Cardiovascular disease (CVD) is the leading cause of death in the United States and aging is a major risk factor for CVD development. One of the major age-related arterial phenotypes thought to be responsible for the development of CVD in older adults is endothelial dysfunction. Endothelial function is modulated by traditional CVD risk factors in young adults, but advancing age is independently associated with the development of vascular endothelial dysfunction. This endothelial dysfunction results from a reduction in nitric oxide bioavailability downstream of endothelial oxidative stress and inflammation that can be further modulated by traditional CVD risk factors in older adults. Greater endothelial oxidative stress with aging is a result of augmented production from the intracellular enzymes NADPH oxidase and uncoupled eNOS, as well as from mitochondrial respiration in the absence of appropriate increases in antioxidant defenses as regulated by relevant transcription factors, such as FOXO. Interestingly, it appears that NFkB, a critical inflammatory transcription factor, is sensitive to this age-related endothelial redox change and its activation induces transcription of pro-inflammatory cytokines that can further suppress endothelial function, thus creating a vicious feed-forward cycle. This review will discuss the two macro-mechanistic processes, oxidative stress and inflammation, that contribute to endothelial dysfunction with advancing age as well as the cellular and molecular events that lead to the vicious cycle of inflammation and oxidative stress in the aged endothelium. Other potential mediators of this pro-inflammatory endothelial phenotype are increases in immune or senescent cells in the vasculature. Of note, genomic instability, telomere dysfunction or DNA damage have been shown to trigger cell senescence via the p53/p21 pathway that results in increased inflammatory signaling in arteries from older adults. This review will discuss the current state of knowledge regarding the emerging concepts of senescence and genomic instability as mechanisms underlying oxidative stress and inflammation in the aged endothelium. Lastly, energy sensitive/stress resistance pathways (SIRT-1, AMPK, mTOR) are altered in endothelial cells and/or arteries with aging and these pathways may modulate endothelial function via key oxidative stress and inflammation-related transcription factors. This review will also discuss what is known about the role of “energy sensing” longevity pathways in modulating endothelial function with advancing age. With the growing population of older adults, elucidating the cellular and molecular mechanisms of endothelial dysfunction with age is critical to establishing appropriate and measured strategies to utilize pharmacological and lifestyle interventions aimed at alleviating CVD risk.

Brachial artery flow-mediated dilation (FMD) is impaired with aging and is associated with increased risk for cardiovascular disease (CVD). We determined if regular aerobic exercise improves brachial artery FMD in middle-aged/older (MA/O) men and postmenopausal women. In sedentary MA/O adults (age 55 – 79 years) without CVD, 8 weeks of brisk walking (6 days/week for ~50 min/day; randomized, controlled design) increased treadmill time ~20% in both MA/O men (n=11) and postmenopausal women (n=15) (P<0.01), without altering body composition or circulating CVD risk factors. Brachial artery FMD increased > 50% in the MA/O men (4.6 ± 0.6 to 7.1 ± 0.6%, P < 0.01), but did not change in the postmenopausal women (5.1 ± 0.8 vs. 5.4 ± 0.7%, P = 0.50). No changes occurred in the non-exercising controls. In a separate cross-sectional study (n =167), brachial artery FMD was ~50% greater in endurance exercise-trained (6.4 ± 0.4%, n = 45) vs. sedentary (4.3 ± 0.3%, n = 60) MA/O men (P < 0.001), whereas there were no differences between endurance-trained (5.3 ± 0.7%, n = 20) and sedentary (5.6 ± 0.5%, n = 42) postmenopausal women (P = 0.70). Brachial artery lumen diameter, peak hyperemic shear rate and endothelium independent dilation did not differ with exercise intervention or in the endurance-exercise vs. sedentary groups. Regular aerobic exercise is consistently associated with enhanced brachial artery FMD in MA/O men, but not in postmenopausal women. Some postmenopausal women without CVD may be less responsive to habitual aerobic exercise than MA/O men.

Abstract-We tested the hypothesis that vascular endothelial function, assessed by endothelium-dependent dilation, is related to serum vitamin D status among middle-aged and older adults without clinical disease, and that this is linked to inflammation. Brachial artery flow-mediated dilation, a measure of endothelium-dependent dilation, was lower (PϽ0. Key Words: aging Ⅲ endothelium-dependent dilation Ⅲ NFB Ⅲ interleukin-6 Ⅲ 1-␣ hydroxylase Ⅲ VDR C ardiovascular diseases (CVDs) remain the leading cause of death in modern societies, and advancing age is the major risk factor for CVD. [1][2][3] The increase in CVD risk with aging is attributable in large part to the development of vascular endothelial dysfunction, most commonly assessed as impaired endothelium-dependent dilation. 2,4,5 Consistent with this, middle-aged and older adults demonstrate reduced brachial artery flow-mediated dilation (FMD), a measure of endothelium-dependent dilation, 6 compared with young adults. 7 However, there is considerable variability in brachial artery FMD among middle-aged/older adults, and the contributing factors to impaired brachial FMD in this at-risk group are incompletely understood.Vitamin D deficiency is an independent predictor of CVD and all-cause mortality. 8 -10 Patients with chronic clinical diseases who are vitamin D deficient and young adults with severe vitamin D deficiency demonstrate impaired brachial artery FMD. [11][12][13] The physiological mechanisms by which vitamin D deficiency is linked to brachial artery FMD in these settings have not been established but may involve vascular inflammation. In humans, vitamin D deficiency is associated with increased circulating inflammatory proteins, 10,14,15 whereas in cultured vascular endothelial cells, vitamin D inhibits activation of the proinflammatory transcription factor nuclear factor B (NFB), 16 as well as the release of the inflammatory cytokine interleukin-6 (IL-6), 17 a downstream target of NFB activation. However, it is unknown whether vitamin D deficiency is associated with impaired brachial artery FMD among middle-aged/older adults without CVD and, if so, whether this is related to vascular inflammation.In the present study, we tested the hypothesis that brachial artery FMD is inversely related to vitamin D status (as reflected by serum concentrations of 25-hydroxyvitamin D