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EPCR−PAR1 biased signaling regulates perfusion recovery and neovascularization in peripheral ischemia via mechanism involving nitric oxide

1Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany, Mainz, Rheinland-Pfalz, Germany, 2 University Medical Center Mainz, Mainz, Germany, Mainz, Rheinland-Pfalz, Germany, 3Department of Cardiology, University Medical Center Mainz, Mainz, Germany, Mainz, Rheinland-Pfalz, Germany, 4Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Evros, Greece, 5Center for Cardiology - Cardiology I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany, Mainz, Rheinland-Pfalz, Germany, 6Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, United States, 7Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany, Mainz, Rheinland-Pfalz, Germany, 8Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, Mainz, Rheinland-Pfalz, Germany, 9University Medical Center Mainz, Mainz, Germany, Mainz, Rheinland-Pfalz, Germany

Abstract Number: PB1299

Meeting: ISTH 2022 Congress

Theme: Vascular Biology » Protease Activated Receptors

Background: Blood clot formation initiates ischemic events, but the role of coagulation during postischemic tissue repair is poorly understood. The endothelial protein C receptor (EPCR) regulates coagulation and vascular signaling by protease activated receptors (PARs).

Aims: To study the effect of coagulation receptors in ischemia-induced new vessel formation.

Methods: The mouse model of unilateral hindlimb ischemia (HLI) was used to induce new vessel formation, and reperfusion of the distal hindlimbs was monitored over four weeks using Laser Doppler perfusion imaging (LDPI). Gastrocnemius (GC) muscles of the ischemic and contralateral control hindlimb were analyzed. Human microvascular endothelial cells were subjected to hypoxia (1% oxygen) and the role of EPCR was examined.

Results: Here, we show in an unilateral hindlimb ischemia model in mice that endothelial EPCR−PAR1 signaling supports reperfusion and neovascularization. Whereas deletion of PAR2 or PAR4 did not impair angiogenesis, EPCR and PAR1 deficiency or PAR1 resistance to cleavage by activated protein C in PAR1 R46Q mice caused markedly reduced postischemic reperfusion in vivo and angiogenesis in vitro. These findings were corroborated in primary human endothelial cells stimulated with biased PAR1 agonist peptides. 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, and NO scavenging or inhibition of endothelial NO signaling increased hemoglobin and mesenchymal marker expression in primary endothelial cells. Endarterectomy specimens from patients with ischemic peripheral artery disease also showed reduced endothelial EPCR expression associated with increased hemoglobin expression and NO bioavailability.

Conclusion(s): Our data implicate endothelial EPCR−PAR1 signaling in neovascularization after ischemia and identify endothelial hemoglobin expression as an unexpected link between coagulation signaling and the preservation of endothelial cell NO bioavailability and prevention of fibrosis.

To cite this abstract in AMA style:

Bochenek M, Gogiraju R, Großmann S, Krug J, Orth J, Reyda S, Georgiadis G, Konstantinides S, Münzel T, Griffin J, Wild P, Espinola-Klein C, Ruf W, Schäfer K. EPCR−PAR1 biased signaling regulates perfusion recovery and neovascularization in peripheral ischemia via mechanism involving nitric oxide [abstract]. https://abstracts.isth.org/abstract/epcr%e2%88%92par1-biased-signaling-regulates-perfusion-recovery-and-neovascularization-in-peripheral-ischemia-via-mechanism-involving-nitric-oxide/. Accessed September 22, 2023.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/epcr%e2%88%92par1-biased-signaling-regulates-perfusion-recovery-and-neovascularization-in-peripheral-ischemia-via-mechanism-involving-nitric-oxide/