Download PDF
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 (online)

Also available at
    Permissions and Reprints

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

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

 

  • References

  • 1 Hoeper MM, Barberà JA, Channick RN. , et al. Diagnosis, assessment, and treatment of non-pulmonary arterial hypertension pulmonary hypertension. J Am Coll Cardiol 2009; 54 (1, Suppl): S85-S96
    CrossrefPubMedGoogle Scholar
  • 2 Simonneau G, Gatzoulis MA, Adatia I. , et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013; 62 (25, Suppl): D34-D41
    CrossrefPubMedGoogle Scholar
  • 3 Eddahibi S, Morrell N, d'Ortho MP, Naeije R, Adnot S. Pathobiology of pulmonary arterial hypertension. Eur Respir J 2002; 20 (06) 1559-1572
    CrossrefPubMedGoogle Scholar
  • 4 Guignabert C, Tu L, Girerd B. , et al. New molecular targets of pulmonary vascular remodeling in pulmonary arterial hypertension: importance of endothelial communication. Chest 2015; 147 (02) 529-537
    CrossrefPubMedGoogle Scholar
  • 5 Klinger JR, Abman SH, Gladwin MT. Nitric oxide deficiency and endothelial dysfunction in pulmonary arterial hypertension. Am J Respir Crit Care Med 2013; 188 (06) 639-646
    CrossrefPubMedGoogle Scholar
  • 6 Rajendran P, Rengarajan T, Thangavel J. , et al. The vascular endothelium and human diseases. Int J Biol Sci 2013; 9 (10) 1057-1069
    CrossrefPubMedGoogle Scholar
  • 7 Weinbaum S, Tarbell JM, Damiano ER. The structure and function of the endothelial glycocalyx layer. Annu Rev Biomed Eng 2007; 9: 121-167
    CrossrefPubMedGoogle Scholar
  • 8 Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch 2007; 454 (03) 345-359
    CrossrefPubMedGoogle Scholar
  • 9 Mehta D, Ravindran K, Kuebler WM. Novel regulators of endothelial barrier function. Am J Physiol Lung Cell Mol Physiol 2014; 307 (12) L924-L935
    CrossrefPubMedGoogle Scholar
  • 10 Curry FE, Adamson RH. Endothelial glycocalyx: permeability barrier and mechanosensor. Ann Biomed Eng 2012; 40 (04) 828-839
    CrossrefPubMedGoogle Scholar
  • 11 Endo K, Takino T, Miyamori H. , et al. Cleavage of syndecan-1 by membrane type matrix metalloproteinase-1 stimulates cell migration. J Biol Chem 2003; 278 (42) 40764-40770
    CrossrefPubMedGoogle Scholar
  • 12 Li Q, Park PW, Wilson CL, Parks WC. Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury. Cell 2002; 111 (05) 635-646
    CrossrefPubMedGoogle Scholar
  • 13 Massena S, Christoffersson G, Hjertström E. , et al. A chemotactic gradient sequestered on endothelial heparan sulfate induces directional intraluminal crawling of neutrophils. Blood 2010; 116 (11) 1924-1931
    CrossrefPubMedGoogle Scholar
  • 14 Biasin V, Wygrecka M, Marsh LM. , et al. Meprin β contributes to collagen deposition in lung fibrosis. Sci Rep 2017; 7: 39969
    CrossrefPubMedGoogle Scholar
  • 15 Quintero PA, Knolle MD, Cala LF, Zhuang Y, Owen CA. Matrix metalloproteinase-8 inactivates macrophage inflammatory protein-1 alpha to reduce acute lung inflammation and injury in mice. J Immunol 2010; 184 (03) 1575-1588
    CrossrefPubMedGoogle Scholar
  • 16 Dean RA, Cox JH, Bellac CL, Doucet A, Starr AE, Overall CM. Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR+ CXC chemokines and generates CCL2, -7, -8, and -13 antagonists: potential role of the macrophage in terminating polymorphonuclear leukocyte influx. Blood 2008; 112 (08) 3455-3464
    CrossrefPubMedGoogle Scholar
  • 17 Biasin V, Marsh LM, Egemnazarov B. , et al. Meprin β, a novel mediator of vascular remodelling underlying pulmonary hypertension. J Pathol 2014; 233 (01) 7-17
    CrossrefPubMedGoogle Scholar
  • 18 Bedau T, Peters F, Prox J. , et al. Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin β and promotes transendothelial cell migration. FASEB J 2017; 31 (03) 1226-1237
    CrossrefPubMedGoogle Scholar
  • 19 Banerjee S, Oneda B, Yap LM. , et al. MEP1A allele for meprin A metalloprotease is a susceptibility gene for inflammatory bowel disease. Mucosal Immunol 2009; 2 (03) 220-231
    CrossrefPubMedGoogle Scholar
  • 20 Herzog C, Haun RS, Kaushal V, Mayeux PR, Shah SV, Kaushal GP. Meprin A and meprin alpha generate biologically functional IL-1beta from pro-IL-1beta. Biochem Biophys Res Commun 2009; 379 (04) 904-908
    CrossrefPubMedGoogle Scholar
  • 21 Rabinovitch M, Guignabert C, Humbert M, Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res 2014; 115 (01) 165-175
    CrossrefPubMedGoogle Scholar
  • 22 Marsh LM, Jandl K, Grünig G. , et al. The inflammatory cell landscape in the lungs of patients with idiopathic pulmonary arterial hypertension. Eur Respir J 2018; 51 (01) 1701214
    CrossrefPubMedGoogle Scholar
  • 23 Jain PP, Leber R, Nagaraj C. , et al. Liposomal nanoparticles encapsulating iloprost exhibit enhanced vasodilation in pulmonary arteries. Int J Nanomedicine 2014; 9: 3249-3261
    PubMedGoogle Scholar
  • 24 Nagaraj C, Tang B, Nagy BM. , et al. Docosahexaenoic acid causes rapid pulmonary arterial relaxation via KCa channel-mediated hyperpolarisation in pulmonary hypertension. Eur Respir J 2016; 48 (04) 1127-1136
    CrossrefPubMedGoogle Scholar
  • 25 Hoffmann J, Wilhelm J, Marsh LM. , et al. Distinct differences in gene expression patterns in pulmonary arteries of patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis with pulmonary hypertension. Am J Respir Crit Care Med 2014; 190 (01) 98-111
    CrossrefPubMedGoogle Scholar
  • 26 Hoffmann J, Marsh LM, Pieper M. , et al. Compartment-specific expression of collagens and their processing enzymes in intrapulmonary arteries of IPAH patients. Am J Physiol Lung Cell Mol Physiol 2015; 308 (10) L1002-L1013
    CrossrefPubMedGoogle Scholar
  • 27 McLean IW, Nakane PK. Periodate-lysine-paraformaldehyde fixative. A new fixation for immunoelectron microscopy. J Histochem Cytochem 1974; 22 (12) 1077-1083
    CrossrefPubMedGoogle Scholar
  • 28 Becker-Pauly C, Höwel M, Walker T. , et al. The alpha and beta subunits of the metalloprotease meprin are expressed in separate layers of human epidermis, revealing different functions in keratinocyte proliferation and differentiation. J Invest Dermatol 2007; 127 (05) 1115-1125
    CrossrefPubMedGoogle Scholar
  • 29 Bärnthaler T, Maric J, Platzer W. , et al. The role of PGE2 in alveolar epithelial and lung microvascular endothelial crosstalk. Sci Rep 2017; 7 (01) 7923
    CrossrefPubMedGoogle Scholar
  • 30 Koodie L, Yuan H, Pumper JA. , et al. Morphine inhibits migration of tumor-infiltrating leukocytes and suppresses angiogenesis associated with tumor growth in mice. Am J Pathol 2014; 184 (04) 1073-1084
    CrossrefPubMedGoogle Scholar
  • 31 Balenga NA, Aflaki E, Kargl J. , et al. GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils. Cell Res 2011; 21 (10) 1452-1469
    CrossrefPubMedGoogle Scholar
  • 32 Wang L, Fuster M, Sriramarao P, Esko JD. Endothelial heparan sulfate deficiency impairs L-selectin- and chemokine-mediated neutrophil trafficking during inflammatory responses. Nat Immunol 2005; 6 (09) 902-910
    CrossrefPubMedGoogle Scholar
  • 33 Smith CH, Barker JN, Morris RW, MacDonald DM, Lee TH. Neuropeptides induce rapid expression of endothelial cell adhesion molecules and elicit granulocytic infiltration in human skin. J Immunol 1993; 151 (06) 3274-3282
    PubMedGoogle Scholar
  • 34 Huguenin M, Müller EJ, Trachsel-Rösmann S. , et al. The metalloprotease meprinbeta processes E-cadherin and weakens intercellular adhesion. PLoS One 2008; 3 (05) e2153
    CrossrefPubMedGoogle Scholar
  • 35 Jefferson T, Auf dem Keller U, Bellac C. , et al. The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin β and ADAM10. Cell Mol Life Sci 2013; 70 (02) 309-333
    CrossrefPubMedGoogle Scholar
  • 36 Long L, Ormiston ML, Yang X. , et al. Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nat Med 2015; 21 (07) 777-785
    CrossrefPubMedGoogle Scholar
  • 37 Daley E, Emson C, Guignabert C. , et al. Pulmonary arterial remodeling induced by a Th2 immune response. J Exp Med 2008; 205 (02) 361-372
    CrossrefPubMedGoogle Scholar
  • 38 Cornish-Bowden A. The origins of enzyme kinetics. FEBS Lett 2013; 587 (17) 2725-2730
    CrossrefPubMedGoogle Scholar
  • 39 Parish CR. Heparan sulfate and inflammation. Nat Immunol 2005; 6 (09) 861-862
    CrossrefPubMedGoogle Scholar
  • 40 Tang J, Zarbock A, Gomez I. , et al. Adam17-dependent shedding limits early neutrophil influx but does not alter early monocyte recruitment to inflammatory sites. Blood 2011; 118 (03) 786-794
    CrossrefPubMedGoogle Scholar
  • 41 Simon T, Bromberg JS. Regulation of the immune system by laminins. Trends Immunol 2017; 38 (11) 858-871
    CrossrefPubMedGoogle Scholar
  • 42 Herter JM, Rossaint J, Block H, Welch H, Zarbock A. Integrin activation by P-Rex1 is required for selectin-mediated slow leukocyte rolling and intravascular crawling. Blood 2013; 121 (12) 2301-2310
    CrossrefPubMedGoogle Scholar
  • 43 Hafezi-Moghadam A, Thomas KL, Prorock AJ, Huo Y, Ley K. L-selectin shedding regulates leukocyte recruitment. J Exp Med 2001; 193 (07) 863-872
    CrossrefPubMedGoogle Scholar
  • 44 Walcheck B, Kahn J, Fisher JM. , et al. Neutrophil rolling altered by inhibition of L-selectin shedding in vitro. Nature 1996; 380 (6576): 720-723
    CrossrefPubMedGoogle Scholar
  • 45 Minder P, Bayha E, Becker-Pauly C, Sterchi EE. Meprinα transactivates the epidermal growth factor receptor (EGFR) via ligand shedding, thereby enhancing colorectal cancer cell proliferation and migration. J Biol Chem 2012; 287 (42) 35201-35211
    CrossrefPubMedGoogle Scholar
  • 46 Arnold P, Boll I, Rothaug M. , et al. Meprin metalloproteases generate biologically active soluble interleukin-6 receptor to induce trans-signaling. Sci Rep 2017; 7: 44053
    CrossrefPubMedGoogle Scholar
  • 47 Vazeille E, Bringer MA, Gardarin A. , et al. Role of meprins to protect ileal mucosa of Crohn's disease patients from colonization by adherent-invasive E. coli. PLoS One 2011; 6 (06) e21199
    CrossrefPubMedGoogle Scholar
  • 48 Wichert R, Ermund A, Schmidt S. , et al. Mucus detachment by host metalloprotease meprin β requires shedding of its inactive pro-form, which is abrogated by the pathogenic protease RgpB. Cell Reports 2017; 21 (08) 2090-2103
    CrossrefPubMedGoogle Scholar
  • 49 Wu CY, Asano Y, Taniguchi T, Sato S, Yu HS. Serum level of circulating syndecan-1: a possible association with proliferative vasculopathy in systemic sclerosis. J Dermatol 2016; 43 (01) 63-66
    CrossrefPubMedGoogle Scholar
  • 50 Stacher E, Graham BB, Hunt JM. , et al. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 186 (03) 261-272
    CrossrefPubMedGoogle Scholar
  • 51 Balabanian K, Foussat A, Dorfmüller P. , et al. CX(3)C chemokine fractalkine in pulmonary arterial hypertension. Am J Respir Crit Care Med 2002; 165 (10) 1419-1425
    CrossrefPubMedGoogle Scholar
  • 52 Dorfmüller P, Zarka V, Durand-Gasselin I. , et al. Chemokine RANTES in severe pulmonary arterial hypertension. Am J Respir Crit Care Med 2002; 165 (04) 534-539
    CrossrefPubMedGoogle Scholar