This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Coronary artery reactivity modulation is a rarely recognized, but important, consequence of gonadal steroid actions on primate blood vessels. This factor has profound significance in aging menopausal women. This project addresses coronary hyperreactivity as an aspect of increased heart disease that is relatively overlooked. The major increase in heart disease risk 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 important. The imbalance of E, P, and T, the 3 ovarian steroids, is hypothesized to lead to loss of a protected state.Previously, we showed that return of even subphysiological estrogen and progesterone levels 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, when there is a deficiency of P. Without P, conversion of T to DHT rather than to E is favored. P directly suppresses TxA2 receptor expression. Less than threshold P is 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, Ca2+ and protein kinase C cellular studies will be made to probe these mechanisms of coronary hyperreactivity with multiple manipulations of E, P, and DHT.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Primate Research Center Grants (P51)
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Special Emphasis Panel (ZRR1-CM-8 (02))
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University of Washington
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