Abstract
Aging is a primary risk factor for cardiovascular disease (CVD), which is the leading cause of death in developed countries. Globally, the population of adults over the age of 60 is expected to double by the year 2050. CVD prevalence and mortality rates differ between men and women as they age in part due to sex-specific mechanisms impacting the biological processes of aging. Measures of vascular function offer key insights into cardiovascular health. Changes in vascular function precede changes in CVD prevalence rates in men and women and with aging. A key mechanism underlying these changes in vascular function is the endothelin (ET) system. Studies have demonstrated sex and sex hormone effects on endothelin-1 (ET-1), and its receptors ETA and ETB. However, with aging there is a dysregulation of this system resulting in an imbalance between vasodilation and vasoconstriction. Thus, ET-1 may play a role in the sex differences observed with vascular aging. While most research has been conducted in pre-clinical animal models, we describe more recent translational data in humans showing that the ET system is an important regulator of vascular dysfunction with aging and acts through sex-specific ET receptor mechanisms. In this review, we present translational evidence (cell, tissue, animal, and human) that the ET system is a key mechanism regulating sex-specific changes in vascular function with aging, along with therapeutic interventions to reduce ET-mediated vascular dysfunction associated with aging. More knowledge on the factors responsible for the sex differences with vascular aging allow for optimized therapeutic strategies to attenuate CVD risk in the expanding aging population.
Highlights
Aging is a primary risk factor for cardiovascular disease (CVD), which is the leading cause of death in developed countries
Identifying windows of opportunity for preventative or early treatment, and optimizing exercise interventions that effectively protect against endothelial impairment, is critical for reducing CVD in women given the stark reduction in vasoprotective sex hormones and endothelial function along with a concomitant rise in prevalence of hypertension and CVD with menopause
Sex-specific differences in the ET-1 signaling pathway plays a large role in sex differences observed in endothelial function with aging (Figure 4)
Summary
Aging is a primary risk factor for cardiovascular disease (CVD), which is the leading cause of death in developed countries. The rate of decline is much greater in women compared to men as they age (Celermajer et al, 1994) These sex-specific declines in endothelial function with aging mirror the observed increase in CVD prevalence with aging. The mechanisms underlying sex differences in the age-related decline in endothelial function remain under investigation, but accumulating evidence indicates that the ET system is a key sexspecific regulator of vascular dysfunction associated with aging. In contrast to age-associated endothelial dysfunction, there are disparities in the literature on whether there are sex differences in the age-related increase in arterial stiffness, with some studies reporting a similar progression in the age-related increase in arterial stiffness, a steeper progression in men after the age of 50, and greater age-related rates of aortic and carotid artery stiffening in women (DuPont et al, 2019). The focus of this review will be on endothelial function, we wish to refer the reader to these excellent reviews on arterial stiffness (Safar, 2018; DuPont et al, 2019)
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