Smad1 Activation In Infarct Macrophages Restrains Angiogenesis And Accentuates Adverse Remodeling Of The Infarcted Myocardium

Macrophages play multiple roles in repair and remodeling of the infarcted heart, contributing to phagocytosis of dead cells, regulation of inflammation, fibrosis and angiogenesis. TGF-β superfamily members are critically involved in regulation of macrophage phenotype through the Smad cascades. In most cell types, TGF-βs signal predominantly by activating Smad2/3 signaling, whereas BMPs act through Smad1/5-mediated pathways. We previously showed that TGF-β/Smad3 signaling in macrophages protects the infarcted heart from adverse remodeling by mediating phagocytotic activity and anti-inflammatory transition. However, the in vivo role of Smad1/5 signaling in macrophages remains unknown. We examined the role of macrophage-specific Smad1 signaling in a mouse model of myocardial infarction (MI). Smad1 is activated in a subset of myeloid cells infiltrating the infarcted myocardium. In vitro, TGF-β1, TGF-β3, BMP4, BMP7, but not TGF-β2, BMP2, BMP6 markedly activated Smad1/5 signaling in macrophages. In order to examine the role of Smad1 in regulation of macrophage phenotype we generated myeloid cell-specific Smad1 KO mice (MyS1KO). MyS1KO mice had better survival compared to S1fl/fl controls 28 days post MI ( p =0.0009, n=26-27). Echocardiographic data showed that MyS1KO mice had reduced left ventricular dilation and attenuated systolic dysfunction 28 days after MI. Although scar size was comparable between groups at the 7 day timepoint, MyS1KO animals had significantly smaller scars 28 days after MI, suggesting improved scar remodeling. MyS1KO mice exhibited increased microvessel density in the infarct, suggesting that Smad1 activation in macrophages may restrain angiogenesis. In order to explore the mechanisms, we isolated infarct macrophages from MyS1KO and S1fl/fl hearts and compared angiogenesis-related protein expression by performing a proteomic array. Smad1 loss in macrophages did not affect VEGF-A expression, but significantly increased levels of the angiogenic chemokine CXCL12. Our findings suggest that Smad1 is directly activated by TGF-βs in macrophages, and that Smad1 activation in infarct macrophages may promote adverse remodeling by restraining angiogenic effects through suppression of angiogenic chemokines.