Authors:	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
Title:	EPCR-PAR1 biased signaling regulates perfusion recovery and neovascularization in peripheral ischemia
Online publication date:	8-Feb-2023
Year of first publication:	2022
Language:	english
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:	610 Medizin 610 Medical sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 04 Medizin
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-8655
Version:	Published version
Publication type:	Zeitschriftenaufsatz
Document type specification:	Scientific article
License:	CC BY
Information on rights of use:	https://creativecommons.org/licenses/by/4.0/
Journal:	JCI insight 7 14
Pages or article number:	e157701
Publisher:	JCI Insight
Publisher place:	Ann Arbor, Michigan
Issue date:	2022
ISSN:	2379-3708
Publisher DOI:	10.1172/jci.insight.157701
Appears in collections:	DFG-491381577-G