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29 p. main text and figure legends+ 20 p. figures and M&M, Microvascular dysfunction and resulting tissue hypoxia is a major contributor to the pathogenesis and evolution of cardiovascular diseases (CVD). Diverse gene and cell therapies have been proposed to preserve the microvasculature or boost angiogenesis in CVD with moderate benefit. In this study, we tested in vivo the impact of sequential delivery by bone marrow cells of the pro-angiogenic factors vascular endothelial growth factor (VEGFA) and sphingosine-1-phosphate (S1P) in a myocardial infarction model. For that we transduced mouse bone marrow cells with lentiviral vectors coding for VEGFA or sphingosine kinase (SPHK1), which catalyzes S1P production, and injected them intravenously 4 and 7 days after cardiac ischemia/reperfusion in mice. Sequential delivery by transduced BM cells of VEGFA and S1P led to increased endothelial cell numbers and shorter extravascular distances in the infarct zone which support better oxygen diffusion 28 days post-MI as shown by automated 3D image analysis of the microvasculature. Milder effects were observed in the remote zone together with increased proportion of capillaries. BM cells delivering VEGFA and S1P also decreased myofibroblast abundance and restricted adverse cardiac remodeling without major impact on cardiac contractility. Our results indicate that BM cells engineered to sequentially deliver VEGFA/S1P angiogenic factors may constitute a promising strategy to improve micro-vascularization and oxygen diffusion thus limiting the adverse consequences of cardiac ischemia., This study was supported by grants from the Spanish Ministerio de Ciencia, Innovación y Universidades SAF2014-52050-R and SAF2017-83229-R to A.G.A. and BIO2015-67580-P to J.V.) and the Carlos III Institute of Health-Fondo de Investigación Sanitaria (PRB2, IPT13/0001-ISCIII-SGEFI/FEDER, ProteoRed). The research leading to these results has received funding from the People Programme (Marie Curie Action) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant Agreement 608027.