Cellular communication across tissues is an essential process during embryonic development. Secreted factors with potent morphogenetic activity are key elements of this cross-talk, and precise regulation of their expression is required to elicit appropriate physiological responses. MicroRNAs (miRNAs) are versatile post-transcriptional modulators of gene expression. However, the large number of putative targets for each miRNA hinders the identification of physiologically relevant miRNA-target interactions. Here we show that miR-1 and miR-206 negatively regulate angiogenesis during zebrafish development. Using target protectors, our results indicate that miR-1/206 directly regulate the levels of Vascular endothelial growth factor A (VegfA) in muscle, controlling the strength of angiogenic signaling to the endothelium. Conversely, reducing the levels of VegfAa, but not VegfAb, rescued the increase in angiogenesis observed when miR-1/206 were knocked down. These findings uncover a novel function for miR-1/206 in the control of developmental angiogenesis through the regulation of VegfA, and identify a key role for miRNAs as regulators of cross-tissue signaling.