The aorta is divided into sections by location; the ascending aorta, aortic arch, and the descending aorta. The descending aorta can be divided into thoracic and abdominal sections. Branches of interest include the left and right coronary arteries, which branch from the aortic root, and the brachiocephalic, left carotid, and left subclavian, which branch from the aortic arch. As the aorta descends there are numerous branches which supply the surrounding muscles and organs including intercostal, celiac, hepatic, gastric, splenic, renal, mesenteric, and gonadal arteries. The abdominal aorta bifurcates into the iliac arteries which extend inferiorly, turning into the femoral arteries, which supply blood flow to each leg.

The morphometric properties of the aorta differ along its length. The aorta tapers, with the average systolic diameter decreasing from the proximal to the distal aortic tree (Hickson et al., 2010). In healthy humans, helical computed tomography showed that maximum aortic diameter is in the ascending aorta, distal to the aortic valve sinus and proximal to the innominate artery (Hager et al., 2002). The aortic diameter then decreases progressively along the thoracic aorta and continues to decrease from the infrarenal abdominal aorta to the lower abdominal aorta (Hager et al., 2002; Rogers et al., 2013). Overall thickness of the aortic wall also decreases down the thoracic aorta, but then remains constant in the abdominal aorta (Sokolis, 2007). In the pig, the tunica media decreases in thickness distally along the thoracic and abdominal aorta, while the tunica adventitia thickness is negligible in the thoracic aorta, but increases down the length of the abdominal aorta (Sokolis, 2007). Aging results in morphometric changes to the diameter, length, and thickness of the aorta. Overall, the diameter and length increase progressively with age (Komutrattananont et al., 2019), with the greatest change in diameter occurring at the level of the ascending aorta (+0.96 mm/decade) (Hickson et al., 2010). The tunica intima and media of the aortic wall thicken with age (Komutrattananont et al., 2019).

The most important mechanism studied as a cause of age-related increases in vascular stiffness is alteration in the extracellular matrix (ECM), resulting from an increase in collagen and decrease in elastin. The ECM is composed of a complex network of different matrix proteins, metalloproteases, and glycosaminoglycans, which are also responsible for the structural integrity of the vasculature, and therefore contribute to its stiffness (Ma et al., 2020). Collagen is a very stiff protein with the function of limiting vessel elasticity and distension (Briones et al., 2010), and is therefore fundamental to defining the stiffness of the arterial wall. Collagen deposition throughout the vasculature increases with age, which alters the normal ECM network (Kohn et al., 2015). This has been shown to occur in the intima, media, and adventitia of the vessel wall leading to substantial changes in its morphology and function (Greenberg, 1986; Fleenor et al., 2010, 2012). In addition to increased collagen deposition, there is also increased non-enzymatic glycation. This is also responsible for age-related increases in arterial stiffness (Schleicher et al., 1997), as it induces collagen cross-linking, which increases stiffness (Reddy, 2004).

Unlike collagen, elastin, the other major ECM protein, provides flexibility and extensibility of the vessel wall (Wagenseil and Mecham, 2012). Elastin fibers are mainly found in the medial layer of large elastic arteries and are oriented around smooth muscle cells and collagen. Elastin content decreases, while collagen content increases from the proximal to distal aorta (Fischer and Llaurado, 1966; Sokolis, 2007). The elastin/collagen ratio is highest in the thoracic aorta and decreases distally (Hager et al., 2002), whereas the reverse is found in the collagen/elastin ratio (Figures 1, 2). Smooth muscle cell content remains similar throughout the length of the aorta, but increases with aging and is another mechanism for increased aortic stiffness. Degradation of elastin fibers with aging is mediated by the increases of proteolytic enzymes, e.g., matrix metalloproteases (MMP), which degrade elastin fibers, resulting in an increase in collagen/elastin ratio, which in turn increase vessel wall stiffness (Wolinsky, 1970). Nevertheless, the extent to which increases in collagen and decreases in elastin contribute to increased vascular stiffness with aging remains controversial.

Using old world monkeys, we previously found that collagen density in the thoracic aorta did not change with age, whereas that in the abdominal aorta increased. In contrast, we found that elastin in both the thoracic and abdominal aorta decreased with age (Zhang et al., 2016; Babici et al., 2020; Figures 1, 2, 6). Relatively few studies have examined changes in both thoracic and abdominal aortic stiffness with age, in vivo (Farrar et al., 1984; Rogers et al., 2001; Nelson et al., 2009; Hickson et al., 2010; Taviani et al., 2011; Westenberg et al., 2011; Devos et al., 2015). Some studies measured collagen and elastin with aging, but did not measure aortic stiffness, in vivo. Interestingly, the results of these studies are controversial, with some studies finding an increase (Faber and Oller-Hou, 1952; Chamiot-Clerc et al., 2001; Aronson, 2003; Nosaka et al., 2003; Astrand et al., 2011; Taviani et al., 2011; Wheeler et al., 2015) and others finding no change in collagen (Hosoda et al., 1984) or a decrease in collagen (Nosaka et al., 2003; Qiu et al., 2007a; Astrand et al., 2011; Taviani et al., 2011; Atanasova et al., 2012) or no change in elastin (Wheeler et al., 2015).

In contrast to the thoracic aorta, collagen content rose by 34% in the abdominal aorta with aging, which was a significantly greater increase than that observed in the thoracic aorta (Zhang et al., 2016). Elastin was decreased in the abdominal compared to the thoracic aorta in young animals, and decreased to even lower levels with aging (Zhang et al., 2016). Consistent with our finding that stiffness in the abdominal aorta of young monkeys equaled or was greater than that of the thoracic aorta in old monkeys, the collagen and elastin levels in the abdominal aortas of young monkeys equaled the values observed in the thoracic aorta for old monkeys (Zhang et al., 2016; Babici et al., 2020), emphasizing the importance for studying regional aortic stiffness changes with aging. However, basal levels of collagen and elastin are not the only mechanism accounting for greater stiffness observed in the abdominal compared to the thoracic aorta both in young and old monkeys. From our previous studies, we also observed marked disarray of both collagen and elastin; a finding that was more prominent with aging and in the abdominal vs. thoracic aorta. In fact, the marked disarray of elastin and collagen in the young abdominal aorta is likely responsible for the unexpected more severe stiffness than even in the old thoracic aorta (Zhang et al., 2016; Babici et al., 2020). The elastin and collagen disarray correlated better with stiffness than did elastin and collagen content (Figure 6). Another study also found elastic tissue in the abdominal aorta is most affected by aging (Maurel et al., 1987). Elastic fibers become damaged and thicken the tunica intima. Within the tunica media, elastic lamellae become damaged and elastic fibers become fragmented and disarrayed (Maurel et al., 1987). It is surprising that this marked architectural disarray we observed in the aging aorta with increased stiffness has not been noted extensively in the past, even though isolated observations have previously found disarray in aortae related to aneurysms (Hofmann Bowman et al., 2010; Pezzini et al., 2012; Lee et al., 2014), hypertension (Sans and Moragas, 1993), and aging (Fornieri et al., 1992).

Other important mechanisms mediating increased vascular stiffness, include increases in calcium deposition, endothelial dysfunction, and increases in the stiffness of vascular smooth muscle cells.

Calcification of the vessel wall occurs with normal aging, reducing the vessel wall’s distensibility (London et al., 2003). In humans there is a direct correlation between aortic calcification and arterial stiffness (Guo et al., 2017). Calcinosis of arterial walls with aging has been associated with increased cholesterol content in the elderly, suggesting a relationship between these processes (Kanabrocki et al., 1960). However, it is unknown which process occurs first, although some have speculated that calcinosis increases interaction with cholesterol molecules in the arterial wall (Hornebeck and Partridge, 1975). Another explanation for the increase in calcium deposition within the arterial wall is via an increase in inflammation and oxidative stress, both of which occur with normal aging. Increases in oxidative stress that occur with aging, mainly due to decreases in mitophagy and autophagy (Pescatore et al., 2019), stimulate vascular calcification by activating several signaling cascades (Byon et al., 2008). One of the best studied signaling pathways involves the upregulation of bone morphogenetic proteins due to increases in oxidative stress, which results in increased vascular calcification (Sorescu et al., 2004; Johnson et al., 2006).

The relationship between calcification and aortic stiffness differs depending on the location of the calcification. Carotid artery stiffness was more strongly associated with thoracic aorta calcification than calcification of the coronary arteries (Blaha et al., 2009). This may be because calcification of the coronary arteries usually involves only the intimal layer, while in large arteries calcification involves both the intima and media (Blaha et al., 2009); with medial calcification being more strongly associated with aging, diabetes, and severe renal disease (Iribarren et al., 2000). In addition, structural features may be involved: carotid arteries, being more elastic, are more similar to the aorta than to coronary arteries, which are non-elastic, predominantly conduit vessels.

The vascular endothelium is the innermost, monolayer of cells in blood vessels. When the endothelium is healthy, vascular tone is regulated by a balance of vasoconstriction and vasodilation; the latter controlled by nitric oxide (NO) release (Furchgott and Zawadzki, 1980). Reduced bioavailability of nitric oxide leads to endothelial dysfunction, resulting in impaired vasodilation, which increases arterial stiffness (Mceniery et al., 2006). Endothelium impairment and decreased NO bioavailability occur with normal aging, ultimately leading to a proinflammatory, vasoconstrictive state, resulting in increased vascular fibrosis and arterial stiffness (Santhanam et al., 2010; Santos-Parker et al., 2014). Furthermore, endothelial dysfunction leads to an increase in oxidative stress through an increase in the production of superoxide causing damage to the vessels leading to changes in hemodynamics (Donato et al., 2018). Recently, it has also been proposed that autophagy, the cellular housekeeping mechanism that maintains cellular homeostasis, decreases in the aging endothelium, further leading to increases in oxidative stress (Larocca et al., 2012). This was further confirmed with the use of a pro-autophagy treatment, which reduced arterial stiffness and oxidative stress in aged mice (Larocca et al., 2013).

Age-related endothelial dysfunction may affect the arterial network differently based on location and vessel type. Aging results in endothelial dysfunction in the aorta but not in the femoral artery (Barton et al., 1997). The anatomic variation in the influence of age on endothelial function may be related to increased pulse pressure and reduced eNOS mRNA expression in the aorta (Barton et al., 1997). In rats, acetylcholine-induced vasorelaxation is impaired in large conduit arteries (abdominal aorta and iliac arteries) but not in smaller conduit (femoral arteries) or resistance arteries (Luttrell et al., 2020).

Vascular smooth muscle cells have recently been discovered as important contributors to age-related increases in arterial stiffness (Trache et al., 2020). This mechanism, which we named “Vascular Smooth Muscle Cell Stiffness Syndrome” (Sehgel et al., 2015b), was elucidated in aged non-human primates that displayed an increase in VSMC stiffness in large arterial vessels (Qiu et al., 2010; Sehgel et al., 2015a; Figure 7). This increased VSMC stiffness is due to the direct relationship between VSMCs and endothelial cells. Endothelial cells regulate vascular tone mainly through the release of nitric oxide. This reduces active tone of VSMCs (Furchgott and Zawadzki, 1980; Van Bussel et al., 2015), which counteracts the increase in wall shear stress that occurs with both aging and high blood pressure (Boutouyrie et al., 1995; Van Bussel et al., 2015; Jaminon et al., 2019; Figure 8). However, aging also leads to a decrease in the number of cells within the vascular wall due to a decrease in cell proliferation with age (Greenwald, 2007; Chi et al., 2019). Multiple mechanisms mediate the decrease of VSMCs with age, but most notably inflammation and calcification, which increase VSMC apoptosis (Lacolley et al., 2012). In humans, the VSMCs lost with aging are replaced by collagen fibers in the media of the arterial wall, resulting in increased vascular stiffness (Schlatmann and Becker, 1977). Interestingly, when the stiffness of isolated VSMCs was measured with atomic force microscopy, it did not differ with age between the thoracic and abdominal aorta (Zhang et al., 2016). This suggests that VSMC stiffness is not the mechanism by which stiffness varies regionally within the aorta, unless it is related to differences in VSMC function as a result of altered endothelial cell function, inflammation or calcium mechanisms that occur variably along the aortic tree with aging.

The greater increases in vascular stiffness in aged-matched men, than in women prior to menopause, is reversed, so that after menopause women show more severe increases in vascular stiffness. The difference in vascular stiffness between pre- and postmenopausal women is primarily ascribed to proposed protective roles of estrogen, which reduces increased stiffness with age. Estrogen levels rapidly decrease just before menopause and continue to fall after menopause (Moreau and Hildreth, 2014). This coincides with the timing of the accelerated age-associated vascular stiffness seen in women after menopause, when compared to age-matched men and premenopausal women. Animal studies have found that estrogen can increase elastin content, inhibit collagen deposition, and prevent abnormal VSMC proliferation and migration (Dubey et al., 2000a,b; Yoon et al., 2001). In other words, estrogen appears to counteract many of the mechanisms associated with age-dependent vascular stiffening. Furthermore, hormonal therapy with estrogen, initiated around the time of menopause, decreases arterial stiffening in postmenopausal women when compared to non-hormonal therapy-treated postmenopausal women (Moreau and Hildreth, 2014). Arterial stiffening is also associated with increased vascular tone and increased oxidative stress. Estrogen is also a potent antioxidant and prevents scavenging of nitric oxide (NO) by reactive oxygen species (Moreau and Hildreth, 2014). Thus, prolonged estrogen deficiency in postmenopausal women, by limiting availability of estrogen as an antioxidant and of NO, may contribute to an increase in vascular tone, and in susceptibility to oxidative stress. Nevertheless, it is of interest that despite the evidence for a protective role of estrogen with respect to arterial stiffness during the fertile period, epidemiological evidence suggests that there is no sudden increase in the rate of cardiovascular disease in women at the time of menopause, but this is observed rather after menopause (Woodward, 2019). Furthermore, clinical trials have found no overall cardiovascular benefit of exogenous estrogen in postmenopausal women (Boardman et al., 2015).

In mice, NO bioavailability has been directly linked to the mechanical properties of the vessel wall, corroborating that the effect of estrogen is mediated by NO. Female ovariectomized mice display increased circumferential elastic modulus in all arteries, suggesting stiffening, as well as decreased eNOS protein expression, and reduced endogenous NO production (Guo et al., 2006). Female mice lacking the endothelial NO synthase gene displayed increases in circumferential modulus in the aorta and decreased NO production in the femoral and carotid arteries (Guo et al., 2006). This supports the idea that estrogen works to reduce stiffness by stimulating NO production, which maintains structural and mechanical properties of arteries. When rodent models were given an NO synthase inhibitor, either acutely or chronically, PWV increased compared to that in controls. In fact, chronic administration showed an additional 8% increase in PWV when compared to the control experimental group (Fitch et al., 2001).

Administration of BH₄ (tetrahydrobiopterin), a critical cofactor for NO production, increased carotid artery compliance and brachial artery flow-mediated dilatation in postmenopausal, but not premenopausal women (Moreau et al., 2012). This increase in carotid compliance was also seen when estradiol was administered to postmenopausal women (Moreau et al., 2012). However, no additional improvement was seen when BH₄ and estradiol were co-administered (Moreau et al., 2012). Therefore, reduced BH₄ may contribute to arterial stiffness in postmenopausal women and estrogen may increase BH₄ bioavailability.

These varying trends between men and women significantly impact their cardiovascular disease susceptibility (Dupont et al., 2019). Heart failure with preserved ejection fraction (HFpEF) is observed twice as commonly in women than men. This increased incidence of HFpEF in women may be associated with the increased proximal aortic stiffness in post-menopausal women, when compared to men (Coutinho et al., 2013). The mean age in this study was 65 years for post-menopausal women and 67 for men (Coutinho et al., 2013). Women also exhibit more pronounced age-related increases in aortic flow impedance than men (Coutinho et al., 2013). These pathophysiological changes may have a cascade effect whereby lower aortic compliance leads to greater impedance to flow. In turn, this increases hemodynamic load on the left ventricle, resulting in an enhanced propensity for women to develop heart failure.

The enhanced arterial stiffness of older postmenopausal women, compared to their male counterparts, is an issue that warrants greater research not only to better understand the mechanisms behind this phenomenon, but also to develop more targeted and effective therapies for postmenopausal women. Isolated systolic hypertension is more common in older women and these women are less likely to achieve optimal blood pressure control than age-matched men (Dupont et al., 2019).

As mentioned previously, findings from studies of vascular aging in rodents are limited, as rodents have a shorter lifespan than monkeys or humans, and do not go through menopause. This may explain why one study of aging in rats showed similar levels of aortic stiffness at 6, 12, and 24 months of age in males and females (Mitchell et al., 2004). One rodent species that does live over 20 years, the naked mole rat, has been found to be better protected against aging-induced oxidative stress and apoptotic cell death than its shorter-living counterparts; differences that likely contribute to their exceptional longevity (Csiszar et al., 2007). This provides insight into the key roles oxidative stress may have on age-related arterial stiffness. Further studies may also be warranted of male and female naked mole rats to determine if, like human and monkeys, they also display sex-specific differences in longevity.

Sexually dimorphic longevity is observed in many mammalian species, with females living longer than males (Hagg and Jylhava, 2021). Despite differences in cardiac physiology and anatomy, rodent models have been helpful in beginning to understand mechanisms underlying sex-specific differences in vascular aging (Blenck et al., 2016). However, monkey models are more applicable to humans than rodents because they live longer and have a menstrual cycle. But with the availability of non-human primate models, more research is required to fully elucidate the key drivers of sex-specific differences in vascular aging.

Sex differences in arterial stiffening have been found even in prepubescent human subjects and may be attributed to both sex steroids and intrinsic differences. Prepubescent girls, for example, have less compliant arteries and higher central and peripheral PWV than their male counterparts (Ahimastos et al., 2003). However, after puberty, central PWV falls in females but increases in male (Ahimastos et al., 2003). Interestingly, prepubescent and postmenopausal arterial stiffness are both likely due to the same mechanism, namely, low levels of sex steroids.

Aortic stiffness and arterial pressure are strongly correlated in hypertension with vascular stiffness being both a cause and a consequence of hypertension (Humphrey et al., 2016). High blood pressure may cause vascular damage and elastin fragmentation, leading to increased stiffness. On the other hand, aortic stiffness widens pulse pressure which affects systolic blood pressure. Hypertension and aging may have an additive effect evidenced by elderly hypertensive patients having stiffer arteries than age-matched normotensive patients (Verwoert et al., 2014). However, these differences may be attributed to hypertension, rather than intrinsic vascular changes associated with increased stiffness (Bavishi et al., 2016).

Vascular stiffness is linearly related to age both in normotensive and severely hypertensive subjects (Figure 9; Safar et al., 2018). Interestingly the slope of these linear relationships is not that different (Figure 9); arterial stiffness rising in normotensive people almost as much as in those who are hypertensive. Aortic stiffness is also increased in spontaneously hypertensive rats, even at a young age, but much more in older rats (Sehgel et al., 2013, 2015a,b; Figure 8). As discussed above, elastin breakdown, due to matrix metallopeptidases and serum elastase, is a major mediator of increased vascular stiffness (4). Serum MMP-9 and MMP-2 levels, and serum elastase activity, which degrade elastin degradation and increase aortic and brachial PWV, are increased in subjects with isolated systolic hypertension (Yasmin et al., 2005).

Isolated systolic hypertension, defined as systolic blood pressure > 140 mmHg and diastolic blood pressure < 90 mm Hg (Mancia et al., 2013), is the predominant form of hypertension in the elderly, and is associated with increased arterial stiffness (Franklin et al., 1997; Yasmin et al., 2005; Bavishi et al., 2016). Interestingly, in older patients, systolic arterial pressure continues to increase along with aortic stiffness, but diastolic hypertension declines, further demonstrating the important relationship between systolic arterial hypertension and aortic stiffness (Franklin et al., 1997). Systolic-diastolic hypertension due to elevation of both systolic and diastolic arterial pressures is less common in older adults (Tsimploulis et al., 2017), but is associated with an increased incidence of heart failure and cardiovascular mortality (Tsimploulis et al., 2017). Also, pre-eclampsia, which induces hypertension during pregnancy, is associated with increased vascular stiffness (Hausvater et al., 2012).

Salt intake, a key mechanism mediating hypertension, is positively correlated with carotid-femoral P; the slope of the linear regression line linking these two parameters was steeper in women than in men (0.0199 ± 0.0045 vs. 0.0326 ± 0.0052 m/s per gram of salt, respectively, P < 0.05). However, after adjustment in the data of outliers, the association remained significant only in men (Baldo et al., 2019).

Calcium deposition in the aorta is another mechanism mediating the increase in arterial stiffness in hypertension (Guo et al., 2017). Interestingly, it was most pronounced in subjects who were resistant to anti-hypertensive therapy, suggesting that arterial stiffness not only contributes to isolated systolic hypertension development, but may also be involved in resistance to hypertension treatment (Mceniery et al., 2009).

Another important mechanism of aortic stiffness in hypertension is vascular smooth muscle stiffness (Sehgel et al., 2013, 2015a,b). Changes to the intrinsic stiffness of VSMCs and to their adhesion properties are observed in hypertension. Using atomic force microscopy and a reconstituted aortic tissue model, it was found that spontaneously hypertensive rats had increased aortic VSMC stiffness as well as different temporal oscillations in VSMC stiffness compared to normotensive control rats (Sehgel et al., 2013). In a later study in which VSMC stiffness and adhesions to the ECM were also found to be increased in hypertensive rats (Sehgel et al., 2015a), hypertension did not increase the amount of collagen in the thoracic aorta, suggesting that increased vascular stiffness associated with hypertension is likely not exclusively mediated by altered collagen and elastin content, but by increased VSMC stiffness and adhesion (Sehgel et al., 2015a). VSMC changes with aging are augmented when hypertension is superimposed on aging.

Atherosclerosis, which is more common with aging, is a chronic inflammatory disease in which atheromatous plaques form, resulting in arterial narrowing. Many studies, such as the Rotterdam study (Van Popele et al., 2001), show that stiffness of the aorta increases with plaque burden and conclude that arterial stiffness is strongly associated with atherosclerosis. However, these conclusions must be tempered by the fact that increased vascular stiffness is also a feature of aging in the absence of atherosclerosis (Sun, 2015). Atherosclerosis can occur at an earlier age in a condition known as Pediatric atherosclerosis (Wilson, 2000). Also, as discussed above the autosomal recessive premature aging disorder, Hutchison-Gilford Progeria syndrome, is characterized by precocious atherosclerosis and stiffening of the arteries, which cause early death in affected individuals (Keay et al., 1955). Consistent with the arterial stiffness found in these children, their carotid-femoral PWV is also markedly increased (Gerhard-Herman et al., 2012; Gordon et al., 2012). One way to address the question of mechanisms of atherosclerosis in a younger population is to examine atherosclerosis mechanisms in animal models that develop disease at a young age. Our laboratory has begun to study aortic stiffness in Watanabe rabbits, an animal model of atherosclerosis (Aliev and Burnstock, 1998). Our preliminary data suggest that aortic stiffness is increased even in relatively young Watanabe rabbits, as compared to aged-matched New Zealand White rabbit controls. In hypercholesterolemia Kurosawa and Kusanagi rabbits, PWV reflecting the atherosclerotic regions found that vascular stiffness was increased more in these regions and more in the abdominal vs. the thoracic aorta (Katsuda et al., 2014).

Many different mechanisms have been implicated in the stiffening of arteries associated with atherosclerosis. Hypercholesterolemia is most commonly implicated in the pathogenesis of atherosclerosis in humans and animal models, ranging from rodents to rabbits, pigs and monkeys (Linton et al., 2000; Getz and Reardon, 2012). Extracellular matrix proteins are also involved in the development of increased vascular stiffness in atherosclerosis. Elastin degradation is increased by the build-up of atheromatous plaques. Non-atherosclerotic arteries contain MMP-2 as well as inhibitors of MMP, such as TIMP 1 and 2 (Galis et al., 1994). In contrast, atheromatous plaques also contain macrophages that secrete MMP-1, MMP-9, and MMP-3, smooth muscle cells, lymphocytes, and endothelium (Galis et al., 1994). Based on SDS-PAGE zymography, plaques have been found to contain activated forms of MMP-2 and MMP-9 (Galis et al., 1994). In addition, patients with hypercholesterolemia exhibit more circulating CD31⁺/CD42^– microparticles, less endothelial progenitors (EPCs), and have stiffer aortae than controls. The ratio of CD31⁺/CD42^– microparticles to EPCs was found to be directly associated with arterial PWV (aPWV) (Pirro et al., 2006). This suggests that hypercholesterolemia contributes to large artery stiffness by increasing microparticle release and by reducing the number of circulating EPCs (Pirro et al., 2006). In addition, the extracellular matrix protein, fibrillin-1, has been found to modulate large-artery stiffness and pulse pressure (Medley et al., 2002).

Elevated oxidative stress also plays a role in increased arterial stiffening in patients with atherosclerosis. A study examining patients with peripheral arterial disease found an independent association of aPWV with serum levels of osteopontin and oxidized low-density lipoprotein, which are involved in oxidative stress, thus supporting the role for oxidative stress in mediating arterial stiffness in patients with atherosclerosis (Zagura et al., 2012).

Intimal arterial calcification within atherosclerotic plaques may also be responsible for increased vascular stiffness (Mackey et al., 2007). A study in the Twins United Kingdom population suggests that it is the propensity of plaques to calcify rather than the amount of plaque that determines arterial stiffness (Cecelja et al., 2013). Aortic stiffness was correlated with calcified plaques in the carotid and femoral arteries detected by ultrasound and with total aortic calcification measured by computed tomography (Cecelja et al., 2013).

Diabetes predisposes to cardiovascular disease and accelerated arterial stiffness. The magnitude of the effect of diabetes on central stiffness has been compared to the equivalent of 6–15 years of chronological aging on vessels (Cameron and Cruickshank, 2007; Loehr et al., 2016). It has been suggested that vascular stiffness in diabetic patients may be attributed more to the role of diabetes and metabolism, than to aging, per se (Cameron et al., 2003). One major metabolic mechanism is the non-enzymatic advanced glycation of proteins observed in diabetes. The accelerated production of advanced glycation end-products (AGEs) is implicated in diabetes-associated increasing stiffness. AGEs form in hyperglycemic environments, accumulate in the vessel wall, and form cross-links with collagen and elastin fibers, decreasing arterial wall distensibility (Goldin et al., 2006). The incidence of atherosclerosis is also increased in diabetic patients (Poznyak et al., 2020) and, thus, increased vascular stiffening due to accelerated atherosclerosis also contributes to the increase vascular stiffness in diabetic patients (Stehouwer et al., 2008; Prenner and Chirinos, 2015). Patients with type 2 diabetes also displayed endothelial dysfunction and a reduced contractile response to endothelin-1, suggesting these mechanisms factor into the development of vascular stiffness, due to the role of vasoconstriction in mediating vascular stiffness (Rizzoni et al., 2001). For example, endothelium-dependent dilation has shown to be abnormal in patients with type 2 diabetes attributed mainly to dyslipidemia (Schofield et al., 2002).

It has been shown that vascular stiffness increases as glucose tolerance deteriorates. Impaired glucose metabolism and type 2 diabetes (DM-2) are associated with decreased total systemic arterial compliance and increased aortic augmentation index, indicating increased central artery stiffness (Schram et al., 2004). Central artery stiffness is greater and carotid-femoral transit time is decreased in patients with DM-2 (Schram et al., 2004). It has also been shown that stiffness of the peripheral arteries increases with deteriorating glucose tolerance (Henry et al., 2003). Together, these studies suggest that stiffness due to impaired glucose metabolism and DM-2 are worse in peripheral than central arteries (Henry et al., 2003; Schram et al., 2004). Interestingly, in children with type 1 diabetes, especially males, stiffness of peripheral arteries is more common than of central arteries (Urbina et al., 2010).

As noted throughout this review, an important mechanism mediating increased vascular stiffness is increased oxidative stress (Giacco and Brownlee, 2010; Pasupuleti et al., 2020). It is well known that diabetes leads to increased oxidative stress, involving mitochondrial superoxide overproduction in the vasculature and in in the myocardium (Giacco and Brownlee, 2010; Pasupuleti et al., 2020). It is also recognized that increased intracellular reactive oxygen species cause defective angiogenesis in response to ischemia, and activate a number of proinflammatory pathways in diabetes and mediate the atherosclerosis and cardiomyopathy associated with diabetes (Giacco and Brownlee, 2010; Pasupuleti et al., 2020).

Even patients with prediabetes experience increased arterial stiffness. In one study, diabetes was associated with higher aortic PWV and prediabetes was associated with higher brachial-ankle PWV, a measure of composite stiffness (Loehr et al., 2016). Similarly, it has been shown that higher baPWV is associated with an increased risk of developing diabetes and that arterial stiffness may precede the increase in fasting blood glucose (Zheng et al., 2020). Arterial stiffness is also increased in patients with impaired fasting glucose but no other cardiovascular complications (Rerkpattanapipat et al., 2009). That study found that total vascular stiffness, but not thoracic aortic stiffness, is increased in patients with impaired fasting glucose compared to control subjects (Rerkpattanapipat et al., 2009).