Recent advances in endometrial angiogenesis research

Abstract

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.

Adrenomedullin and its receptor, calcitonin receptor-like receptor, are aberrantly expressed in women with idiopathic menorrhagia

“…The human endometrium is a mucosa served by a microvascular blood supply that involves benign angiogenesis, which is under the control of ovarian steroids throughout reproductive life (14,15). In agreement with previous studies, we found AM and CLR to be expressed in all endometrial cell types (2).…”

The UDP-Glucose Receptor P2RY14 Triggers Innate Mucosal Immunity in the Female Reproductive Tract by Inducing IL-8

“…Consistent with our hypothesis, Caballero-Campo et al (49) demonstrated using in vitro coculture experiments that both IL-8 mRNA expression and protein production were up-regulated in endometrial epithelial cells in the presence of a human blastocyst. In both menstruation and implantation, IL-8 production and infiltrated neutrophils may play a role in the angiogenesis for endometrial remodeling/regeneration, trophoblast invasion, and placentation, rather than prevention of the progression of infection (50). Further studies are needed to elucidate the role of P2RY14 in the various physiological processes of reproduction.…”

Importance of Serum Copper and Vascular Endothelial Growth Factor (VEGF-A) Levels in Postmenopausal Bleeding

“…Copper has been shown to influence the bioactivity or production of a number of angiogenic factors including VEGF-A [5,8] and shares some of the pathways utilized by hypoxia to regulate VEGF-A expression [2,5] demonstrated that copper is having anti-tumor activity [9]. Copper is also required in hemoglobin synthesis and in the catalysis of metabolic oxidation [10].…”

“…The uterine endometrium is a dynamic tissue that undergoes regular cycles of growth and breakdown, and has long been recognized as one of the few adult tissues where significant angiogenesis occurs on a routine, physiological basis. Abnormal angiogenesis may contribute to several different endometrial-related pathologies including endometrial cancer, endometriosis, menorrhagia and breakthrough bleeding [2].…”