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The circulating milieu, bioactive molecules in the bloodstream, is altered with aging and interfaces constantly with the vasculature. This anatomic juxtaposition suggests that circulating factors may actively modulate arterial function. Here, we developed a novel, translational experimental model that allows for direct interrogation of the influence of the circulating milieu on age-related arterial dysfunction (aortic stiffening and endothelial dysfunction). To do so, we exposed young and old mouse arteries to serum from young and old mice and young and midlife/older (ML/O) adult humans. We found that old mouse and ML/O adult human, but not young, serum stiffened young mouse aortic rings, assessed via elastic modulus (mouse and human serum, P = 0.003 vs. young serum control), and impaired carotid artery endothelial function, assessed by endothelium-dependent dilation (EDD) (mouse serum, P < 0.001; human serum, P = 0.006 vs. young serum control). Furthermore, young mouse and human, but not old, serum reduced aortic elastic modulus (mouse serum, P = 0.009; human serum, P < 0.001 vs. old/MLO serum control) and improved EDD (mouse and human serum, P = 0.015 vs. old/MLO serum control) in old arteries. In human serum-exposed arteries, in vivo arterial function assessed in the human donors correlated with circulating milieu-modulated arterial function in young mouse arteries (aortic stiffness, r = 0.634, P = 0.005; endothelial function, r = 0.609, P = 0.004) and old mouse arteries (aortic stiffness, r = 0.664, P = 0.001; endothelial function, r = 0.637, P = 0.003). This study establishes novel experimental approaches for directly assessing the effects of the circulating milieu on arterial function and implicates changes in the circulating milieu as a mechanism of in vivo arterial aging. NEW & NOTEWORTHY Changes in the circulating milieu with advancing age may be a mechanism underlying age-related arterial dysfunction. Ex vivo exposure of young mouse arteries to the circulating milieu from old mice or midlife/older adults impairs arterial function whereas exposure of old mouse arteries to the circulating milieu from young mice or young adults improves arterial function. These findings establish that the circulating milieu directly influences arterial function with aging. [ABSTRACT FROM AUTHOR]

Despite data showing that estrogen is vasculoprotective in large conduit arteries, hormone therapy (HT) during menopause has not proven to mitigate cardiovascular disease (CVD) risk. Estrogen exposure through prolonged oral contraceptive use and gender-affirming therapy can also increase cis- and trans-females' risk for future CVD, respectively. The microvasculature is a unique vascular bed that when dysfunctional can independently predict future adverse cardiac events; however, studies on the influence of estrogen on human microvessels are limited. Here, we show that isolated human arterioles from females across the life span maintain nitric oxide (NO)-mediated dilation to flow, whereas chronic (16-20 h) exposure to exogenous (100 nM) 17β-estradiol promotes microvascular endothelial dysfunction in vessels from adult females of <40 and ≥40 yr of age. The damaging effect of estrogen was more dramatic in arterioles from biological males, as they exhibited both endothelial and smooth muscle dysfunction. Furthermore, females of <40 yr have greater endothelial expression of estrogen receptor-β (ER-β) and G protein-coupled estrogen receptor (GPER) compared with females of ≥40 yr and males. Estrogen receptor-α (ER-α), the prominent receptor associated with protective effects of estrogen, was identified within the adventitia as opposed to the endothelium across all groups. To our knowledge, this is the first study to report the detrimental effects of estrogen on the human microvasculature and highlights differences in estrogen receptor expression. [ABSTRACT FROM AUTHOR]

Intensive glycemic regulation has resulted in an increased incidence of hypoglycemia. Hypoglycemic burden correlates with adverse cardiovascular complications and contributes acutely and chronically to endothelial dysfunction. Prior data indicate that mitochondrial dysfunction contributes to hypoglycemia-induced endothelial dysfunction, but the mechanisms behind this linkage remain unknown. We attempt to determine whether clinically relevant lowglucose (LG) exposures acutely induce endothelial dysfunction through activation of the mitochondrial fission process. Characterization of mitochondrial morphology was carried out in cultured endothelial cells by using confocal microscopy. Isolated human arterioles were used to explore the effect LG-induced mitochondrial fission has on the formation of detrimental reactive oxygen species (ROS), bioavailability of nitric oxide (NO), and endothelial-dependent vascular relaxation. Fluorescence microscopy was employed to visualize changes in mitochondrial ROS and NO levels and videomicroscopy applied to measure vasodilation response. Pharmacological disruption of the profission protein Drp1 with Mdivi-1 during LG exposure reduced mitochondrial fragmentation among vascular endothelial cells (LG: 0.469; LGMdivi-1: 0.276; P = 0.003), prevented formation of vascular ROS (LG: 2.036; LGMdivi-1: 1.774; P = 0.005), increased the presence of NO (LG: 1.352; LG+Mdivi-1: 1.502; P = 0.048), and improved vascular dilation response to acetylcholine (LG: 31.6%; LG+Mdivi-1; 78.5% at maximum dose; P < 0.001). Additionally, decreased expression of Drp1 via siRNA knockdown during LG conditions also improved vascular relaxation. Exposure to LG imparts endothelial dysfunction coupled with altered mitochondrial phenotypes among isolated human arterioles. Disruption of Drp1 and subsequent mitochondrial fragmentation events prevents impaired vascular dilation, restores mitochondrial phenotype, and implicates mitochondrial fission as a primary mediator of LG-induced endothelial dysfunction. [ABSTRACT FROM AUTHOR]

Inreased intraluminal pressure can reduce endothelial function in resistance arterioles; however, the mechanism of this impairment is unknown. The purpose of this study was to determine the effect of local renin-angiotensin system inhibition on the pressure-induced blunting of endothelium-dependent vasodilation in human adipose arterioles. Arterioles (100-200 μm) were dissected from fresh adipose surgical specimens, cannulated onto glass micropipettes, pressurized to an intraluminal pressure of 60 mmHg, and constricted with endothelin-1. Vasodilation to ACh was assessed at 60 mmHg and again after a 30-min exposure to an intraluminal pressure of 150 mmHg. The vasodilator response to ACh was significantly reduced in vessels exposed to 150 mmHg. Exposure of the vessels to the superoxide scavenger polyethylene glycol-SOD (100 U/ml), the ANG II type 1 receptor antagonist losartan (10-6 mol/l), or the angiotensin-converting enzyme inhibitor captopril (10-5 mol/l) prevented the pressureinduced reduction in ACh-dependent vasodilation observed in untreated vessels. High intraluminal pressure had no effect on papaverine- induced vasodilation or ANG II sensitivity. Increased intraluminal pressure increased dihydroethidium fluorescence in cannulated vessels, which could be prevented by polyethylene glycol-SOD or losartan treatment and endothelial denudation. These data indicate that high intraluminal pressure can increase vascular superoxide and reduce nitric oxide-mediated vasodilation via activation of the vascular renin-angiotensin system. This study provides evidence showing that the local renin-angiotensin system in the human microvasculature may be pressure sensitive and contribute to endothelial dysfunction after acute bouts of hypertension. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction is now considered an important early event in the development of atherosclerosis, which precedes gross morphological signs and clinical symptoms. The assessment of flow-mediated dilation (FMD) was introduced almost 20 years ago as a noninvasive approach to examine vasodilator function in vivo. FMD is widely believed to reflect endothelium-dependent and largely nitric oxide-mediated arterial function and has been used as a surrogate marker of vascular health. This noninvasive technique has been used to compare groups of subjects and to evaluate the impact of interventions within individuals. Despite its widespread adoption, there is considerable variability between studies with respect to the protocols applied, methods of analysis, and interpretation of results. Moreover, differences in methodological approaches have important impacts on the response magnitude, can result in spurious data interpretation, and limit the comparability of outcomes between studies. This review results from a collegial discussion between physiologists with the purpose of developing considered guidelines. The contributors represent several distinct research groups that have independently worked to advance the evidence base for improvement of the technical approaches to FMD measurement and analysis. The outcome is a series of recommendations on the basis of review and critical appraisal of recent physiological studies, pertaining to the most appropriate methods to assess FMD in humans. [ABSTRACT FROM AUTHOR]

The author reflects on the risks of sedenterism or habitual physical inactivity in the U.S. He says that much of the risk of sedenterim has been ascribed to the onset of obesity, which is a well known risk factor for the development of insulin resistance and has been connected to endothelial dysfunction. He mentions the studies which used model protocols that impose strict, acute bed rest on healthy people to find out the sedenterism's hemodynamic, metabolic, and vascular effects.

The article presents the author's view concerning shear stress and flow-mediated dilation (FMD). It mentions that since the introduction of brachial artery reactivity testing, the measurement of endothelial function with the use of ultrasonography has proven to be an effective research tool for the assessment of cardiovascular risk while measurement of FMD in the brachial artery future risk remains low. It states that the lack of specificity is credited to the technical limitations of the FMD.