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

Thrombosis and haemostasis 2018 Oct

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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. Georg Thieme Verlag KG Stuttgart · New York.

Citation

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. Docking of Meprin α to Heparan Sulphate Protects the Endothelium from Inflammatory Cell Extravasation. Thrombosis and haemostasis. 2018 Oct;118(10):1790-1802