The control and manipulation of angiogenesis in the primate corpus luteum

of Thesis The corpus luteum is formed from the preovulatory follicle after ovulation and its main function is the secretion of progesterone which is essential for the establishment of pregnancy. Growth of the corpus luteum is associated with extensive vascular remodelling, so that by the mid-luteal phase every steroidogenic cell is adjacent to a capillary for optimal synthesis and secretion of progesterone. In the non-fertile cycle luteal vascular regression takes place and progesterone production falls. If conception occurs the corpus luteum is rescued and continues to produce progesterone. The corpus luteum provides a unique example of tightly controlled physiological angiogenesis. Little is known about the effect of inhibition of physiological angiogenesis that occurs in female reproductive tissues. Elucidation of the process of luteal angiogenesis may provide new insights into tumour therapy and treatment of infertility, and offer a novel approach to contraception research. Previous research focused on angiogenesis in the non-primate ovary but the mechanisms that regulate luteal function in primates are markedly different, therefore the marmoset monkey, supplemented with archived human corpora lutea, was used for the research described in this thesis. Angiogenesis is a dynamic process of endothelial cell proliferation and capillary tubule formation, controlled primarily by vascular endothelial cell growth factor (VEGF); and capillary stabilisation by the association of pericytes. In vivo luteal angiogenesis was assessed by measuring these parameters in luteal sections by quantitative immunocytochemistry. It was established that 1) quantification of cell proliferation by bromodeoxyuridine administration to label DNA during the S phase of the cell cycle was a robust and reproducible technique; 2) over 80% of proliferating cells in marmoset corpora lutea were endothelial cells; and 3) quantification of these parameters in one luteal section reflected the angiogenic activity of the whole corpus luteum. In the primate, early luteal development was associated with intense angiogenesis, expression of VEGF and the growth of a stable microvascular network. In the mid-luteal mature gland angiogenesis was ongoing but at a reduced level, VEGF expression remained high and a full microvascular network had been established containing both stable microvessels and small immature capillaries, optimal for maximal progesterone production and secretion. In the late corpus luteum, endothelial cell proliferation and VEGF expression declined, there were signs of immature vessel regression and progesterone levels decreased markedly. Human chorionic gonadotropin administered to women from the mid-luteal phase to rescue the corpus luteum, was associated with increased angiogenesis and VEGF production, and stabilisation of newly formed vessels.