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.

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.

Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors α and β

“…5). This level of induction is comparable to the documented induction of VEGF mRNA by estradiol in primary human endometrial cells (9). A series of deletion constructs prepared by digestion with restriction enzymes were transiently transfected into Ishikawa cells in the presence of the ER␣ expression vector.…”

“…Estradiol and VEGF, respectively, are the hypothetical mediators that we chose to investigate. In the human endometrium, VEGF mRNA begins to increase in the midproliferative phase and reaches a maximum in late proliferative and secretory endometrium (9). Beginning in the late proliferative phase, under the influence of ovarian estradiol production, a complex subepithelial capillary plexus develops in the cycling endometrium (41).…”

“…VEGF is the principal temporal and spatial mediator of cyclical neovascularization occurring in the ovary and uterus (8)(9)(10) and is an important angiogenic factor in other primate estrogen target tissues, including the placenta (11), neonatal (12) and pubertal growth plate cartilage (13), osteoblasts (14), human hair follicles (15), normal breast tissue (16), and some cases of breast carcinoma (17). The classical experiments of Markee, who directly observed endometrial vascularization in heterotopic rhesus endometrium transplanted into the anterior chamber of the eye, emphasize the endocrine regulation of this process (18).…”

Changes in endometrial receptivity in women with Asherman’s syndrome undergoing hysteroscopic adhesiolysis

“…Several studies have shown the role of vascular endothelial growth factor (VEGF) expression in the vascularization of the endometrium. Low VEGF results in poor development which in turn decreases the blood flow to the endometrium [22][23][24][25][26]. Miwa et al [27] showed that thin endometrium is characterized by poor growth of the glandular epithelium, high uterine blood flow impedance of radial artery, decreased VEGF and poor vascular development.…”

Zyklische Angiogeneseprozesse im Ovar

“…Die indirekte angiogene Wirkung von Östrogenen manifestiert sich in ihrer Wirkung, die Expression von angiogenen Faktoren zu steuern. So konnte gezeigt werden, daß Östrogene die Expression des bedeutsamsten angiogenen Wachstumsfaktors VEGF in einer Reihe von Zellen (Endometriumzellen, Makrophagen) deutlich stimulieren können [32,52].…”