Recent advances in endometrial angiogenesis research.

This review summarises recent research into the mechanisms and regulation of endometrial angiogenesis. Understanding of when and by what mechanisms angiogenesis occurs during the menstrual cycle is limited, as is knowledge of how it is regulated. Significant endometrial endothelial cell proliferation occurs at all stages of the menstrual cycle in humans, unlike most animal models where a more precise spatial relationship exists between endothelial cell proliferation and circulating levels of oestrogen and progesterone. Recent stereological data has identified vessel elongation as a major endometrial angiogenic mechanism in the mid-late proliferative phase of the cycle. In contrast, the mechanisms that contribute to post-menstrual repair and secretory phase remodelling have not yet been determined. Both oestrogen and progesterone/progestins appear to have paradoxical actions, with recent studies showing that under different circumstances both can promote as well as inhibit endometrial angiogenesis. The relative contribution of direct versus indirect effects of these hormones on the vasculature may help to explain their pro- or anti-angiogenic activities. Recent work has also identified the hormone relaxin as a player in the regulation of endometrial angiogenesis. While vascular endothelial growth factor (VEGF) is fundamental to endometrial angiogenesis, details of how and when different endometrial cell types produce VEGF, and how production and activity is controlled by oestrogen and progesterone, remains to be elucidated. Evidence is emerging that the different splice variants of VEGF play a major role in regulating endometrial angiogenesis at a local level. Intravascular neutrophils containing VEGF have been identified as having a role in stimulating endometrial angiogenesis, although other currently unidentified mechanisms must also exist. Future studies to clarify how endometrial angiogenesis is regulated in the human, as well as in relevant animal models, will be important for a better understanding of diseases such as breakthrough bleeding, menorrhagia, endometriosis and endometrial cancer.