Kuczmarski Andrew V, Welti Laura M, Moreau Kerrie L, Wenner Megan M
University of Delaware, Kinesiology and Applied Physiology, Newark, DE, United States.
University of Colorado, Anschutz Medical Campus, Aurora, CO, United States.
Front Aging. 2021 Aug 31;2:727416. doi: 10.3389/fragi.2021.727416. eCollection 2021.
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.
衰老为心血管疾病（CVD）的主要风险因素，而心血管疾病是发达国家的首要死因。全球范围内，预计到2050年，60岁以上成年人的数量将翻倍。随着男性和女性年龄增长，CVD的患病率和死亡率存在差异，部分原因是特定性别的机制影响了衰老的生物学过程。血管功能的测量为心血管健康提供了关键见解。男性和女性以及随着年龄增长，血管功能的变化先于CVD患病率的变化。这些血管功能变化的一个关键潜在机制是内皮素（ET）系统。研究已证明性别和性激素对内皮素-1（ET-1）及其受体ETA和ETB有影响。然而，随着年龄增长，该系统会出现失调，导致血管舒张和血管收缩之间失衡。因此，ET-1可能在血管衰老中观察到的性别差异中起作用。虽然大多数研究是在临床前动物模型中进行的，但我们描述了人类中最新的转化数据，表明ET系统是衰老过程中血管功能障碍的重要调节因子，并通过特定性别的ET受体机制发挥作用。在本综述中，我们展示了转化证据（细胞、组织、动物和人类），即ET系统是调节衰老过程中血管功能性别特异性变化的关键机制，以及减少与衰老相关的ET介导的血管功能障碍的治疗干预措施。对导致血管衰老性别差异的因素有更多了解，有助于制定优化的治疗策略，以降低不断扩大的老年人群中的CVD风险。
