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http://doi.org/10.25358/openscience-8655
Autoren: | Bochenek, Magdalena L. Gogiraju, Rajinikanth Großmann, Stefanie Krug, Janina Orth, Jennifer Reyda, Sabine Georgiadis, George S. Spronk, Henri M. Konstantinides, Stavros Münzel, Thomas Griffin, John H. Wild, Philipp Espinola-Klein, Christine Ruf, Wolfram Schäfer, Katrin |
Titel: | EPCR-PAR1 biased signaling regulates perfusion recovery and neovascularization in peripheral ischemia |
Online-Publikationsdatum: | 8-Feb-2023 |
Erscheinungsdatum: | 2022 |
Sprache des Dokuments: | Englisch |
Zusammenfassung/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. |
DDC-Sachgruppe: | 610 Medizin 610 Medical sciences |
Veröffentlichende Institution: | Johannes Gutenberg-Universität Mainz |
Organisationseinheit: | FB 04 Medizin |
Veröffentlichungsort: | Mainz |
ROR: | https://ror.org/023b0x485 |
DOI: | http://doi.org/10.25358/openscience-8655 |
Version: | Published version |
Publikationstyp: | Zeitschriftenaufsatz |
Weitere Angaben zur Dokumentart: | Scientific article |
Nutzungsrechte: | CC BY |
Informationen zu den Nutzungsrechten: | https://creativecommons.org/licenses/by/4.0/ |
Zeitschrift: | JCI insight 7 14 |
Seitenzahl oder Artikelnummer: | e157701 |
Verlag: | JCI Insight |
Verlagsort: | Ann Arbor, Michigan |
Erscheinungsdatum: | 2022 |
ISSN: | 2379-3708 |
DOI der Originalveröffentlichung: | 10.1172/jci.insight.157701 |
Enthalten in den Sammlungen: | DFG-491381577-G |
Dateien zu dieser Ressource:
Datei | Beschreibung | Größe | Format | ||
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epcrpar1_biased_signaling_reg-20230126104013796.pdf | 5.18 MB | Adobe PDF | Öffnen/Anzeigen |