Muscle regeneration involves the coordination of myogenesis and revascularization in order to restore proper muscle function. Myogenesis is driven by resident stem cells termed satellite cells (SC) whereas angiogenesis arises from endothelial cells and perivascular cells of pre-existing vascular segments and the collateral vasculature. Communication between myogenic and angiogenic cells seems plausible, especially given the number of growth factors produced by SC. To characterize these interactions, we developed an in vitro co-culture model composed of SC and microvascular fragments (MVF). In this system, isolated MVF suspended in collagen gel are cultured over a rat SC monolayer culture. In the presence of SC, MVF exhibit greater indices of angiogenesis than MVF cultured alone. A positive dose-dependent effect of SC conditioned medium (CM) on MVF growth was observed suggesting that SC secrete soluble-acting growth factor(s). Next, we specifically blocked VEGF action in SC CM and this was sufficient to abolish satellite cell-induced angiogenesis. Finally, hypoxia inducible factor-1alpha (HIF-1), a transcriptional regulator of VEGF gene expression, was found to be expressed in cultured SC and in putative SC in sections of stretch-injured muscle. Hypoxic culture conditions increased SC HIF-1 activity which was positively associated with SC VEGF gene expression and protein levels. Collectively, these initial observations suggest that a heretofore unexplored aspect of satellite cell activation is the initiation of a pro-angiogenic program.