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
1  Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
,
Malgorzata Wygrecka
2  Department of Biochemistry, Universities Giessen and Marburg Lung Centre, German Centre for Lung Research, Giessen, Germany
,
Thomas Bärnthaler
3  Otto Loewi Research Center, Medical University of Graz, Graz, Austria
,
Katharina Jandl
1  Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
,
Pritesh P. Jain
1  Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
,
Zoltán Bálint
1  Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
4  Department of Physics, Babes-Bolyai University, Cluj-Napoca, Romania
,
Gabor Kovacs
1  Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
5  Department of Pulmonology, Medical University of Graz, Graz, Austria
,
Gerd Leitinger
6  Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
7  Center for Medical Research, Medical University of Graz, Graz, Austria
,
Dagmar Kolb-Lenz
6  Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
7  Center for Medical Research, Medical University of Graz, Graz, Austria
,
Karin Kornmueller
6  Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
,
Florian Peters
8  Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, Kiel, Germany
,
Katharina Sinn
1  Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
9  Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
,
Walter Klepetko
9  Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
,
Akos Heinemann
3  Otto Loewi Research Center, Medical University of Graz, Graz, Austria
10  BioTechMed Graz, Graz, Austria
,
Andrea Olschewski
1  Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
,
Christoph Becker-Pauly
8  Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, Kiel, Germany
,
Grazyna Kwapiszewska
1  Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
3  Otto Loewi Research Center, Medical University of Graz, Graz, Austria
› Author Affiliations
Funding This study was funded by Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria, Jubilee Foundation of the Austrian National Bank (Grant 16187 to G.K.), The Austrian Science Foundation (FWF, Grant P 27848-B28) and Deutsche Forschungsgemeinschaft SFB877, project A9.
Further Information

Publication History

20 March 2018

08 August 2018

Publication Date:
20 September 2018 (eFirst)

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.

Authors' Contributions

Data acquisition, analysis and design: V.B., M.W., T.B., Z.B., K.J., G.L., D.K. and G.K. Human material: G.K., K.S. and W.K. Production of the recombinant meprin α: F.P. Drafting of the manuscript: V.B., G.K., K.M., A.H., A.O. and C.B.P.


Supplementary Material