Steroid hormone regulation of angiogenesis in the primate endometrium

The human endometrium develops new capillaries from existing microvessels, i.e. angiogenesis, which then undergo maturation and remodeling, i.e. investment of microvessels with periendothelial mural cells, into a new vascular network during each menstrual cycle. Improper vascularization of the endometrium may cause implantation failure and infertility. Estrogen and progesterone have pivotal roles in establishing this vascular bed, but the cellular sites and mechanisms of action of these steroid hormones are incompletely understood. Vascular endothelial growth factor (VEGF), angiopoietin-1, and angiopoietin-2 and their receptors are expressed in the human and nonhuman primate endometrium and interact to control vascular development and remodeling. VEGF synthesis within and neovascularization of the endometrium seem to be sustained and ongoing processes designed to progressively promote growth and development of the endometrium with advancing stages of the menstrual cycle. However, estrogen rapidly upregulates VEGF expression by endometrial glandular epithelial and stromal cells in vivo in the nonhuman primate and in vitro in the human. Reports of the effects of progesterone on endometrial VEGF formation, however, are inconsistent and may reflect regulatory actions on particular isoforms of VEGF. In addition, estrogen has effects on vascular endothelial and smooth muscle cells, which may be direct or mediated by VEGF. Very little is known, however, about the steroid hormone regulation of other angiostimulatory and angioinhibitory factors, e.g. angiopoietin-1 and -2, in the endometrium. Moreover, the role of steroid hormones acting directly, or indirectly via VEGF and other angiogenic factors, on expression of integrins, cell adhesion and other molecules required for cell-cell and cell-extracellular matrix interactions important for angiogenesis in the human and nonhuman primate endometrium is largely unknown. Finally, further study is needed of cell-specific responsivity and function in the human endometrium with respect to steroid hormone regulation of angiogenesis.