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Fetal weight and the placenta of sheep at high altitude (HA) are affected by hypoxia. Placental changes (an increase in placental size and vascularization) are greater in ewes from populations that have lived for several generations at HA than in those exposed during just 1 gestation. This study investigated placental expression of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS), 2 molecules involved in placental angiogenesis that could be upregulated by hypoxia. Two groups of ewes were maintained at HA (3589 m) during pregnancy: HA-native ewes (group HH) and ewes native to lowlands but moved to HA immediately after the diagnosis of pregnancy (group LH). A control group (LL) was kept at sea level. Near term, placentomes were removed, weighed, and processed for immunohistochemical detection of VEGF and eNOS, as well as for vascular area measurement. Placental weight was significantly higher in the HH group than in the LH and LL groups; between the latter 2 groups there was no significant difference. The placental area occupied by vasculature was significantly greater in both the HA groups than in the LH group; the number of placentomes was greatest in the LL group. The density of VEGF and eNOS in the placentome tissue was significantly greater in both HA groups than in the LL group. Although the density of VEGF was significantly lower in the HH group than in the LH group, no differences were observed in eNOS density between the HH and LH animals. These results demonstrate that chronic hypoxia upregulates the expression of placental VEGF and eNOS, suggesting an important role of these molecules in the placental response to HA hypoxia. In addition, an attenuated response to hypoxia in VEGF synthesis may be part of the long-term process of adaptation to HA.