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Regulation of Nitric Oxide Synthase to Promote Cytostasis in Ovarian Follicular Development¹

^a Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo, Japan ^b Investigative Treatment Division, National Cancer Center Research Institute East, Kashiwa, Japan ^c Department of Histology and Cell Biology, Nagasaki University School of Medicine, Nagasaki, Japan

ABSTRACT

Our own recent studies have demonstrated that inducible nitric oxide synthase (iNOS) is predominantly localized in granulosa cells of healthy immature follicles in the rat ovary, whereas granulosa cells of either healthy mature follicles or follicles destined to be atretic are devoid of iNOS. These findings suggest that iNOS is pivotal for immature follicles to remain dormant. To test this hypothesis, we examined the effects of a GnRH agonist (buserelin), a proapoptotic substance, and epidermal growth factor (EGF), a mitogenic and, consequently, antiapoptotic factor, on the amount of iNOS mRNA in rat granulosa cells. Administration of buserelin in immature female rats transiently diminished iNOS mRNA levels in the ovaries as determined by Northern blot analysis. In cultured rat granulosa cells, buserelin and EGF increased the incidence of apoptosis and DNA synthesis, respectively, whereas both reduced iNOS mRNA levels as determined by reverse transcription-coupled polymerase chain reaction. The concomitant addition of S-nitroso-N-acetyl-DL-penicillamine, an NO donor, together with buserelin or EGF eliminated the observed effects of these substances (i.e., induction of apoptosis and stimulation of DNA synthesis, respectively). These results suggest that the changes in developmental status of immature follicles either into development or atresia are associated with reduced iNOS levels in granulosa cells, thus reinforcing the notion of NO as a cytostatic factor in ovarian follicles.

FOOTNOTES

First decision: 19 January 2000.

¹ Supported by the Yamada Scholar Award from the Yamada Scholarship Foundation (H.M.) and in part by grants-in-aid from the Ministry of Education, Science and Culture, from the Science and Technology Agency, and from the Ministry of Health and Welfare for the second-term Comprehensive 10-Year Strategy for Cancer Control, Japan.

² Correspondence: Tetsu Yano, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. FAX: 81 3 3816 2017; tetu-tky{at}umin.ac.jp

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