Physiological levels of hypoxia promote embryonic development and angiogenesis. The protein tyrosine phosphatase PTP-PEST is essential for mouse embryonic survival, but the reason for this has remained elusive. In this work, Madhulika Dixit and co-workers (Chandel et al., 2021) reveal the role of PTP-PEST in hypoxia-mediated endothelial autophagy and angiogenesis. They find that both the levels and phosphatase activity of PTP-PEST are upregulated in response to hypoxia. Using a pulldown-mass spectrometry approach in endothelial cells, they show that PTP-PEST interacts with the catalytic domain of AMPK, a known inducer of autophagy, in normoxic, but not hypoxic, conditions. Moreover, PTP-PEST regulates the dephosphorylation and enhances the catalytic activity of AMPK in response to hypoxia. Consequently, hypoxia-induced autophagy is attenuated upon knockdown of PTP-PEST, but can be rescued by treatment with the AMPK activator metformin, suggesting that PTP-PEST regulates autophagy through AMPK. Similarly, hypoxia-induced angiogenesis is attenuated by PTP-PEST knockdown, but can be rescued by subjecting cells to the autophagy inducer rapamycin. Therefore, PTP-PEST controls hypoxia-induced angiogenesis through an AMPK-dependent autophagy pathway. Thus, this study identifies PTP-PEST as a novel regulator of autophagy and angiogenesis in endothelial cells, which may also be relevant for angiogenesis occurring in cancer.