It is increasingly recognized that biological differences in the mechanisms regulating cardiovascular function in women and men critically impact the expression, clinical presentation, and outcomes of chronic diseases such as hypertension, diabetes, and heart failure. This is borne out from epidemiological and clinical studies that have explored the prevalence and presentation of heart disease in women, as well as a robust experimental literature demonstrating a role of estrogens in cardioprotection. Sex differences in mortality after myocardial infarction tell the story since data show a worse prognosis of death post-myocardial infarction for women (38% within the first year) compared to men (25% within the first year).

The studies described in this dissertation investigated estrogens' mechanisms through the nitric oxide pathway in the expression of diastolic dysfunction. The research was performed in an unique estrogen- and salt-sensitive rat model of chronic hypertension and cardiac dysfunction that is associated with the presence of left ventricular hypertrophy and eventual development of renal disease. Our research has documented that female mRen2.Lewis rats display diastolic dysfunction and cardiac fibrosis which is further aggravated by removal of the ovaries. To explore mechanisms accounting for the interaction between estrogens, diastolic dysfunction, and the cardiac actions of the nitric oxide system, we performed a series of experiments that documented increased radical oxygen species associated with depleted levels of cardiac BH4 and decreased nitric oxide release in mRen2.Lewis female rats. The changes in lusitropic activity in female mRen2.Lewis rats following nNOS inhibition were associated with diminished left ventricular remodeling, increased nitric oxide release, and limited generation of radical oxygen species. In the same model, BH4 repletion exhibited protection against ovarian hormonal loss on diastolic function and cardiac structure in mRen2.Lewis rats through restoration of NO release and mitigation of superoxide generation.

The data collected in this series of experiments has increased the understanding of an important interaction between estrogens and the nitric oxide pathway in the regulation of cardiac function, the composition of the cardiac extracellular matrix, and their role in the development and progression of diastolic dysfunction. This knowledge will allow the design of a more rational approach to the treatment of heart disease in women.