vascular Smooth Muscle Cells.International journal of molecular sciences · 2020Review
- Role of Extracellular Matrix in Pathophysiology of Patent Ductus Arteriosus: Emphasis on Vascular Remodeling.International journal of molecular sciences · 2020Review
- Excessive EP4 Signaling in Smooth Muscle Cells Induces Abdominal Aortic Aneurysm by Amplifying Inflammation.Arteriosclerosis, thrombosis, and vascular biology · 2020Article
- Role of Tissue-Type Plasminogen Activator in Remodeling of the Ductus Arteriosus.Circulation reports · 2020Review
- Molecular and Mechanical Mechanisms Regulating Ductus Arteriosus Closure in Preterm Infants.Frontiers in pediatrics · 2020Review
- Understanding the pathobiology in patent ductus arteriosus in prematurity-beyond prostaglandins and oxygen.Pediatric research · 2019Review
- VSMC-specific EP4 deletion exacerbates angiotensin II-induced aortic dissection by increasing vascular inflammation and blood pressure.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
2 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 5 institutions in 2 countries.
Funding
Abstract
PGE, a potent vasodilator, plays a primary role in maintaining the patency of the ductus arteriosus (DA). Genetic disruption of the PGE-specific receptor EP4, however, paradoxically results in fatal patent DA (PDA) in mice. Here we demonstrate that EP4-mediated signals promote DA closure by hyaluronic acid-mediated (HA-mediated) intimal cushion formation (ICF). Chronic EP4 stimulation by ONO-AE1-329, a selective EP4 agonist, significantly enhanced migration and HA production in rat DA smooth muscle cells. When HA production was inhibited, EP4-mediated migration was negated. Activation of EP4, adenylyl cyclase, and PKA all increased HA production and the level of HA synthase 2 (HAS2) transcripts. In immature rat DA explants, ICF was promoted by EP4/PKA stimuli. Furthermore, adenovirus-mediated Has2 gene transfer was sufficient to induce ICF in EP4-disrupted DA explants in which the intimal cushion had not formed. Accordingly, signals through EP4 have 2 essential roles in DA development, namely, vascular dilation and ICF. The latter would lead to luminal narrowing, helping adhesive occlusion and permanent closure of the vascular lumen. Our results imply that HA induction serves as an alternative therapeutic strategy for the treatment of PDA to the current one, i.e., inhibition of PGE signaling by cyclooxygenase inhibitors, which might delay PGE-mediated ICF in immature infants.
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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.