Mechanism of Gender-Specific Differences in Aortic Stiffness With Aging in Nonhuman Primates

Abstract

Background-Our hypothesis was that the changes in vascular properties responsible for aortic stiffness with aging would be greater in old male monkeys than old female monkeys. Methods and Results-We analyzed the effects of gender differences in aging on in vivo measurements of aortic pressure and diameter and on extracellular matrix of the thoracic aorta in young adult (age, 6.6Ϯ0.5 years) versus old adult (age, 21.2Ϯ0.2 years) monkeys (Macaca fascicularis). Aortic stiffness, as represented by the pressure strain elastic modulus (Ep), increased more in old male monkeys (5.08Ϯ0.81; PϽ0.01) than in old females (3.06Ϯ0.52). In both genders, collagen density was maintained, collagen-bound glycation end products increased, and collagen type 1 decreased. However, elastin density decreased significantly (from 22Ϯ1.5% to 15Ϯ1.2%) with aging (PϽ0.05) only in males. Furthermore, only old males were characterized by a decrease (PϽ0.05) in collagen type 3 (an isoform that promotes elasticity) and an increase in collagen type 8 (an isoform that promotes the neointimal migration of vascular smooth muscle cells). In contrast to the data in monkeys, collagen types 1 and 3 both increased significantly in aging rats. Conclusions-There are major species differences in the effects of aging on aortic collagen types 1 and 3. Furthermore, because alterations in collagen density, collagen content, hydroxyproline, and collagen advanced glycation end products were similar in both old male and female monkeys, these factors cannot be responsible for the greater increase in stiffness in old males. However, changes in collagen isoforms and the decrease in elastin observed only in old males likely account for the greater increase in aortic stiffness. (Circulation. 2007;116:669-676.)

Sex differences in myocardial infarction and rupture

“…These clinical observations of sex differences in the incidence and the prognosis of acute cardiovascular events correlate with several studies conducted in large mammals [7][8][9][10]. In a monkey model of aging, gender differences in gene and protein expression can explain several aspects of the characteristic protection of females against cardiovascular disease, including a better preservation with aging of the expression of enzymes of glycolytic and oxidative pathways [10], a better cardiovascular response to β-adrenergic stimulation [9], less apoptosis and myocyte hypertrophy in old female monkeys than in old male monkeys [11], as well as differences in the composition of the extracellular matrix of conductance vessels, such as elastin and collagen isoforms, which correlates with lower vascular stiffness in females compared to males [7,8].…”

“…This poorer prognosis in men is also supported by the observation that myocardial rupture after MI is observed twice as often in men than in women [5]. The prognosis of MI is also usually worse in younger patients due to the absence of a history of chronic ischemia and secondary collateral development, and because an early MI is usually due to the accumulation of several risk factors, such as diabetes, smoking, metabolic syndrome and consumption of recreational drugs [6].These clinical observations of sex differences in the incidence and the prognosis of acute cardiovascular events correlate with several studies conducted in large mammals [7][8][9][10]. In a monkey model of aging, gender differences in gene and protein expression can explain several aspects of the characteristic protection of females against cardiovascular disease, including a better preservation with aging of the expression of enzymes of glycolytic and oxidative pathways [10], a better cardiovascular response to β-adrenergic stimulation [9], less apoptosis and myocyte hypertrophy in old female monkeys than in old male monkeys [11], as well as differences in the composition of the extracellular matrix of conductance vessels, such as elastin and collagen isoforms, which correlates with lower vascular stiffness in females compared to males [7,8].…”

Vascular smooth muscle cells direct extracellular dysregulation in aortic stiffening of hypertensive rats

“…This new concept further clarifies the cause and effect relationship between aortic stiffening and hypertension in aged individuals. Additionally, our previous studies in monkey have demonstrated that aortic stiffening is also strongly associated with aging (Qiu et al., 2007). Specifically, our recent studies with atomic force microscopy (AFM) have demonstrated similar characteristics of aortic vascular smooth muscle cells (VSMCs) in both aging and hypertension, indicating that VSMC‐mediated regulation is a fundamental basis of aortic stiffening in both conditions (Qiu et al., 2010; Zhou, Lee, Stoll, Ma, Costa, et al.…”

Reversal of Aging‐Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein‐Protein Interfaces

“…We have also observed an age‐related increase in ex vivo activated smooth muscle stiffness of the mouse 16. Indeed, there is now a significant amount of evidence from multiple laboratories to suggest that the smooth muscle cell contributes significantly to the development of age‐related increases in active aortic stiffness 16, 17, 18, 19, 20, 21, 22, 49, 50. Our findings point to the FA complex and the attached, nonmuscle actin cytoskeleton as key sources for the increase in smooth muscle cell stiffness.…”

“…However, it has also been proposed that aging of the vascular smooth muscle cell (VSMC) can adversely modulate the fractional engagement of collagen, leading to a dynamic increase in stiffness 16, 17, 18, 19, 20, 21, 22. In fact, recent studies in a mouse model, where viable smooth muscle preparations can be readily obtained and activated with vasoactive agents to measure active stiffness, have demonstrated that close to half of the total stiffness of the aortic wall is attributable to the active stiffness of the VSMC,16 with the remaining fraction due to the extracellular matrix.…”