MMP-12, Secreted by Pro-Inflammatory Macrophages, Targets Endoglin in Human Macrophages and Endothelial Cells Aristorena, Mikel Gallardo-Vara, Eunate Vicen, Matej de Las Casas-Engel, Mateo Ojeda-Fernandez, Luisa Nieto, Concepción Blanco, Francisco J. Valbuena-Diez, Ana C. Botella, Luisa M. Nachtigal, Petr Corbi, Angel L. Colmenares, María Bernabeu, Carmelo Monocytes Macrophages Endothelial cells Inflammation MMP-12 endoglin Upon inflammation, monocyte-derived macrophages (MF) infiltrate blood vessels to regulate several processes involved in vascular pathophysiology. However, little is known about the mediators involved. Macrophage polarization is crucial for a fast and e cient initial response (GM-MF) and a good resolution (M-MF) of the inflammatory process. The functional activity of polarized MF is exerted mainly through their secretome, which can target other cell types, including endothelial cells. Endoglin (CD105) is a cell surface receptor expressed by endothelial cells and MF that is markedly upregulated in inflammation and critically involved in angiogenesis. In addition, a soluble form of endoglin with anti-angiogenic activity has been described in inflammation-associated pathologies. The aim of this work was to identify components of the MF secretome involved in the shedding of soluble endoglin. We find that the GM-MF secretome contains metalloprotease 12 (MMP-12), a GM-MF specific marker that may account for the anti-angiogenic activity of the GM-MF secretome. Cell surface endoglin is present in both GM-MF and M-MF, but soluble endoglin is only detected in GM-MF culture supernatants. Moreover, MMP-12 is responsible for the shedding of soluble endoglin in vitro and in vivo by targeting membrane-bound endoglin in both MF and endothelial cells. These data demonstrate a direct correlation between GM-MF polarization, MMP-12, and soluble endoglin expression and function. By targeting endothelial cells, MMP-12 may represent a novel mediator involved in vascular homeostasis. 2019-10-11T11:14:06Z 2019-10-11T11:14:06Z 2019-06-02 info:eu-repo/semantics/article Aristorena, M., Gallardo-Vara, E., Vicen, M., de Las Casas-Engel, M., Ojeda-Fernandez, L., Nieto, C., ... & Corbi, A. L. (2019). MMP-12, Secreted by Pro-Inflammatory Macrophages, Targets Endoglin in Human Macrophages and Endothelial Cells. International journal of molecular sciences, 20(12), 3107. http://hdl.handle.net/10481/57311 10.3390/ijms20123107 eng http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Atribución 3.0 España MDPI