A pinboard by
Giannie Barsha

PhD student, Monash University


Understanding sex differences in CVD, to develop novel therapeutics for postmenopausal hypertension

Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in the Western world. In Australia, it affects one in six people, and is responsible for claiming a life every twelve minutes. More importantly, it remains the single biggest killer of women in Australia each year, with a three times greater likelihood of death occurring from heart disease rather than breast cancer. Hypertension, defined as high blood pressure (≥ 140/90 mmHg), is the prime risk factor for the development of CVD. Pre-menopausal women are generally protected from hypertension, cardiovascular and kidney disease, relative to age-matched men and post-menopausal women. In fact, there is a four-fold increase in the incidence of hypertension in postmenopausal women (40%) compared to premenopausal women (10%). With increasing age, blood pressure in women, drastically approaches and eventually surpasses the levels we normally see in men, such that by the age of 65 there is a greater proportion of women (80%) than men being diagnosed with hypertension. This suggests that the mechanisms that regulate blood pressure are altered with age in females. It has also become apparent that women do not respond to current treatments for hypertension as effectively as males, and this may explain why females have a higher risk of mortality following a cardiovascular event. Such mechanisms regulating the sex differences of hypertension and CVD remain unclear. However, much evidence from the literature suggests that sex-hormones are likely to be playing a role in the long-term regulation of blood pressure due to their interaction with the body's blood pressure control system - the Renin Angiotensin System (RAS). In this way, using an aged female mouse model, we aim to determine whether targeting the RAS and in particular, the Angiotensin Type II Receptor (AT2R) with ovarian hormones such as Estrogen or Relaxin, can confer protection against cardiovascular and kidney disease. This would have benefits for both the control of blood pressure and end-organ damage, leading to improvements in cardiac and renal function, thus promoting an overall reduction in cardiovascular risk. In doing so, hormone replacement therapy may serve as a viable, novel therapeutic to target post-menopausal hypertension.


Sex hormones as potential modulators of vascular function in hypertension.

Abstract: The greater incidence of hypertension in men and postmenopausal women compared with premenopausal women has suggested gender differences in vascular function. Vascular effects of the female sex hormones estrogen and progesterone and the male hormone testosterone have been described. Sex steroid receptors have been identified in vascular endothelium and smooth muscle. Interaction of sex hormones with cytosolic/nuclear receptors initiates long-term genomic effects that stimulate endothelial cell growth but inhibit smooth muscle proliferation. Activation of sex hormone receptors on the plasma membrane triggers nongenomic effects that stimulate endothelium-dependent vascular relaxation via NO-cGMP, prostacyclin-cAMP, and hyperpolarization pathways. Sex hormones also cause endothelium-independent inhibition of vascular smooth muscle contraction, [Ca2+]i, and protein kinase C. These vasorelaxant/vasodilator effects suggested vascular benefits of hormone replacement therapy (HRT) during natural and surgically induced deficiencies of gonadal hormones. Although some clinical trials showed minimal benefits of HRT in postmenopausal hypertension, the lack of effect should not be generalized because it could be related to the type/dose of sex hormone, subjects' age, and other cardiovascular conditions. The prospect of HRT relies on continued investigation of the molecular mechanisms underlying the vascular effects of sex hormones and identification of compounds that specifically target the vascular sex hormone receptors. Naturally occurring hormones and phytoestrogens may be more beneficial HRT than synthesized compounds. Also, the type/dose, time of initiation, and duration of HRT should be customized depending on the subject's age and preexisting cardiovascular condition, and thereby enhance the outlook of sex hormones as potential modulators of vascular function in hypertension.

Pub.: 29 Jun '05, Pinned: 30 Oct '17