Macrophage Smad1 contributes to post-infarction dysfunction, suppressing angiogenic chemokine expression, and stimulating extracellular matrix remodeling

In healing infarcts, macrophages undergo dramatic phenotypic changes in response to cytokines and growth factors and serve as central effectors in cardiac repair and remodeling. TGF-β superfamily members are key regulators of macrophages and signal predominantly through activation of Smad-dependent cascades. Although the involvement of TGF-β/Smad3 in regulation of macrophage phenotype has been documented, there is no information on the in vivo effects of macrophage Smad1 signaling. To study the role of macrophage Smad1 in myocardial infarction, we performed in vitro studies and in vivo experiments using mice with myeloid cell-specific Smad1 loss. Macrophage Smad1 activation peaked 7 days after infarction. In vitro, TGF-β1, TGF-β3 and BMP6, but not by BMP2, BMP4 and BMP7, stimulated Smad1 activation. In vivo, myeloid cell-specific Smad1 loss attenuated post-infarction adverse remodeling and ventricular dysfunction, increasing angiogenesis and decreasing extracellular matrix denaturation. Acquisition of an angiogenic profile by macrophages in the absence of Smad1, involved upregulation of the angiogenic chemokine CXCL12. In conclusion, our findings demonstrate for the first time that macrophage Smad1 inhibits release of angiogenic chemokines and enhances expression of genes involved in extracellular matrix remodeling.