We have recently shown that receptors for the regulatory peptide Ang II (angiotensin II) are present on the granulosa cell layer of several, but not all developing rat ovarian follicles. We have also demonstrated: 1) that Ang II causes an increase in the secretion of estradiol-17 beta from the rat ovary; and 2) that both Ang II and angiotensin I converting enzyme (ACE) are present in the rat ovary. Collectively, these studies suggest, for the first time, that Ang II may be an autocrine or paracrine regulator of follicular estrogen levels. Because follicular estrogen levels are critical for the development of dominant follicles, we hypothesize that follicular responsiveness to Ang II may play a role in the selection and maintenance of dominant follicles. We propose: a) to define the cellular mechanism of Ang II- mediated estradiol-17 beta secretion, since the functional response of Ang II in the ovary is a key part of the overall hypothesis; b) to determine whether angiotensinergic input to the rat ovary is consequential by studying the effects of chronic Ang II receptor blockade and ACE inhibition on the incidence of ovulation over several consecutive estrus cycles; c) to determine, using in vitro autoradiography, whether given follicles that contain FSH receptors also contain Ang II receptors, because follicular responsivity to FSH is known to be important for the development of preovulatory follicles; d) to determine if locally produced Ang II contributes to ovarian function by examining the effects of Ang II receptor antagonist on basal estradiol-17 beta secretion from ovarian slices during different phases of the estrus cycle; e) to correlate functional changes in steroidogenic responses to locally produced Ang II with variations in ovarian renin and Ang II levels during the estrus cycle; f) to examine if autocrine or paracrine modulation of granulosa cell function by Ang II occurs within the follicle by defining a functional renin- angiotensin system in primary cell cultures of the granulosa cell; and g) to study the regulation of the ovarian granulosa renin- angiotensin system by estradiol-17 beta. There are considerable gaps in our understanding of ovarian follicular selection processes. Studies defining the factors that initiate and maintain dominant follicles are likely to have an important bearing on our understanding of fertility disorders. The studies proposed are designed to provide the first steps toward defining the role of Ang II in ovarian function, and should ultimately prove to be useful in understanding the follicular selection processes in the human ovary.
