PARENT SESSION
MINISYMPOSIUM VI. Regulation of Angiogenesis in the Reproductive System.
11:00 AM-12:30 PM
Harborside E
Chair: Koos, Robert¹, ¹

(M16) INHIBITION OF VASCULAR ENDOTHELIAL GROWTH FACTOR ACTION IN THE PRIMATE REPRODUCTIVE SYSTEM.

Fraser, Hamish¹, Wulff, Christine², Wiegand, Stanley³, Rudge, John³, ¹ MRC Human Reproductive Sciences Unit, Edinburgh² Dept of Obstetrics and Gynaecolgy, Ulm, Germany³ Regeneron Pharmaceuticals, Tarrytown, NY.

ABSTRACT- Because of their distinctive cyclical angiogenesis during the ovulatory cycle, the ovary and uterus have long been recognised as ideal sites in which to investigate the regulation of physiological angiogenesis. Subsequently, the ovary has proved a source for discovery of factors regulating the angiogenic process. A major advance in our ability to investigate the regulation of angiogenesis stems from the development of specific antagonists to angiogenic factors and their receptors. Our programme seeks to determine the physiological role of angiogenic factors in the reproductive system of the primate by, 1) quantifying changes in angiogenesis and blood vessel area using immunocytochemistry for bromodeoxyuridine and endothelial cell markers in developing follicles, corpora lutea and uteri, 2) monitoring changes in expression patterns of putative angiogenic factors using in situ hybridization and, 3) by determining changes in angiogenesis and gene expression after inhibition of putative factors by specific targeting in vivo at selected stages of the ovulatory cycle. This presentation focuses on the effects of inhibition of vascular endothelial growth factor (VEGF) using either a monoclonal antibody or VEGF Traps (truncated soluble forms of the VEGF receptors). To dissect the role of VEGF during the ovulatory cycle, these inhibitors have been administered to marmosets in the following schedules: 1) throughout the 10 day follicular phase, 2) from day 0-3 or, 3) day 0-10 of the luteal phase, 4) luteal day 3-4 or, 5) luteal days 7-10. Ovaries and uteri were studied at the end of these treatment periods. All treatment schedules had a marked effect on ovarian angiogenesis and function. Follicular phase treatment resulted in a marked decrease in endothelial cell proliferation in developing antral follicles, accompanied by a decline in granulosa cell proliferation and inhibition of ovulation. Inhibition of VEGF during luteal days 0-3 or days 0-10 caused in a marked suppression in luteal angiogenesis, failure of development of the microvascular tree and an inhibition of luteal function as judged by suppression of plasma progesterone concentrations. Treatments during luteal days 3-4 and 7-10 showed that on-going angiogenesis and luteal function could also be inhibited by the VEGF antagonists. The uterine microvasculature was much less affected by these treatments. These results show that VEGF plays a crucial role in follicular and luteal function. While the early corpus luteum is probably the most sensitive site for observing suppressive effects of angiogenic inhibitors, follicular development is also markedly responsive to inhibition of VEGF. It is suggest that manipulation of angiogenesis should be a powerful approach to either promoting or inhibiting the normal processes of folliculogenesis, ovulation and corpus luteum function.

KEY WORDS: Angiogenesis, Follicle, Corpus luteum, Marmoset