OVARIAN-STEROID REGULATION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR IN THE HUMAN ENDOMETRIUM - IMPLICATIONS FOR ANGIOGENESIS DURING THE MENSTRUAL-CYCLE AND IN THE PATHOGENESIS OF ENDOMETRIOSIS

The human endometrium undergoes a complex process of vascular and glan dular proliferation, differentiation, and regeneration with each menst rual cycle in preparation for implantation. Vascular endothelial growt h factor (VEGF) is an endothelial cell-specific angiogenic protein tha t appears to play an important role in both physiological and patholog ical neovascularization. To investigate whether VEGF may regulate huma n endometrial angiogenesis, we examined VEGF messenger ribonucleic aci d (mRNA) and protein throughout the menstrual cycle and studied the re gulation of VEGF by reproductive steroids in isolated human endometria l cells. By ribonuclease protection analysis, VEGF mRNA increased rela tive to early proliferative phase expression by 1.6-, 2.0-, and 3.6-fo ld in midproliferative, late proliferative, and secretory endometrium, respectively. In histological sections, VEGF mRNA and protein were lo calized focally in glandular epithelial cells and more diffusely in su rrounding stroma, with greatest VEGF expression in secretory endometri um. Consistent with these in vivo results, the treatment of isolated h uman endometrial cells with Estradiol (E(2)), medroxyprogesterone acet ate (MPA), or E(2) plus MPA significantly increased VEGF mRNA expressi on over the control value by 3.1-, 2.8-, and 4.7-fold, respectively. T he VEGF response to E(2) was rapid, with steady state levels of VEGF m RNA reaching 85% maximum 1 h after the addition of steroid. E(2) also caused a 46% increase in secreted VEGF protein, and the combination of E(2) and MPA caused an 18% increase, VEGF expression in endometriosis , an angiogenesis-dependent, estrogen-sensitive disease was similar to that seen in eutopic endometrium. Peritoneal fluid concentrations of VEGF were significantly higher in women with moderate to severe endome triosis than in women with minimal to mild endometriosis or no disease . VEGF, therefore, may be important in both physiological and patholog ical angiogenesis of human endometrium, as it is an estrogen-responsiv e angiogenic factor that varies throughout the menstrual cycle and is elevated in women with endometriosis.