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Coronary artery disease results in progressive vascular stenosis associated with chronic myocardial ischemia. Vascular endothelial growth factor (VEGF) stimulates endothelial cell angiogenic responses to revascularize ischemic tissues; however, the effect of chronic hypoxia on the responsiveness of endothelial cells to VEGF remains unclear. We, therefore, investigated whether hypoxia alters VEGF-stimulated signaling and angiogenic responses in primary human coronary artery endothelial (HCAE) cells. Exposure of HCAE cells to hypoxia (1% O₂) for 24 h decreased VEGF-stimulated endothelial cell migration (∼82%), proliferation (∼30%), and tube formation. Hypoxia attenuated VEGF-stimulated activation of endothelial nitric oxide (NO) synthase (eNOS) (∼72%) and reduced NO production in VEGF-stimulated cells from 237 ± 38.8 to 61.3 ± 28.4 nmol/l. Moreover, hypoxia also decreased the ratio of …