MINISYMPOSIUM VI. Regulation of Angiogenesis in the Reproductive System.
11:00 AM-12:30 PM
Chair: Koos, Robert1, 1
(M18) REGULATION OF ANGIOGENESIS IN THE ENDOEMTRIUM.
Smith, Stephen1, 1 Departments of Obstetrics and Gynaecology and Pathology, Cambridge, UK
ABSTRACT- Angiogenesis, the formation of new blood vessels, is a key feature in the cyclical development of the endometrium. In primates and women, the endometrium undergoes growth and differentiation in order to provide a receptive endometrium for implantation Withdrawal of progesterone at the end of the ovarian cycle, results in shedding of the endometrium and menstruation. These processes are central to the reproductive health of women from failed implantation in spontaneous and assisted reproductive cycles to abnormal menstrual bleeding and endometriosis. Endometrium expresses members of the VEGF family of genes but in a tightly regulated way. VEGF-A is expressed in glandular and stromal cells in the proliferative phase of the cycle but only in the glandular cells in the luteal phase. Steroids are not the main factor to regulate VEGF expression. Rather hypoxia induces greater than a six fold increase in mRNA encoding VEGF-A in endometrium. This is important because desquamated endometrium is exposed to significant hypoxia and necrosis resulting in very high levels of VEGF-A in the uterus at menstruation. VEGF-B is not present in normal endometrium but its expression is increased in hyperplastic endoemtrial epithelial cells. Interestingly, its expression declines when the malignant transformation has occurred. VEGF-C is expressed exclusively in the large granular lymphocytes (LGL) that proliferate and migrate into the endometrium in the mid-secretory phase of the cycle. Angiopoietin 1 (Ang-1) is present in stromal cells but Ang-2 is only found in the LGLs. Genomic analysis of angiogenic gene expression identifies several "new" pathways that seem to regulate the endometrial vasculature. Members of the Wnt family are expressed and alter endothelial cell cycle and morphology. The importance of the vasculature is demonstrated by four interesting findings. Estrogen induction of endometrial epithelial mitosis is prevented by anti-VEGF antagonists. Endometrium implanted in NUDE mice will not grow when the mice are administered anti-angiogenic agents. Very early primate implantation can be blocked by anti-VEGF antibody and finally women with proven heavy periods express significantly lower levels of VEGF-A in endometrium but only at the time of menstruation. These observations demonstrate the critical importance of the blood vessels to normal and pathological processes that occur in the female reproductive tract.
KEY WORDS: angiogenesis, endometrium