Running title: Macrophages and post-MI EndMT

30 p.-7 fig.-3 tab.-12 fig. supl.Macrophages (Mφs) produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. Here, we demonstrated that cardiac Mφs increased expression of Mmp14 (MT1-MMP) 7 days post-MI. We selectively inactivated the Mmp14 gene in Mφs using a genetic strategy (Mmp14f/f:Lyz2-Cre). This conditional KO (MAC-Mmp14 KO) resulted in attenuated post-MI cardiac dysfunction, reduced fibrosis, and preserved cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in Mφs, leading to paracrine SMAD2-mediated signaling in endothelial cells (ECs) and endothelial-to-mesenchymal transition (EndMT). Post-MI MAC-Mmp14 KO hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and Mmp14-deficient Mφs showed a reduced ability to induce EndMT in co-cultures with ECs. Our results indicate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify Mφ MT1-MMP as a key regulator of this process.This study was supported by grants from the Spanish Ministry of Science, Innovation and Universities (SAF2017-90604-REDT-NurCaMein, RTI2018-095928-BI00 to M.R.; SAF2017-83229-R to A.G.A.), Comunidad de Madrid (MOIR-B2017/BMD-3684) to M.R, and La Marató de TV3 Foundation to D.G.D, A.G.A., and M.R.Peer reviewe