The aging process is associated with marked sexual dimorphism in the incidence of human cardiovascular diseases, but it is unclear why the male cardiovascular system appears to """"""""age"""""""" more rapidly and often develops disease more frequently than the female system. It is clear that gonadal steroid hormones influence cardiovascular function, but the molecular basis of these effects is largely unknown, particularly for the male steroid hormones, the androgens. The long-term goal of the applicants is to elucidate the humoral mechanisms important in the regulation of vascular function and blood pressure in normotension (NT) and during the development of hypertension (HT). This proposal is based upon recent findings by the PI and others that: acute injections of testosterone (TES) reduce angina pectoris and increase coronary blood flow in men;TES produces rapid, dose-dependent vasodilation of systemic and coronary vasculatures in NT as well as HT animals;vasodilation by TES is endothelium-, sex-, and intracellular androgen receptor-independent;and TES-induced vasodilation is a structurally-specific effect of the androgen molecule on vascular smooth muscle (VSM). The objectives of this research are to elucidate the cellular and molecular mechanisms underlying TES-induced vasodilation of mesenteric arteriolar (microvascular) VSM, and to quantify the effects of HT on the cellular and molecular mechanisms of TES- induced vasodilation.
The specific aims of the proposed research are to: 1) Elucidate the mechanisms of TES-induced vasodilation in NT and during development of HT;2) Quantify the importance of single K+ channel function in TES-induced vasodilation in NT and HT;3) Quantify the role of the NO-cGMP signal transduction pathway in TES-induced vasodilation in NT and HT;4) Elucidate the structure-function relationship of the androgen molecule and its interaction with VSM cell membrane K+ channels in TES- induced vasodilation;and 5) Determine interactions between the acute (nongenomic) and long-term (genomic) mechanisms of TES action in the regulation of TES-induced vasodilation in NT and HT. This multifaceted proposal will provide a unique examination, in detail, of the cellular and molecular mechanisms underlying androgen-induced vasodilation of the peripheral microvasculature and the role of androgens in the acute regulation of vascular tone in NT and HT. It is well-established that marked sexual dimorphism exists in a variety of human cardiovascular diseases;thus the proposed research is directly relevant to human health and cardiovascular disease.
