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  2. Johannes Gutenberg-Universität Mainz
  3. DFG-491381577-G
Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-8655
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dc.contributor.authorBochenek, Magdalena L.-
dc.contributor.authorGogiraju, Rajinikanth-
dc.contributor.authorGroßmann, Stefanie-
dc.contributor.authorKrug, Janina-
dc.contributor.authorOrth, Jennifer-
dc.contributor.authorReyda, Sabine-
dc.contributor.authorGeorgiadis, George S.-
dc.contributor.authorSpronk, Henri M.-
dc.contributor.authorKonstantinides, Stavros-
dc.contributor.authorMünzel, Thomas-
dc.contributor.authorGriffin, John H.-
dc.contributor.authorWild, Philipp-
dc.contributor.authorEspinola-Klein, Christine-
dc.contributor.authorRuf, Wolfram-
dc.contributor.authorSchäfer, Katrin-
dc.date.accessioned2023-02-08T08:01:21Z-
dc.date.available2023-02-08T08:01:21Z-
dc.date.issued2022-
dc.identifier.urihttps://openscience.ub.uni-mainz.de/handle/20.500.12030/8671-
dc.description.abstractBlood 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.en_GB
dc.description.sponsorshipGefördert durch die Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 491381577de
dc.language.isoengde
dc.rightsCC BY*
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/*
dc.subject.ddc610 Medizinde_DE
dc.subject.ddc610 Medical sciencesen_GB
dc.titleEPCR-PAR1 biased signaling regulates perfusion recovery and neovascularization in peripheral ischemiaen_GB
dc.typeZeitschriftenaufsatzde
dc.identifier.doihttp://doi.org/10.25358/openscience-8655-
jgu.type.contenttypeScientific articlede
jgu.type.dinitypearticleen_GB
jgu.type.versionPublished versionde
jgu.type.resourceTextde
jgu.organisation.departmentFB 04 Medizinde
jgu.organisation.number2700-
jgu.organisation.nameJohannes Gutenberg-Universität Mainz-
jgu.rights.accessrightsopenAccess-
jgu.journal.titleJCI insightde
jgu.journal.volume7de
jgu.journal.issue14de
jgu.pages.alternativee157701de
jgu.publisher.year2022-
jgu.publisher.nameJCI Insightde
jgu.publisher.placeAnn Arbor, Michigande
jgu.publisher.issn2379-3708de
jgu.organisation.placeMainz-
jgu.subject.ddccode610de
jgu.publisher.doi10.1172/jci.insight.157701de
jgu.organisation.rorhttps://ror.org/023b0x485-
jgu.subject.dfgLebenswissenschaftende
Appears in collections:DFG-491381577-G

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