MicroRNAs are key regulators of angiogenesis, as illustrated by the vascular defects observed in miR-126-deficient animals. The miR-126 duplex gives rise to two mature microRNAs (miR-126-3p and-5p). The vascular defects in these mutant animals were attributed to the loss of miR-126-3p but the role of miR-126-5p during normal angiogenesis in vivo remains unknown. Here, we show that miR-126-5p is expressed in endothelial cells but also by retinal ganglion cells (RGCs) of the mouse postnatal retina and participates in protecting endothelial cells from apoptosis during the establishment of the retinal vasculature. miR-126-5p negatively controls class 3 semaphorin protein (Sema3A) in RGCs through the repression of SetD5, an uncharacterized member of the methyltransferase family of proteins. In vitro, SetD5 controls Sema3A expression independently of its SET domain and co-immunoprecipitates with BRD2, a bromodomain protein that recruits transcription regulators onto the chromatin. Both SetD5 and BRD2 bind to the transcription start site and to upstream promoter regions of the Sema3a locus and BRD2 is necessary for the regulation of Sema3A expression by SetD5. Thus, neuronally expressed miR-126-5p regulates angiogenesis by protecting endothelial cells of the developing retinal vasculature from apoptosis.