Docking of Meprin α to Heparan Sulphate Protects the Endothelium from Inflammatory Cell Extravasation

Valentina Biasin; Malgorzata Wygrecka; Thomas Bärnthaler; Katharina Jandl; Pritesh P. Jain; Zoltán Bálint; Gabor Kovacs; Gerd Leitinger; Dagmar Kolb-Lenz; Karin Kornmueller; Florian Peters; Katharina Sinn; Walter Klepetko; Akos Heinemann; Andrea Olschewski; Christoph Becker-Pauly; Grazyna Kwapiszewska

doi:10.1055/s-0038-1670657

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2018; 118(10): 1790-1802
DOI: 10.1055/s-0038-1670657

Endothelium and Angiogenesis

Georg Thieme Verlag KG Stuttgart · New York

Docking of Meprin α to Heparan Sulphate Protects the Endothelium from Inflammatory Cell Extravasation

Valentina Biasin

¹Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria

,

Malgorzata Wygrecka

²Department of Biochemistry, Universities Giessen and Marburg Lung Centre, German Centre for Lung Research, Giessen, Germany

,

Thomas Bärnthaler

³Otto Loewi Research Center, Medical University of Graz, Graz, Austria

,

Katharina Jandl

¹Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria

,

Pritesh P. Jain

¹Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria

,

Zoltán Bálint

¹Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria

⁴Department of Physics, Babes-Bolyai University, Cluj-Napoca, Romania

,

Gabor Kovacs

¹Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria

⁵Department of Pulmonology, Medical University of Graz, Graz, Austria

,

Gerd Leitinger

⁶Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria

⁷Center for Medical Research, Medical University of Graz, Graz, Austria

,

Dagmar Kolb-Lenz

⁶Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria

⁷Center for Medical Research, Medical University of Graz, Graz, Austria

,

Karin Kornmueller

⁶Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria

,

Florian Peters

⁸Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, Kiel, Germany

,

Katharina Sinn

¹Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria

⁹Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria

,

Walter Klepetko

⁹Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria

,

Akos Heinemann

³Otto Loewi Research Center, Medical University of Graz, Graz, Austria

¹⁰BioTechMed Graz, Graz, Austria

,

Andrea Olschewski

¹Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria

,

Christoph Becker-Pauly

⁸Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, Kiel, Germany

,

Grazyna Kwapiszewska

¹Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria

³Otto Loewi Research Center, Medical University of Graz, Graz, Austria

› Author Affiliations

Abstract

Pulmonary arterial hypertension (PAH) is a rare disease characterized by increased pulmonary pressure and vascular remodelling as a consequence of smooth muscle cell proliferation, endothelial cell dysfunction and inflammatory infiltrates. Meprin α is a metalloproteinase whose substrates include adhesion and cell–cell contact molecules involved in the process of immune cell extravasation. In this study, we aimed to unravel the role of meprin α in PAH-induced vascular remodelling. Our results showed that meprin α was present in the apical membrane of endothelial cells in the lungs and pulmonary arteries of donors and idiopathic PAH (IPAH) patients. Elevated circulating meprin α levels were detected in the plasma of IPAH patients. In vitro binding assays and electron microscopy confirmed binding of meprin α to the glycocalyx of human pulmonary artery endothelial cells (hPAECs). Enzymatic and genetic approaches identified heparan sulphate (HS) as an important determinant of the meprin α binding capacity to hPAEC. Meprin α treatment protected from excessive neutrophil infiltration and the protective effect observed in the presence of neutrophils was partially reversed by removal of HS from hPAEC. Importantly, HS levels in pulmonary arteries were decreased in IPAH patients and binding of meprin α to HS was impaired in IPAH hPAEC. In summary, our results suggest a role of HS in docking meprin α to the endothelium and thus in the modulation of inflammatory cell extravasation. In IPAH, the decreased endothelial HS results in the reduction of meprin α binding which might contribute to enhanced inflammatory cell extravasation and potentially to pathological vascular remodelling.

Keywords

meprin α - endothelial cells - inflammatory cells - extravasation

Full Text

References

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Supplementary Material