(Verbatim from the application): Coronary artery reactivity modulation is a rarely recognized, but important, consequence of gonadal steroid actions on blood vessels of primates, and thus this factor has profound significance for aging in menopausal women. This project addresses coronary hyperreactivity as an aspect of increased heart disease that is relatively overlooked. The major increase in risk of heart disease with age in women during menopause is strongly correlated with falling levels of estrogens (E), and more profoundly of progesterone (P), in the presence of continued non-ovarian E and testosterone (T) production. The androgen path, particularly dihydrotestosterone (DHT), appears to be important. The imbalance of E & P & T, the 3 ovarian steroids, is hypothesized to lead to loss of a protected state. Previously, we showed that return of even subphysiological levels of estrogen and progesterone restores normal coronary reactivity in ovariectomized primates. In this project, surgically menopausal monkeys will be treated for 2 weeks with E and/or P with controlled levels of DHT, or with 2 week increases or decreases in DHT during controlled E and P, to further probe the coronary roles of these 3 steroid hormones and their balance. E, P, and DHT appear to physiologically regulate coronary reactivity and thromboxane A2 (TxA2) receptors. DHT, the most potent known inducer of TxA2 receptors is formed locally in coronary arteries, more than is E from 1, when there is a deficiency of P. Without P, the balance favors conversion of T to DHT rather than to E. P also directly suppresses TxA2 receptor expression. Less than threshold P is thus hypothesized to be a triple adverse influence. Studies of E, P, and TxA2 receptor distribution in the coronary artery wall by immunocytochemistry, TxA2 receptor binding by Scatchard analysis, blood levels of E, P, and DHT, coronary diameter, blood pressure, and cellular studies of Ca2+ and protein kinase C will be made to probe these pathophysiological mechanisms of coronary hyperreactivity with multiple manipulations of E, P, and DHT. In vivo catheterization laboratory studies will be combined with gross and histopathological examination of coronary arteries to determine correlations with hyperreactivity and TxA2 receptor expression. Tests of E, P, and DHT effects on cellular factors underlying vasodilator and vasoconstrictor changes in primate coronary arteries are important for understanding how to protect against coronary artery risks during the post-menopausal aging process.
| Mishra, Rajesh G; Hermsmeyer, R Kent; Miyagawa, Koichi et al. (2005) Medroxyprogesterone acetate and dihydrotestosterone induce coronary hyperreactivity in intact male rhesus monkeys. J Clin Endocrinol Metab 90:3706-14 |
