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The endothelial glycocalyx is a dynamic, gel-like layer that is critical to normal vascular endothelial function. Heparin impairs the endothelial glycocalyx and reduces vascular endothelial function in a murine model; however, this has yet to be tested in healthy humans. We hypothesized that a single bolus dose of heparin would increase circulating glycocalyx components and decrease endothelial glycocalyx thickness resulting in blunted brachial artery vasodilation in healthy younger adults. Healthy adults (n = 19, aged 18-39 yr, 53% female) underwent measurements of the endothelial glycocalyx and vascular endothelial function at baseline and after a single bolus 5,000 U dose of heparin. The glycocalyx components syndecan-1 and heparan sulfate were measured from plasma samples using enzyme-linked immunosorbent assays. Glycocalyx thickness was determined as perfused boundary region (PBR) in sublingual microvessels using the GlycoCheck. Endothelial function was measured via ultrasonography and quantified as brachial artery flowmediated dilation (FMD). Following acute heparin administration, there was no increase in syndecan-1 or heparan sulfate (P = 0.90 and P = 0.49, respectively). In addition, there was no change in PBR 4-7 μm (P = 0.55), PBR 10-25 lm (P = 0.63), or 4-25 lm (P = 0.49) after heparin treatment. Furthermore, we did not observe a change in FMDmm (P = 0.23), FMD% (P = 0.35), or plasma nitrite concentrations (P = 0.10) in response to heparin. Finally, time to peak dilation and peak FMD normalized to shear stress were unchanged following heparin (P = 0.59 and P = 0.21, respectively). Our pilot study suggests that a single bolus intravenous dose of heparin does not result in endothelial glycocalyx degradation or vascular endothelial dysfunction in healthy younger adults. [ABSTRACT FROM AUTHOR]

Systemic inhibition of the mammalian target of rapamycin (mTOR) delays aging and many age‐related conditions including arterial and metabolic dysfunction. However, the mechanisms and tissues involved in these beneficial effects remain largely unknown. Here, we demonstrate that activation of S6K, a downstream target of mTOR, is increased in arteries with advancing age, and that this occurs preferentially in the endothelium compared with the vascular smooth muscle. Induced endothelial cell‐specific deletion of mTOR reduced protein expression by 60–70%. Although this did not significantly alter arterial and metabolic function in young mice, endothelial mTOR reduction reversed arterial stiffening and improved endothelium‐dependent dilation (EDD) in old mice, indicating an improvement in age‐related arterial dysfunction. Improvement in arterial function in old mice was concomitant with reductions in arterial cellular senescence, inflammation, and oxidative stress. The reduction in endothelial mTOR also improved glucose tolerance in old mice, and this was associated with attenuated hepatic gluconeogenesis and improved lipid tolerance, but was independent of alterations in peripheral insulin sensitivity, pancreatic beta cell function, or fasted plasma lipids in old mice. Lastly, we found that endothelial mTOR reduction suppressed gene expression of senescence and inflammatory markers in endothelial‐rich (i.e., lung) and metabolically active organs (i.e., liver and adipose tissue), which may have contributed to the improvement in metabolic function in old mice. This is the first evidence demonstrating that reducing endothelial mTOR in old age improves arterial and metabolic function. These findings have implications for future drug development. [ABSTRACT FROM AUTHOR]

The article presents a study which generated induced pluripotent stem cells-endothelial cell (iPSC-EC) from five systemic sclerosis (SSc) patients and five age- and sex-matched healthy controls at the Utah Regenerative Medicine Stem Cell Core. Topics discussed include importance of human ECS in research, observations that are of critical importance to SSc researchers, and the value of electric cell-substrate impedance sensing (ECIS) for evaluation of cell motion in SSc.

Donato A J, Uberoi A, Bailey DM, Wray DW, Richardson RS. Exercise-induced brachial artery vasodilation: effects of antioxidants and exercise training in elderly men. Am J Physiol Heart Circ Physiol 298: H671-H678, 2010. First published December 4, 2009; doi: 10.1152/ajpheart.00761.2009.--Aging, vascular function, and exercise are thought to have a common link in oxidative stress. Of the 28 subjects studied (young, 26 [+ or -] 2 yr; old, 71 [+ or -] 6 yr), 12 took part in a study to validate an antioxidant cocktail (AOC: vitamins C, E, and [alpha]-lipoic acid), while the remaining 8 young and 8 old subjects performed submaximal forearm handgrip exercise with placebo or AOC. Old subjects repeated forearm exercise with placebo or AOC following knee-extensor (KE) exercise training. Brachial arterial diameter and blood velocity (Doppler ultrasound) were measured at rest and during exercise. During handgrip exercise, brachial artery vasodilation in the old subjects was attenuated compared with that in young subjects following placebo (maximum = ~3.0 and ~6.0%, respectively). In contrast to the previously documented attenuation in exercise-induced brachial artery vasodilation in the young group with AOC, in the old subjects the AOC restored vasodilation (maximum = ~7.0%) to match the young. KE training also improved exerciseinduced brachial artery vasodilation. However, in the trained state, AOC administration no longer augmented brachial artery vasodilation in the elderly, but rather attenuated it. These data reveal an age-related pro-/antioxidant imbalance that impacts vascular function and show that exercise training is capable of restoring equilibrium such that vascular function is improved and the AOC-mediated reduction in free radicals now negatively impacts brachial artery vasodilation, as seen in the young. aging; free radicals; oxidative stress; arterial function doi: 10.1152/ajpheart.00761.2009

To determine whether impaired endothelium-dependent dilation (EDD) in older adults is associated with changes in the expression of major vasoconstrictor or vasodilator proteins in the vascular endothelium, endothelial cells (EC) were obtained from the brachial artery and peripheral veins of 56 healthy men, aged 18-78 yr. Brachial artery EC endothelin-1 (ET-1) [0.99 [+ or -] 0.10 vs. 0.57 [+ or -] 0.10 ET-1/human umbilical vein EC (HUVEC) intensity, P = 0.01] and serine 1177 phosphorylated endothelial nitric oxide synthase (PeNOS) (0.77 [+ or -] 0.09 vs. 0.44 [+ or -] 0.07 PeNOS/ HUVEC intensity, P < 0.05) (quantitative immunofluorescence) were greater, and EDD (peak forearm blood flow to intrabrachial acetylcholine) was lower (10.2 [+ or -] 0.9 vs. 14.7 [+ or -] 1.7 ml x 100 [ml.sup.-1] x [min.sup.-1], P < 0.05) in older (n = 18, 62 [+ or -] 1 yr) vs. young (n = 15, 21 [+ or -] 1 yr) healthy men. EDD was inversely related to expression of ET-1 (r = -0.39, P < 0.05). Brachial artery EC eNOS expression did not differ significantly with age, but tended to be greater in the older men (young: 0.23 [+ or -] 0.03 vs. older: 0.33 [+ or -] 0.07 eNOS/HUVEC intensity, P = 0.08). In the sample with venous EC collections, EDD (brachial artery flow-mediated dilation) was lower (3.50 [+ or -] 0.44 vs. 7.68 [+ or -] 0.43%, P < 0.001), EC ET-1 and PeNOS were greater (P < 0.05), and EC eNOS was not different in older (n = 23, 62 [+ or -] 1 yr) vs. young (n = 27, 22 [+ or -] 1 yr) men. EDD was inversely related to venous EC ET-1 (r = -0.37, P < 0.05). ET-1 receptor A inhibition with BQ-123 restored 60% of the age-related impairment in carotid artery dilation to acetylcholine in B6D2F1 mice (5-7 mo, n = 8; 30 mo, n = 11 ; P < 0.05). ET-1 expression is increased in vascular EC of healthy older men and is related to reduced EDD, whereas ET-1 receptor A signaling tonically suppresses EDD in old mice. Neither eNOS nor PeNOS is reduced with aging. Changes in ET-1 expression and bioactivity, but not eNOS, contribute to vascular endothelial dysfunction with aging. endothelium-dependent dilation; brachial artery flow-mediated dilation

To determine if B6D2F1 mice represent a suitable model of oxidative stress--mediated impaired endothelium-dependent dilation (EDD) with aging, mice were studied at 6.9 [+ or -] 0.3 and 31.9 [+ or -] 0.6 months. EDD to acetylcholine (ACh) was 26% (p < .001) and 12% (p < .001) lower, respectively, in isolated carotid (n = 10-11) and femoral (n = 10) arteries from older mice, and reductions in arterial pressure to systemic ACh infusion were smaller in older mice (n = 6-10; p < .01). Nitrotyrosine was marked in aorta of older mice (p < .05, n = 4). Superoxide production in carotid arteries was greater (p < .05), and TEMPOL restored dilation in carotid arteries and systemically in older mice. [N.sup.G]-nitro-L-arginine methyl ester (L-NAME) reduced carotid artery dilation in young more than older mice, whereas TEMPOL restored the effects of L-NAME in older mice. Carotid artery stiffness was increased in older compared with young mice (p = .04). Our results provide the first comprehensive evidence that B6D2F1 mice are a useful model for investigating mechanisms of reduced nitric oxide--dependent, oxidative stress--associated EDD and increased arterial stiffness with aging. Key Words: Superoxide--Arterial stiffness--Carotid artery--Femoral artery--Nitrotyrosine.