Abstract Body: Restoring cardiac function after myocardial infarction (MI) remains a central goal of regenerative therapy, yet the role of subcellular antioxidants in limiting ischemic injury is not fully understood. We previously showed that endothelial cell (EC)-specific mitochondrial superoxide dismutase (Sod2) overexpression enhanced EC oxidative phosphorylation (OxPhos) via improved mitochondrial supercomplex formation, increased coronary angiogenesis, and reduced infarct size, resulting in improved left ventricular function 28 days post-MI in mice. Here, we used spatial transcriptomics to investigate early mechanisms leading to these findings in ischemic myocardium at 7 days post-MI. Binary conditional transgenic mice with tetracycline-inducible EC-Sod2 overexpression (Tet-OFF) were compared to tetracycline-suppressed controls (Tet-ON). Tet-OFF hearts demonstrated reduced infarct area compared to control (p <.0001) at 7 days post-MI. Spatial transcriptomics was performed with differentially-expressed genes (DEGs) defined as FDR <.01 and log2(fold change) > 0.5. Sod2 overexpression in ECs was confirmed, and additional genes related to redox homeostasis, mitochondrial function, and metabolism were upregulated. In infarct zone cardiomyocytes (CMs), > 20 genes related to OxPhos were upregulated including transcripts involving electron transport chain complexes I-V, antioxidant buffering, and NADPH handling. Cardioprotective transcripts were differentially regulated between Tet-OFF vs Tet-ON CMs. Our findings suggest that coordinated redox and mitochondrial changes in ECs and CMs following MI due to EC-specific Sod2 overexpression play crucial roles in mitigating early maladaptive sequelae to myocardial ischemia, and which may facilitate longer-term recovery of post-MI cardiac function.