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.

J L Shifren, Jan L. Shifren, Jennifer F. Tseng, J F Tseng, Charles Zaloudek, C J Zaloudek, I P Ryan, I. Ryan, Y G Meng, Y. Gloria Meng, N Ferrara, Nicola Ferrara, R B Jaffe, Robert B. Jaffe, R N Taylor, Robert N. Taylor
The Journal of clinical endocrinology and metabolism · 1996 · vol. 81(8) , pp. 3112–3118 · doi:10.1210/jcem.81.8.8768883 · PMID:8768883 · W2019931546
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VEGF mRNA and protein expression increases in the human endometrium during the menstrual cycle and is upregulated by ovarian steroids, with similar patterns observed in endometriosis and elevated peritoneal fluid levels in severe disease.

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Abstract

The human endometrium undergoes a complex process of vascular and glandular proliferation, differentiation, and regeneration with each menstrual cycle in preparation for implantation. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific angiogenic protein that appears to play an important role in both physiological and pathological neovascularization. To investigate whether VEGF may regulate human endometrial angiogenesis, we examined VEGF messenger ribonucleic acid (mRNA) and protein throughout the menstrual cycle and studied the regulation of VEGF by reproductive steroids in isolated human endometrial cells. By ribonuclease protection analysis, VEGF mRNA increased relative to early proliferative phase expression by 1.6-,2.0-, and 3.6-fold in midproliferative, late proliferative, and secretory endometrium, respectively. In histological sections, VEGF mRNA and protein were localized focally in glandular epithelial cells and more diffusely in surrounding stroma, with greatest VEGF expression in secretory endometrium. Consistent with these in vivo results, the treatment of isolated human endometrial cells with estradiol (E2), medroxyprogesterone acetate (MPA), or E2 plus MPA significantly increased VEGF mRNA expression over the control value by 3.1-, 2.8-, and 4.7-fold, respectively. The VEGF response to E2 was rapid, with steady state levels of VEGF mRNA reaching 85% maximum 1 h after the addition of steroid. E2 also caused a 46% increase in secreted VEGF protein, and the combination of E2 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 endometriosis than in women with minimal to mild endometriosis or no disease. VEGF, therefore, may be important in both physiological and pathological angiogenesis of human endometrium, as it is an estrogen-responsive angiogenic factor that varies throughout the menstrual cycle and is elevated in women with endometriosis.

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Condition tags

mesh:D004715endometriosis

MeSH descriptors

Endometriosis Endometrium Endothelial Growth Factors Estradiol Lymphokines Medroxyprogesterone Acetate Neovascularization, Physiologic Cells, Cultured Endometriosis Endometriosis Endometrium Endometrium Endothelial Growth Factors Estradiol Female Humans Lymphokines Medroxyprogesterone Acetate Menstrual Cycle Menstrual Cycle

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