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

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 alpha 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 alpha in PAH-induced vascular remodelling. Our results showed that meprin alpha 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 alpha levels were detected in the plasma of IPAH patients. In vitro binding assays and electron microscopy confirmed binding of meprin alpha 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 alpha binding capacity to hPAEC. Meprin alpha 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 alpha to HS was impaired in IPAH hPAEC. In summary, our results suggest a role of HS in docking meprin alpha to the endothelium and thus in the modulation of inflammatory cell extravasation. In IPAH, the decreased endothelial HS results in the reduction of meprin alpha binding which might contribute to enhanced inflammatory cell extravasation and potentially to pathological vascular remodelling.

• Biasin, V.
• Wygrecka, M.
• Barnthaler, T.
• Jandl, K.
• Jain, P. P.
• Balint, Z.
• Kovacs, G.
• Leitinger, G.
• Kolb-Lenz, D.
• Kornmueller, K.
• Peters, F.
• Sinn, K.
• Klepetko, W.
• Heinemann, A.
• Olschewski, A.
• Becker-Pauly, C.
• Kwapiszewska, G.