Vascular endothelial growth factor expression in human endometrium is regulated by hypoxia

Endometrial growth and repair after menstruation are associated with profou nd angiogenesis. Abnormalities in these processes result in excessive or un predictable bleeding patterns and are common in many women. It is therefore important to understand which factors regulate normal endometrial angiogen esis. Vascular endothelial growth factor (VEGF) is an endothelial cell-spec ific mitogen that plays an important role in normal and pathological angiog enesis. In this study we show that expression of VEGF is regulated by hypox ia in human endometrium. Culture in vitro for 24 h under hypoxic conditions resulted in a 2- to 6-fold increase in VEGF secretion by both stromal and epithelial cells isolated from human endometrium. Quantitative RT-PCR was u sed to measure VEGF messenger ribonucleic acid (mRNA) levels in these cells . After hypoxia, VEGF mRNA levels increased 1.8-fold in stromal cells and 3 .4-fold in glandular epithelial cells. The mRNA for each VEGF splice varian t increased to an equal extent. The increase in VEGF secretion by stromal a nd epithelial cells in response to hypoxia was not altered by treatment at the same time with estradiol or progesterone. In situ hybridization of huma n endometrium during menstruation, when steroid levels are low but the tiss ue is subject to ischemia, showed strong hybridization to VEGF mRNA in both stromal and glandular cells. These results show that local factors, such a s hypoxia, can regulate VEGF expression in the endometrium. This may play a n important part in normal endometrial repair after menstruation. The secre tion of VEGF by endometrial cells under hypoxic conditions may also be impo rtant in the pathogenesis of endometriosis, because it would be predicted t o assist revascularization of desquamated endometrial explants when they at tach at ectopic sites.