Alonso-Herranz, LauraSahun-Español, AlvaroParedes, AnaGonzalo, PilarGkontra, PolyxeniNunez, VanessaClemente, CristinaCedenilla, MartaVillalba-Orero, MariaInserte, JavierGarcia-Dorado, DavidArroyo, Alicia GRicote, Mercedes2021-06-232021-06-232020-10Elife. 2020; 9:e57920http://hdl.handle.net/20.500.12105/13182Macrophages (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 the 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.engVoRhttp://creativecommons.org/licenses/by/4.0/Epithelial-Mesenchymal TransitionAnimalsCollagenDisease Models, AnimalEndothelium, VascularFemaleFibrosisFlow CytometryGene Expression RegulationHEK293 CellsHumansMacrophagesMaleMatrix Metalloproteinase 14MiceMice, Inbred C57BLMice, KnockoutMicrocirculationMyocardial InfarctionPhenotypeReperfusion InjuryTransforming Growth Factor beta1Ventricular Dysfunction, LeftAtribución 4.0 Internacional330636659e5792010.7554/eLife.579202050-084XeLifeopen access