Catecholamines have been shown to be involved in vascular remodeling through the stimulation of 1-adrenoreceptors (₁-ARs). Recently it has been demonstrated that catecholamines can stimulate angiogenesis in pathological conditions, even if the mechanisms and the AR subtypes involved still remain unclear. We investigated the influence of hypoxia (3%O2) on the ability of picomolar concentrations of phenylephrine (PHE), unable to induce any vascular contraction, to induce a trophic effect in human endothelial cells through stimulation of the _1D subtype adrenoceptors (_1D-ARs). PHE, at picomolar concentrations, significantly promoted pseudocapillary formation from fragments of human mature vessels in vitro. Exposure to hypoxia significantly potentiated this effect which was inhibited by the selective _1D-AR antagonist BMY 7378 and by the nitric oxide synthase inhibitor L-NAME, suggesting that _1D-adrenoceptors were involved in this effect through activation of the NO pathway. Proliferation and migration of HUVEC were also affected by picomolar PHE concentrations. Again, these effects were significantly potentiated in cells exposed to hypoxia and were inhibited by BMY 3778 and by L-NAME. Conversely, the _1A-AR selective antagonist (S)-(+)-niguldipine hydrochloride and the _1B-AR antagonist chloroethylclonidine dihydrochloride did not modify endothelial cell migration and proliferation in response to PHE. These results demonstrate that the stimulation of _1D-ARs, triggered by picomolar PHE concentrations devoid of any contractile vascular effects, induces a pro-angiogenic phenotype in human endothelial cells which is enhanced in a hypoxic environment. The role of _1D-ARs may become more prominent in the adaptive responses to hypoxic vasculature injury.