Alonso-Herranz, LauraSahún-Español, ÁlvaroParedes, AnaGonzalo, PilarGkontra, PolyxeniNúñez, VanessaClemente, CristinaCedenilla, MartaInserte, JavierGarcía-Dorado, DavidG Arroyo, AliciaRicote, MercedesVillalba Orero, María2024-01-292024-01-292020-10-162050-084X10.7554/elife.57920https://hdl.handle.net/20.500.14352/96096Author contributions Laura Alonso-Herranz, Conceptualization, Data curation, Software, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing-original draft; Álvaro Sahón-Español, Pilar Gonzalo, Data curation, Software, Formal analysis, Investigation, Visualization, Methodology, Writing- review and editing; Ana Paredes, Marta Cedenilla, Javier Inserte, Formal analysis, Investigation, Methodology; Polyxeni Gkontra, Data curation, Software, Formal analysis, Methodology, Writing-review and editing; Vanessa Nuñez, Cristina Clemente, Methodology; María Villalba-Orero, Software, Formal analysis, Validation, Visualization, Methodology; David García-Dorado, Conceptualization, Resources, Investigation, Writing-review and editing; Alicia G Arroyo, Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Writing-original draft, Project administration, Writing- review and editing; Mercedes Ricote, Conceptualization, Resources, Supervision, Funding acquisition, Validation, Investigation,Writing-original draft, Project administration, Writing-review and editing.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 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.engAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/journal articlehttps://elifesciences.org/articles/57920open access636.09Veterinaria2415 Biología Molecular