EPCR-PAR1 biased signaling regulates perfusion recovery and neovascularization in peripheral ischemia
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 endothe...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2022-07-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.157701 |
| _version_ | 1827768085852979200 |
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| author | Magdalena L. Bochenek Rajinikanth Gogiraju Stefanie Großmann Janina Krug Jennifer Orth Sabine Reyda George S. Georgiadis Henri M. Spronk Stavros Konstantinides Thomas Münzel John H. Griffin Philipp Wild Christine Espinola-Klein Wolfram Ruf Katrin Schäfer |
| author_facet | Magdalena L. Bochenek Rajinikanth Gogiraju Stefanie Großmann Janina Krug Jennifer Orth Sabine Reyda George S. Georgiadis Henri M. Spronk Stavros Konstantinides Thomas Münzel John H. Griffin Philipp Wild Christine Espinola-Klein Wolfram Ruf Katrin Schäfer |
| author_sort | Magdalena L. Bochenek |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:07:14Z |
| format | Article |
| id | doaj.art-0909dcd5f8c44e619cf8af8d0733a288 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:07:14Z |
| publishDate | 2022-07-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-0909dcd5f8c44e619cf8af8d0733a2882023-11-07T16:24:21ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-07-01714EPCR-PAR1 biased signaling regulates perfusion recovery and neovascularization in peripheral ischemiaMagdalena L. BochenekRajinikanth GogirajuStefanie GroßmannJanina KrugJennifer OrthSabine ReydaGeorge S. GeorgiadisHenri M. SpronkStavros KonstantinidesThomas MünzelJohn H. GriffinPhilipp WildChristine Espinola-KleinWolfram RufKatrin SchäferBlood 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.https://doi.org/10.1172/jci.insight.157701AngiogenesisVascular biology |
| spellingShingle | Magdalena L. Bochenek Rajinikanth Gogiraju Stefanie Großmann Janina Krug Jennifer Orth Sabine Reyda George S. Georgiadis Henri M. Spronk Stavros Konstantinides Thomas Münzel John H. Griffin Philipp Wild Christine Espinola-Klein Wolfram Ruf Katrin Schäfer EPCR-PAR1 biased signaling regulates perfusion recovery and neovascularization in peripheral ischemia JCI Insight Angiogenesis Vascular biology |
| title | EPCR-PAR1 biased signaling regulates perfusion recovery and neovascularization in peripheral ischemia |
| title_full | EPCR-PAR1 biased signaling regulates perfusion recovery and neovascularization in peripheral ischemia |
| title_fullStr | EPCR-PAR1 biased signaling regulates perfusion recovery and neovascularization in peripheral ischemia |
| title_full_unstemmed | EPCR-PAR1 biased signaling regulates perfusion recovery and neovascularization in peripheral ischemia |
| title_short | EPCR-PAR1 biased signaling regulates perfusion recovery and neovascularization in peripheral ischemia |
| title_sort | epcr par1 biased signaling regulates perfusion recovery and neovascularization in peripheral ischemia |
| topic | Angiogenesis Vascular biology |
| url | https://doi.org/10.1172/jci.insight.157701 |
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