Endothelin and Aged Blood Vessels

Age is one of the most important risk factors for cardiovascular disease. For example, a 30-year-old male smoker with untreated hypertension, diabetes, dyslipidemia, and a strong family history of premature coronary heart disease (CHD) would have a 10-year coronary heart disease event rate of only 16% (“intermediate risk”) by Framingham criteria; however, given exactly the same risk profile for a 60-year-old, the risk climbs to 50%. Aging, particularly sedentary aging, leads not only to the development of atherosclerosis but also to ventricular and arterial stiffening.1 This reduces functional capacity and contributes to chronic diseases of the elderly, such as systolic hypertension or heart failure with a preserved ejection fraction. In the search for the underlying mechanism for this effect of sedentary aging, one common feature that has been identified universally in older men is an increased baseline vascular tone,2 which has both hemodynamic and metabolic consequences.3 Although this age-related increase in vascular tone is mediated in part by a chronically elevated sympathetic -adrenergic vasoconstriction,2 endothelial function also plays a critical role in vascular stability and the regulation of vasomotor function. The endothelium regulates vascular tone through the release of dilator and constrictor substances. Endothelin (ET)-1 is the most potent endothelium-derived constricting factor and influences peripheral vascular tone by interacting with ETA and ETB receptors on smooth muscle cells and the endothelium.4 Several animal studies have examined the profound effects of vascular aging on the ET-1 pathway and support a central role for ET-1 to explain the age-related increase in vascular tone.5–7 In the present issue of Hypertension, Van Guilder et al8 present new and important information regarding the role of aging and physical fitness on the vasomotor effects of ET-1. Using a crosssectional design in a small but carefully studied cohort of healthy sedentary younger and older men, Van Guilder et al8 examined forearm blood flow responses to intrabrachial infusion of ET-1, selective ETA receptor blockade, and dual ETA/B receptor blockade. The combination of these well-established pharmacological methods allows the quantification of both ET-1 production and the role of the individual ET receptors and, thus, has a distinct advantage over other indirect methods, such as plasma concentrations of ET-1. As such, this is the first study in humans adequately demonstrating a pivotal role of ET-1 in the regulation of forearm vascular tone with aging. Based on the constrictor action of ET-1 in older men, an enhanced ET-1 signal transduction mechanism may contribute to the elevations in skeletal muscle vascular resistance and, consequently, systemic vascular resistance. These changes in the ET pathway may partially explain the predisposition of older men to cardiovascular pathology. But what are the mechanisms for this increased ET-1– mediated vascular tone with aging? Potential contributing factors include the synthesis of ET-1, sensitivity or numbers of ETA/B receptors, and/or changes in the activated pathways by the ET receptors. Previous studies in rat skeletal muscle and coronary vessels demonstrate indirect6 and direct5,7 evidence for a central role for the ETA receptor to explain the age-related increase in vascular tone. The findings of Van Guilder et al8 extend these findings to humans and support the central role of the ETA receptors in the age-related elevated vascular tone. In addition, the characteristic sustained vasoconstriction of ET-1 after binding to its receptors is partly caused by the activation of protein kinase C, leading to an increased sensitivity of the contractile apparatus. Changes in this pathway were recently found to explain the increased ET-1–mediated vascular tone with aging.5 Further unraveling these downstream mechanisms in elderly humans will contribute to the understanding of the cardiovascular changes observed with aging. A few caveats should be raised when placing these data in perspective. First, the age-related increase in ET-1–mediated vasoconstrictor tone as demonstrated by Van Guilder et al8 was found in the forearm, eg, a vascular bed that demonstrates similar baseline forearm blood flows compared with younger individuals. Vascular territories characterized by an age-related increase in vascular tone (eg, the lower legs or cerebral arteries) may be more or less affected by the ET-1 pathway. Caution should be used in extrapolating findings from the forearm to other vascular beds; indeed, even in different regions of skeletal muscle, lower limbs demonstrate markedly enhanced -adrenergic vasoconstriction compared with upper limbs, presumably because of chronically elevated hydrostatic gradients.9 In addition, it should be noted that only one dose of ET-1 was used in this study. Therefore, the authors could not construct full stimulus-response curves for ET-1 in their volunteers. It may be that, in fact, sedentary aging leads to a change in the operating point on this curve so that there is less reserve for further activation of the ET-1 pathway without an actual change in ET-1 responsiveness. In this regard, it is curious that the authors (and others) have found a decreased ET-1 responsiveness with aging and associate this observation with increased cardiovascular risk. The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Physiology (D.H.J.T., M.T.E.H.), Institute of Fundamental and Clinical Movement Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; and the Institute for Exercise and Environmental Medicine (B.D.L.), Presbyterian Hospital of Dallas and the University of Texas Southwestern Medical Center at Dallas. Correspondence to Benjamin D. Levine, Institute for Exercise and Environmental Medicine, Presbyterian Hospital of Dallas, University of Texas Southwestern Medical Center, 7232 Greenville Ave, Suite 435, Dallas, TX 75231. E-mail [email protected] (Hypertension. 2007;50:292-293.) © 2007 American Heart Association, Inc.