The goal of this review is to provide further understanding of increased vascular stiffness with aging, and how it contributes to the adverse effects of major human diseases. Differences in stiffness down the aortic tree are discussed, a topic requiring further research, because most prior work only examined one location in the aorta. It is also important to understand the divergent effects of increased aortic stiffness between males and females, principally due to the protective role of female sex hormones prior to menopause. Another goal is to review human and non-human primate data and contrast them with data in rodents. This is particularly important for understanding sex differences in vascular stiffness with aging as well as the changes in vascular stiffness before and after menopause in females, as this is controversial. This area of research necessitates studies in humans and non-human primates, since rodents do not go through menopause. The most important mechanism studied as a cause of age-related increases in vascular stiffness is an alteration in the vascular extracellular matrix resulting from an increase in collagen and decrease in elastin. However, there are other mechanisms mediating increased vascular stiffness, such as collagen and elastin disarray, calcium deposition, endothelial dysfunction, and the number of vascular smooth muscle cells (VSMCs). Populations with increased longevity, who live in areas called “Blue Zones,” are also discussed as they provide additional insights into mechanisms that protect against age-related increases in vascular stiffness. Such increases in vascular stiffness are important in mediating the adverse effects of major cardiovascular diseases, including atherosclerosis, hypertension and diabetes, but require further research into their mechanisms and treatment.

Hypertension and aging are both recognized to increase aortic stiffness, but their interactions are not completely understood. Most previous studies have attributed increased aortic stiffness to changes in extracellular matrix proteins that alter the mechanical properties of the vascular wall. Alternatively, we hypothesized that a significant component of increased vascular stiffness in hypertension is due to changes in the mechanical and adhesive properties of vascular smooth muscle cells, and that aging would augment the contribution from vascular smooth muscle cells when compared with the extracellular matrix. Accordingly, we studied aortic stiffness in young (16-week-old) and old (64-week-old) spontaneously hypertensive rats and Wistar–Kyoto wild-type controls. Systolic and pulse pressures were significantly increased in young spontaneously hypertensive rats when compared with young Wistar–Kyoto rats, and these continued to rise in old spontaneously hypertensive rats when compared with age-matched controls. Excised aortic ring segments exhibited significantly greater elastic moduli in both young and old spontaneously hypertensive rats versus Wistar–Kyoto rats. were isolated from the thoracic aorta, and stiffness and adhesion to fibronectin were measured by atomic force microscopy. Hypertension increased both vascular smooth muscle cell stiffness and vascular smooth muscle cell adhesion, and these increases were both augmented with aging. By contrast, hypertension did not affect histological measures of aortic collagen and elastin, which were predominantly changed by aging. These findings support the concept that stiffness and adhesive properties of vascular smooth muscle cells are novel mechanisms contributing to the increased aortic stiffness occurring with hypertension superimposed on aging.

In recent decades, the pervasiveness of increased arterial stiffness in patients with cardiovascular disease has become increasingly apparent. Though this phenomenon has been well documented in humans and animal models of disease for well over a century, there has been surprisingly limited development in a deeper mechanistic understanding of arterial stiffness. Much of the historical literature has focused on changes in extracellular matrix proteins – collagen and elastin. However, extracellular matrix changes alone appear insufficient to consistently account for observed changes in vascular stiffness, which we observed in our studies of aortic stiffness in aging monkeys. This led us to examine novel mechanisms operating at the level of the vascular smooth muscle cell (VSMC) – that include increased cell stiffness and adhesion to extracellular matrix – which that may be interrelated with other mechanisms contributing to arterial stiffness. We introduce these observations as a new concept – the Smooth Muscle Cell Stiffness Syndrome (SMCSS) – within the field of arterial stiffness and posit that stiffening of vascular cells impairs vascular function and may contribute stiffening to the vasculature with aging and cardiovascular disease. Importantly, this review article revisits the structural basis of arterial stiffness in light of these novel findings. Such classification of SMCSS and its contextualization into our current understanding of vascular mechanics may be useful in the development of strategic therapeutics to directly target arterial stiffness.

Our review of the literature of the major cardiovascular journals for the past three years showed that for all studies using anesthesia for mouse echocardiography, the predominant anesthetic was isoflurane, which was used in 76% of the studies. The goal of this investigation was to determine if isoflurane is indeed the best anesthetic. Accordingly, we compared isoflurane with 2,2,2-tribromoethanol (Avertin), ketamine-xylazine, and ketamine on different days in the same 14 mice, also studied in the conscious state without anesthesia. A randomized crossover study design was employed to compare the effects on left ventricular (LV) systolic function and heart rate of the four different anesthetic agents assessed by transthoracic echocardiography. As expected, each anesthetic depressed LV ejection fraction and heart rate when compared with values in conscious mice. Surprisingly, isoflurane was not the best, but actually second to last in maintaining normal LV function and heart rate. The anesthetic with the least effect on LV function and heart rate was ketamine alone at a dose of 150 mg/kg, followed by Avertin at 290 mg/kg, isoflurane at 3% induction and 1 to 2% maintenance, and lastly ketamine-xylazine at 100 and 10 mg/kg, respectively. In summary, these results indicate that ketamine alone exerts the least depressant effects on LV function and heart rate, with Avertin second, suggesting that these anesthetics should be used when it is not feasible to study the animals in the conscious state as opposed to the most commonly used anesthetic, isoflurane.