SRB Reproduction, Fertility and Development Award Lecture 2008. Regulation and manipulation of angiogenesis in the ovary and endometrium

Abstract

The marked cyclical physiological angiogenesis in the developing follicle, corpus luteum and endometrium implies a critical role in health and disease. Our approach to understanding its regulation has been to localise and quantify the temporal changes in putative angiogenic factors, and their receptors, in human and non-human primate tissue and to use antagonists to dissect their role by specific inhibition at defined periods during the ovulatory cycle in non-human primates in vivo. The course of angiogenesis throughout the cycle and the cellular and molecular effects of inhibitory treatments have been investigated in the marmoset ovary and uterus, whereas consequences on pituitary–ovarian function have been monitored in macaques. Inhibition of vascular endothelial growth factor (VEGF) at the time of follicle recruitment or selection prevents endothelial cell proliferation, leading to inhibition of follicular development. VEGF inhibition during the early luteal phase prevents angiogenesis and restricts development of the luteal microvasculature. Inhibition of angiogenesis at all stages of the cycle leads to profound suppression of ovarian function. Even during the ‘post-angiogenic’ period of the luteal phase, inhibition of VEGF precipitates a suppression of progesterone secretion, pointing to additional roles for VEGF in the ovary. In the endometrium, oestrogen drives endometrial angiogenesis through VEGF. Thus, oestrogen can restore angiogenesis after ovariectomy, but not in the presence of VEGF inhibitors. These investigations enhance our understanding of the regulation of angiogenesis in the ovary and uterus and inform studies on conditions with abnormal vascularisation, such as polycystic ovary syndrome, endometriosis, uterine fibroids and menstrual dysfunction.