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Sulforaphane (SFN) is an isothiocyanate (ITC) derived from a glucosinolate, glucoraphinin found in cruciferous vegetables. There are few studies that focus on the role of SFN in angiogenesis under hypoxic conditions. The effect of SFN on angiogenesis and the underlying mechanisms including the roles of Nrf2 and mitochondrial dynamics were investigated using cultured human umbilical vein endothelial cells (HUVECs) in hypoxia. SFN at low doses (1.25–5 μM) increased hypoxia-induced HUVEC migration and tube formation, and alleviated hypoxia-induced retarded proliferation, but high doses (≥10 μM) exhibited an opposite effect. Under hypoxia, the expression of Nrf2 and heme oxygenase-1 was up-regulated by SFN treatment. Nrf2 knockdown abrogated SFN (2.5 μM)-induced tube formation and further potentiated the inhibitory effect of SFN (10 μM) on angiogenesis. Meanwhile, the mitochondrial function, morphology and expression of dynamic-related proteins suggested that low-dose SFN protected against hypoxia-induced mitochondrial injury and alleviated hypoxia-induced fission Nrf2-dependently without affecting the expression of key effector proteins (Drp1, Fis1, Mfn1/2 and Opa1), while high concentrations (≥10 μM SFN) aggravated hypoxia-induced mitochondrial injury, fission and Drp1 expression, and inhibited Mfn1/2 expression. These findings suggest that SFN biphasically affected the angiogenic capacity of hypoxia challenged HUVECs potentially via mechanisms involving an integrated modulation of Nrf2 and mitochondrial dynamics.