| dc.description.abstract | The purpose of this dissertation was to elucidate the role of androgens in the regulation of systemic BP and uterine vascular function. There is a well-established sexual dimorphism in human cardiovascular disease (CVD), in which men are more likely to develop hypertension and coronary artery disease (CAD) compared to age-matched pre-menopausal women, which suggests that testosterone (TES) is deleterious to cardiovascular health. The findings of the present studies in this dissertation challenge this dogma, and instead, provide support that TES and its metabolites 5α- and 5β- dihydrotestosterone (DHT) are beneficial to blood pressure (BP) and vascular function. The first project utilized male Sprague-Dawley (SD) and testicular feminized male (Tfm) rats to evaluate the long-term effects of endogenous and exogenous androgens on systemic blood pressure (BP). This study provided new evidence and novel findings that androgens (TES and 5α-DHT) exert long-term anti-hypertensive effects on systemic BP in male rats. These anti-hypertensive mechanisms involve estrogen-independent, non-genomic, signaling pathways which reduce the renin angiotensin system (RAS) expression in the kidney. Thus, the antihypertensive effects of androgens appear to involve both rapid effects on systemic vasodilation and long-term effects on the kidney to promote fluid excretion. The present findings are important for future therapeutic applications of TES and/or DHT therapy to treat hypertension in hypogonadal men. The second project utilized female SD rats to investigate the vascular effects and signaling mechanisms of androgens at the uteroplacental interface during normal and preeclampsia (PE). In this study, the deoxycorticosterone (DOCA)-salt pregnant rat was validated as an acceptable animal model of PE, with hallmark characteristic of the disease including hypertension, proteinuria, and fetal intrauterine growth restriction (IUGR). The results reveal that androgens elicit rapid vasorelaxation of isolated uterine arteries (UA) from normal pregnant (NP) and PE pregnant (PEP) rats and evoke mechanisms that appear to be highly dependent on endothelial nitric oxide synthase (eNOS) signaling and the activation of voltage-gated (KV) and Ca2+-activated (BKCa) K+ channels. In PEP rats, UA sensitivity to TES decreased, while UA sensitivity to 5β-DHT increased compared to NP rats. Further, mRNA expression of 5β-reductase decreased in the uterine arteries and placenta of PEP rats compared to NP control rats. Thus, the vasodilatory effects of androgens may contribute to the regulation of uterine blood flow during normal pregnancy and reductions in androgen production may contribute to the pathogenesis of PE. The increased sensitivity of the UA to 5β-DHT and impaired production of 5β-DHT at the uteroplacental interface in the PEP rats suggest a possible therapeutic role for androgens, particularly 5β-DHT, in the treatment of reduced uterine blood flow and hypertension in women with PE. | en |
