Physiological genomics of gender and age differences in neurogenic hypertension.

Age and gender are significant risk factors in the development of hypertension, a major cause of morbidity and mortality in worldwide. Blood pressure (BP) is generally lower in pre-menopausal women compared to age-matched males, and younger men are at greater risk of cardiovascular disease than pre-menopausal women of the same age. However, whilst age is a contributory factor in the development of hypertension in both men and women, the onset of menopause increases hugely the risk of developing high BP in women, such that the prevalence of hypertension in post-menopausal women exceeds that of their male peers. This project is based on the compelling evidence that alterations in the balance of cardiovascular autonomic motor outflow and consequent over-activity of the sympathetic nervous system contributes to essential hypertension (neurogenic hypertension). Indeed, in essential hypertension homeostatic reflexes that regulate arterial pressure are re-set to higher levels due to alterations in central nervous system circuits. Ultimately, the raised BP increases the risk of coronary heart disease, renal failure, stroke and end organ damage. We propose that these changes can be described in terms of altered patterns of gene expression within these central nervous cardiovascular circuits. Knowing more about these genes has considerable therapeutic implications. Specifically, we hypothesise that the expression of genes in key brainstem and hypothalamic structures is different in: - young and old males, and that these differences contribute to the progressive worsening of the symptoms of hypertension. - age-matched male and females, and that these differences contribute to the gender-related development of hypertension. - pre- and post-menopausal females, with and without intact ovaries, and that these differences contribute to the development of post-menopausal hypertension, which is dependent upon ovarian factors in younger life. We will test these hypotheses by comparing normal rats with rats genetically predisposed to develop hypertension. We will interrogate microarrays with targets derived from hypothalamic and brainstem regions known to be important in cardiovascular control. By comparing male and female, young and old, and intact and ovariectomised animals, we will identify gene expression signatures that define, and may mediate, age- and gender-related differences in the prevalence of hypertension.

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