Endometrial microvascular growth in normal and dysfunctional states.

As a tissue that exhibits rapid cyclical growth and shedding throughout the reproductive life of the female, human endometrium provides a good model for the study of normal physiological angiogenesis. The objective of this paper is to summarize recent data on endometrial vascular growth, present new data on regional variability in endothelial cell proliferation within the endometrium, and interpret this information in light of current knowledge of the mechanisms by which angiogenesis occurs. Conventional angiogenesis normally involves a series of steps which include endothelial cell activation, breakdown of the basement membrane, migration and proliferation of the endothelial cell, fusion of sprouts, and tube formation. Other mechanisms by which angiogenesis occurs include intussusception and vessel elongation. Using immunohistochemical techniques we have shown repeatedly that levels of endothelial cell proliferation within human endometrium do not show any consistent pattern across the different stages of the menstrual cycle, which is unexpected since significant vascular growth must occur during the proliferative phase, when the endometrium increases in thickness by up to 4-fold. There are two possible explanations for this; either there is no obligatory link between endometrial endothelial cell proliferation and new vessel formation, or there is significant variation in endothelial cell proliferation within different regions of the same uterus. Multiple samples from hysterectomy specimens subsequently demonstrated that the variability is due to real differences between individuals, as well as showing that the endothelial cell proliferation index is significantly elevated in functionalis compared with basalis. During these studies we observed that endothelial cell proliferation nearly always appeared inside existing endometrial vessels, rather than be associated with structures that could be identified as vascular sprouts. To explore further whether sprout formation occurs during endometrial angiogenesis, we investigated the immunohistochemical distribution of integrin alphavbeta3 on endometrial endothelial cells. As for endothelial cell proliferation, integrin alphavbeta3 immunostaining was seen only on endothelial cells that appeared within existing blood vessels. The results from these studies have major implications for our understanding of the mechanisms that control endometrial angiogenesis. The lack of correlation between menstrual cycle stage and endothelial cell proliferation index, or endothelial cell expression of integrin alphavbeta3, suggests that vascular growth is not under the overall control of oestrogen and progesterone.