Endothelin in the female vasculature: a role in aging?

Abstract

vascular diseases are the leading cause of morbidity and mortality in the world. Aging is associated with an increased incidence of cardiovascular disease. Premenopausal women are relatively protected from vascular alterations compared with age-matched men, likely due to higher levels of the female sex hormones. However, these vasoprotective effects in women are attenuated after menopause. Thus, the vascular system in aging women is affected by both the aging process as well as loss of hormonal protection, positioning women of this age group at a high risk for cardiovascular diseases such as hypertension, myocardial infarction, and stroke. The endothelin system in general and endothelin-1 (ET-1) in particular plays an important role in the pathogenesis of vascular dysfunction associated with aging. Evidence suggests that the female sex steroids can interfere with the vascular expression and actions of ET-1 via several mechanisms, which may further contribute to pathological processes in the vasculature of aging women. In this review, we have summarized hormone-dependent vascular pathways whereby ET-1 may mediate the deleterious effects of aging in postmenopausal females.ET-1; menopause; estrogen; vasoconstriction; inflammation AGING OF THE VASCULAR SYSTEM is a complex process characterized by sustained proinflammatory and proconstrictor changes in the vascular microenvironment. The resulting structural and functional alterations in systemic vasculature lead to increased risk of cardiovascular diseases such as hypertension, myocardial infarction, and stroke in the aging population (12,18,51,70). In the absence of chronic preexisting conditions, such as diabetes, premenopausal women express a favorable cardiovascular phenotype compared with age-matched men, largely due to the vasoprotective role of ovarian steroids such as estrogen (92). An alteration in circulating sex hormones at menopause, such as the decrease in estrogens and a relative excess of androgens, is associated with the conversion from a low-to high-risk cardiovascular profile (19,56). Although the mechanisms underlying the pathogenesis of vascular dysfunction in postmenopausal women are not completely understood, it is believed to result from a complex interplay between the aging process and the decline in ovarian hormones like estrogen.Endothelin has emerged as one of the key mediators of vascular dysfunction and remodeling in aging. Interestingly, there is evidence that female sex steroids (in particular, estrogen) can regulate the endothelin system at various levels from gene transcription and posttranslational modification of the peptide to expression of its vascular receptors and postreceptor signaling events. This review will summarize current knowledge on the impact of aging and female sex hormones on the endothelin system, as well as outline directions where further research is needed. A better understanding of the role of endothelin in the pathogenesis of vascular dysfunction in postmenopausal women may lead to the development of novel sex-...

Sex and gender differences in control of blood pressure

“…Androgens likely stimulate oxidative stress since hypertension in male, but not female, SHR and Dahl salt sensitive rats is mediated in part by oxidative stress (51). Androgens have also been shown to increase (15) and estrogens to attenuate (73) endothelin that would promote or attenuate renal vasoconstriction and sodium reabsorption, respectively.…”

Role of the endothelin system in sexual dimorphism in cardiovascular and renal diseases

“…Healthy older women display higher ET-1 concentrations compared to healthy middle-aged women [59]. Indeed, aging is positively associated with increased ET-1 levels [60–63] and postmenopausal women exhibiting high testosterone levels also display high ET-1 levels, in comparison to those with lower testosterone levels, which may be relevant for increased blood pressure [64] and a proatherogenic profile [65]. …”

“…During the menstrual cycle, plasma ET-1 levels fluctuate. In the follicular and luteal phase, higher amounts of estrogen are secreted and lower plasma ET-1 levels are observed in comparison to the menstrual phase [63]. Pregnancy, another condition linked with increased levels of estrogen and progesterone, is also associated with decreased plasma ET-1 levels [57, 66–68].…”

Endogenous endothelin-1 and femoral artery shear rate

“…ET-1 exhibits mitogenic and proinflammatory properties when bound to the endothelin type A (ET A ) receptor, implicating this pathway in the development and progression of atherosclerosis [20–23]. Additionally, ET-1 has been linked to endothelial dysfunction that accompanies normal aging [23–30] and to the development and progression of several age-related cardiovascular diseases including hypertension, coronary artery disease, and congestive heart failure [31–34]. An abundance of evidence suggests that ET-1 is capable of contributing to age-related alterations in shear rate, but this has yet to be actually documented.…”