The long-term objective of this continuing research is to determine how different cell types within the primate corpus luteum contribute to luteal function, regulation and lifespan during the menstrual cycle. Experiments in this laboratory indicate that multiple subpopulations of nonhuman primate (macaque) luteal cells exist based on functional and regulatory differences in steroid production. Most recently, we reported results based on immunocytochemical localization of steroidogenic enzymes that are consistent with a two-cell model for steroid hormone production in the primate corpus luteum the paraluteal (theca-luteal) cells around the periphery and along the vascular tracts produce androgen substrate which is converted to estrogen by the true (granulosa-) luteal cells in the central parenchyma. However, little is known about the development and activities of the cell type that comprises the largest population in the corpus luteum - the endothelial cells forming the extensive microvasculature. Elegant research in other systems implicated two classes of factors, which act specifically on endothelial or peri-endothelial cells, as key payers in the development, maintenance and remodeling of the vasculature (1) the vascular endothelial growth factors (VEGF), and (2) the angiopoietins (Ang). Recent studies in our laboratory determined that the midcycle gonadotropin surge increases VEGF production more than 8-fold by granulosa cells in the preovulatory follicle. Moreover, when granulosa cells collected from maturing follicles are exposed to """"""""surge levels"""""""" of gonadotropin during 6 days of culture, VEGF production increases over 200-fold. Reverse transcription-polymerase chain reaction assays indicate that mRNAs encoding all three types of VEGF (-A, -B, and -C), two types of ANG (-1 and -2), plus their receptors, are present in macaque luteal tissue. These studies suggest that all the necessary components for endothelial-specific control of angiogenesis are present in the developing corpus luteum. Moreover, the midcycle gonadotropin surge may promote neovascularization of the luteinizing follicle by stimulating VEGF expression. Further studies will examine the production, regulation and action of the various types of VEGF and Ang in the periovulatory follicle and their role(s) in development of the corpus luteum of the menstrual cycle. This research may identify novel (i.e., local vascular) processes whose disruption could lead to specific types of infertility (e.g., anovulation, luteal phase defects) and suggest unique contraceptive approaches.
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