ArticleJCI insight2022
EPCR-PAR1 biased signaling regulates perfusion recovery and neovascularization in peripheral ischemia.
Article in JCI insight, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 16 citations in OpenAlex.
- Liqi Huatan Huoxue Formula Rescued Myocardial Cell Apoptosis of Coronary Microvascular Dysfunction Rat by Inhibiting Endogenous Apoptosis Pathway.Iranian journal of biotechnology · 2026Article
- Review
- Molecular and Biochemical Mechanisms of Cardiomyopathy Development Following Prenatal Hypoxia-Focus on the NO System.Antioxidants (Basel, Switzerland) · 2025Review
- Human endothelial colony forming cells (ECFCs) require endothelial protein C receptor (EPCR) for cell cycle progression and angiogenic activity.Angiogenesis · 2025Article
- Endothelial protein C receptor promotes retinal neovascularization through heme catabolism.Nature communications · 2025Article
- Protease-activated receptors in vascular smooth muscle cells: a bridge between thrombo-inflammation and vascular remodelling.Cell communication and signaling : CCS · 2025Review
- Possibility of Using NO Modulators for Pharmacocorrection of Endothelial Dysfunction After Prenatal Hypoxia.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Endothelial protease-activated receptor 4: impotent or important?Frontiers in cardiovascular medicine · 2025Review
- Identification of stroke biomarkers using proteomic profiling of extracellular vesicles derived from human blood: a preliminary study.Frontiers in neurology · 2025Article
- Identification of endothelial protein C receptor as a novel druggable agonistic target for reendothelialization promotion and thrombosis prevention of eluting stent.Bioactive materials · 2024Article
- Radiation-induced multi-organ injury.International journal of radiation biology · 2024Article
- Circulating Soluble EPCR Levels Are Reduced in Patients with Ischemic Peripheral Artery Disease and Associated with Markers of Endothelial and Vascular Function.Biomedicines · 2023Article
- Activated protein C inhibits mesothelial-to-mesenchymal transition in experimental peritoneal fibrosis.Journal of thrombosis and haemostasis : JTH · 2023Article
Corrections and comments
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Authors and funding
15 authors at 5 institutions in 4 countries.
Funding
Abstract
Blood clot formation initiates ischemic events, but coagulation roles during postischemic tissue repair are poorly understood. The endothelial protein C receptor (EPCR) regulates coagulation, as well as immune and vascular signaling, by protease activated receptors (PARs). Here, we show that endothelial EPCR-PAR1 signaling supports reperfusion and neovascularization in hindlimb ischemia in mice. Whereas deletion of PAR2 or PAR4 did not impair angiogenesis, EPCR and PAR1 deficiency or PAR1 resistance to cleavage by activated protein C caused markedly reduced postischemic reperfusion in vivo and angiogenesis in vitro. These findings were corroborated by biased PAR1 agonism in isolated primary endothelial cells. Loss of EPCR-PAR1 signaling upregulated hemoglobin expression and reduced endothelial nitric oxide (NO) bioavailability. Defective angiogenic sprouting was rescued by the NO donor DETA-NO, whereas NO scavenging increased hemoglobin and mesenchymal marker expression in human and mouse endothelial cells. Vascular specimens from patients with ischemic peripheral artery disease exhibited increased hemoglobin expression, and soluble EPCR and NO levels were reduced in plasma. Our data implicate endothelial EPCR-PAR1 signaling in the hypoxic response of endothelial cells and identify suppression of hemoglobin expression as an unexpected link between coagulation signaling, preservation of endothelial cell NO bioavailability, support of neovascularization, and prevention of fibrosis.
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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.