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ResearchIn-Press PreviewAngiogenesisVascular biology Open Access | 10.1172/jci.insight.157701

EPCR−PAR1 biased signaling regulates perfusion recovery and neovascularization in peripheral ischemia

Magdalena L. Bochenek,1 Rajinikanth Gogiraju,2 Stefanie Großmann,2 Janina Krug,2 Jennifer Orth,2 Sabine Reyda,1 George S. Georgiadis,3 Henri Spronk,4 Stavros Konstantinides,1 Thomas Münzel,1 John H. Griffin,5 Philipp S. Wild,1 Christine Espinola-Klein,2 Wolfram Ruf,1 and Katrin Schäfer1

1Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany

2Department of Cardiology, University Medical Center Mainz, Mainz, Germany

3Department of Vascular Surgery, University Hospital of Alexandroupolis, Alexandroupolis, Greece

4CARIM School for Cardiovascular Disease, Maastricht University, Maastricht, Netherlands

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

Find articles by Bochenek, M. in: PubMed | Google Scholar

1Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany

2Department of Cardiology, University Medical Center Mainz, Mainz, Germany

3Department of Vascular Surgery, University Hospital of Alexandroupolis, Alexandroupolis, Greece

4CARIM School for Cardiovascular Disease, Maastricht University, Maastricht, Netherlands

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

Find articles by Gogiraju, R. in: PubMed | Google Scholar

1Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany

2Department of Cardiology, University Medical Center Mainz, Mainz, Germany

3Department of Vascular Surgery, University Hospital of Alexandroupolis, Alexandroupolis, Greece

4CARIM School for Cardiovascular Disease, Maastricht University, Maastricht, Netherlands

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

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1Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany

2Department of Cardiology, University Medical Center Mainz, Mainz, Germany

3Department of Vascular Surgery, University Hospital of Alexandroupolis, Alexandroupolis, Greece

4CARIM School for Cardiovascular Disease, Maastricht University, Maastricht, Netherlands

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

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1Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany

2Department of Cardiology, University Medical Center Mainz, Mainz, Germany

3Department of Vascular Surgery, University Hospital of Alexandroupolis, Alexandroupolis, Greece

4CARIM School for Cardiovascular Disease, Maastricht University, Maastricht, Netherlands

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

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1Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany

2Department of Cardiology, University Medical Center Mainz, Mainz, Germany

3Department of Vascular Surgery, University Hospital of Alexandroupolis, Alexandroupolis, Greece

4CARIM School for Cardiovascular Disease, Maastricht University, Maastricht, Netherlands

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

Find articles by Reyda, S. in: PubMed | Google Scholar

1Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany

2Department of Cardiology, University Medical Center Mainz, Mainz, Germany

3Department of Vascular Surgery, University Hospital of Alexandroupolis, Alexandroupolis, Greece

4CARIM School for Cardiovascular Disease, Maastricht University, Maastricht, Netherlands

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

Find articles by Georgiadis, G. in: PubMed | Google Scholar

1Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany

2Department of Cardiology, University Medical Center Mainz, Mainz, Germany

3Department of Vascular Surgery, University Hospital of Alexandroupolis, Alexandroupolis, Greece

4CARIM School for Cardiovascular Disease, Maastricht University, Maastricht, Netherlands

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

Find articles by Spronk, H. in: PubMed | Google Scholar |

1Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany

2Department of Cardiology, University Medical Center Mainz, Mainz, Germany

3Department of Vascular Surgery, University Hospital of Alexandroupolis, Alexandroupolis, Greece

4CARIM School for Cardiovascular Disease, Maastricht University, Maastricht, Netherlands

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

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1Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany

2Department of Cardiology, University Medical Center Mainz, Mainz, Germany

3Department of Vascular Surgery, University Hospital of Alexandroupolis, Alexandroupolis, Greece

4CARIM School for Cardiovascular Disease, Maastricht University, Maastricht, Netherlands

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

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1Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany

2Department of Cardiology, University Medical Center Mainz, Mainz, Germany

3Department of Vascular Surgery, University Hospital of Alexandroupolis, Alexandroupolis, Greece

4CARIM School for Cardiovascular Disease, Maastricht University, Maastricht, Netherlands

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

Find articles by Griffin, J. in: PubMed | Google Scholar |

1Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany

2Department of Cardiology, University Medical Center Mainz, Mainz, Germany

3Department of Vascular Surgery, University Hospital of Alexandroupolis, Alexandroupolis, Greece

4CARIM School for Cardiovascular Disease, Maastricht University, Maastricht, Netherlands

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

Find articles by Wild, P. in: PubMed | Google Scholar |

1Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany

2Department of Cardiology, University Medical Center Mainz, Mainz, Germany

3Department of Vascular Surgery, University Hospital of Alexandroupolis, Alexandroupolis, Greece

4CARIM School for Cardiovascular Disease, Maastricht University, Maastricht, Netherlands

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

Find articles by Espinola-Klein, C. in: PubMed | Google Scholar

1Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany

2Department of Cardiology, University Medical Center Mainz, Mainz, Germany

3Department of Vascular Surgery, University Hospital of Alexandroupolis, Alexandroupolis, Greece

4CARIM School for Cardiovascular Disease, Maastricht University, Maastricht, Netherlands

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

Find articles by Ruf, W. in: PubMed | Google Scholar |

1Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany

2Department of Cardiology, University Medical Center Mainz, Mainz, Germany

3Department of Vascular Surgery, University Hospital of Alexandroupolis, Alexandroupolis, Greece

4CARIM School for Cardiovascular Disease, Maastricht University, Maastricht, Netherlands

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

Find articles by Schäfer, K. in: PubMed | Google Scholar |

Published June 14, 2022 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.157701.
Copyright © 2022, Bochenek et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 14, 2022 - Version history
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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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  • Version 1 (June 14, 2022): In-Press Preview
  • Version 2 (July 22, 2022): Electronic publication
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