Aged Vessels Research Articles

Upregulation of Orai Channels Contributes to Aging-Related Vascular Alterations in Rat Coronary Arteries.

Vascular territories display heterogeneous sensitivity to the impacts of aging. The relevance of the STIM/Orai system to vascular function depends on the vascular bed. We aimed to evaluate the contribution of the STIM/Orai system to aging-related vascular dysfunction in rat coronary circulation. Vascular function was evaluated according to myography in coronary arteries from young (three-month-old) and older (twenty-month-old) rats. The effects of aging and STIM/Orai inhibition on the contraction and relaxation of the coronary arteries and on the protein expression of STIM-1, Orai1, and Orai3 in these vessels were determined. Aging-related hypercontractility to serotonin and endothelin-1 in arteries from male rats was reversed by STIM/Orai inhibition with YM-58483 or by specifically blocking the Orai1 channel with Synta66. The inhibitory effects of Synta66 on coronary vasoconstriction were also observed in older female rats. YM-58483 relaxed serotonin- but not KCl-contracted arteries from males. STIM/Orai inhibition improved defective endothelial vasodilations in aged arteries, even in the presence of NO synthase and cyclooxygenase inhibitors, but not in KCl-contracted segments. YM-58483 significantly enhanced relaxations to calcium-activated potassium channel stimulation in aged vessels. Increased protein expression of Orai1 and Orai3 was detected in arterial homogenates and sections from older rats. Upregulation of the Orai channel contributes to aging-related coronary dysfunction, revealing a potential target in reducing CVD risk.

Nicotinamide mononucleotide inhibits oxidative stress-induced damage in a SIRT1/NQO-1-dependent manner

Oxidative stress causes endothelial dysfunction, which is associated with vascular cellular aging and is causally related to cardiovascular disease pathogenesis. Preclinical studies indicate that a nicotinamide adenine dinucleotide (NAD+) precursor, nicotinamide mononucleotide (NMN), alleviates oxidative stress in aged vessels, granting vasoprotective effects. However, the associated cellular mechanism remains largely unclear. In this study, we used human umbilical vein endothelial cells (HUVECs) to demonstrate that NMN inhibits oxidative stress-induced damage by activating the sirtuin 1 (SIRT1)/NAD(P)H: quinone oxidoreductase 1 (NQO-1) axis. We found that NMN inhibited H2O2-induced cytotoxicity and senescence-associated protein expression, such as p16 and p21. Furthermore, NMN prevented H2O2-induced actin cytoskeletal disorganization via inhibiting reactive oxygen species (ROS) production. NMN increased NQO-1 mRNA and protein expression that in turn was abrogated by SIRT1 inhibition, suggesting that NMN-inducible NQO-1 was associated with SIRT1 activity. SIRT1 and NQO-1 inhibition attenuated the inhibitory effect of NMN on H2O2-inducible cytotoxicity, senescence-related protein upregulation, and actin cytoskeletal disorganization. Our findings provide new insights into the mechanism by which NMN exerts protective effects against vascular oxidative stress.

Age-Associated Dysregulation of Integrin Function in Vascular Smooth Muscle.

Arterial aging results in a progressive reduction in elasticity of the vessel wall and an impaired ability of aged blood vessels to control local blood flow and pressure. Recently, a new concept has emerged that the stiffness and decreased contractility of vascular smooth muscle (VSM) cells are important contributors to age-induced arterial dysfunction. This study investigated the hypothesis that aging alters integrin function in a matrix stiffness-dependent manner, which contributes to decreased VSM contractility in aged soleus muscle feed arteries (SFA). The effect of RGD-binding integrins on contractile function of cannulated SFA isolated from young (4 months) and old (24 months) Fischer 344 rats was assessed by measuring constrictor responses to norepinephrine, phenylephrine, and angiotensin II. Results indicated that constrictor responses in presence of RGD were impaired in old compared to young SFA. VSM cells isolated from young and old SFA were used for functional experiments using atomic force microscopy and high-resolution imaging. Aging was associated with a modulation of integrin β1 recruitment at cell-matrix adhesions that was matrix and substrate stiffness dependent. Our data showed that substrate stiffening drives altered integrin β1 expression in aging, while soft substrates abolish age-induced differences in overall integrin β1 expression. In addition, substrate stiffness and matrix composition contribute to the modulation of SMα-actin cytoskeleton architecture with soft substrates reducing age effects. Our results provide new insights into age-induced structural changes at VSM cell level that translates to decreased functionality of aged resistance soleus feed arteries.

어업여건 변화에 대비한 근해어업의 에너지 효율성 평가

This study evaluates the energy efficiency of offshore fisheries by year and gear in preparation for changes in fishery circumstances such as CPTPP and 2050 Carbon neutral roadmap, and provides policy implications based on the results. Accordingly, this study compares estimated technical efficiency using SFA with the energy intensity of offshore fisheries. As a result of the analysis, firstly, it shows that the energy efficiency of offshore fisheries by year is decreasing. Secondly, among gears in the offshore fishery, the energy efficiency of the fleet and the drag net fisheries whose have a large supply of tax-free petroleum is evaluated differently depending on the indicator, so the four indicators need to be complementarily used. Thirdly, it shows that there is a weakly positive correlation between the vessel-age and the energy intensity. Therefore, to improve the energy efficiency of offshore fisheries, it is necessary to shorten the calculation cycle of tax-free petroleum supply limit and reduce the number of fishing vessels in the fleet. In addition, it is necessary to not only promote the development of fuel-saving fishing implements for drag net fisheries, also replace electric hybrid fishing vessels for aged fishing vessels.

Senescence in Vascular Smooth Muscle Cells and Atherosclerosis.

Vascular smooth muscle cells (VSMCs) are the primary cell type involved in the atherosclerosis process; senescent VSMCs are observed in both aged vessels and atherosclerotic plaques. Factors associated with the atherosclerotic process, including oxidative stress, inflammation, and calcium-regulating factors, are closely linked to senescence in VSMCs. A number of experimental studies using traditional cellular aging markers have suggested that anti-aging biochemical agents could be used to treat atherosclerosis. However, doubt has recently been cast on such potential due to the increasingly apparent complexity of VSMCs status and an incomplete understanding of the role that these cells play in the atherosclerosis process, as well as a lack of specific or spectrum-limited cellular aging markers. The utility of anti-aging drugs in atherosclerosis treatment should be reevaluated. Promotion of a healthy lifestyle, exploring in depth the characteristics of each cell type associated with atherosclerosis, including VSMCs, and development of targeted drug delivery systems will ensure efficacy whilst evaluation of the safety and tolerability of drug use should be key aims of future anti-atherosclerosis research. This review summarizes the characteristics of VSMC senescence during the atherosclerosis process, the factors regulating this process, as well as an overview of progress toward the development and application of anti-aging drugs.

Stressor-Induced "Inflammaging" of Vascular Smooth Muscle Cells via Nlrp3-Mediated Pro-inflammatory Auto-Loop.

Calcification of the vessel wall as one structural pathology of aged vessels is associated with high cardiovascular mortality of elderly patients. Aging is linked to chronic sterile inflammation and high burden of reactive oxygen species (ROS), leading to activation of pattern recognition receptors (PRRs) such as Nlrp3 in vascular cells. The current study investigates the role of PRR activation in the calcification of vascular smooth muscle cells (VSMCs). Therefore, in vitro cell culture of primary rat VSMCs and ex vivo aortic stimulations were used to analyze osteogenic, senescence and inflammatory markers via real-time PCR, in situ RNA hybridization, Western Blot, photometric assays and histological staining. Induction of ROS and DNA-damage by doxorubicin induces a shift of VSMC phenotype toward the expression of osteogenic, senescence and inflammatory proteins. Induction of calcification is dependent on Nlrp3 activity. Il-1β as a downstream target of Nlrp3 induces the synthetic, pro-calcifying VSMC phenotype. Inhibition of PRR with subsequent reduction of chronic inflammation might be an interesting target for reduction of calcification of VSMCs, with subsequent reduction of cardiovascular mortality of patients suffering from vessel stiffness.

Deletion of type VIII collagen reduces blood pressure, increases carotid artery functional distensibility and promotes elastin deposition

Arterial stiffening is a significant predictor of cardiovascular disease development and mortality. In elastic arteries, stiffening refers to the loss and fragmentation of elastic fibers, with a progressive increase in collagen fibers. Type VIII collagen (Col-8) is highly expressed developmentally, and then once again dramatically upregulated in aged and diseased vessels characterized by arterial stiffening. Yet its biophysical impact on the vessel wall remains unknown. The purpose of this study was to test the hypothesis that Col-8 functions as a matrix scaffold to maintain vessel integrity during extracellular matrix (ECM) development. These changes are predicted to persist into the adult vasculature, and we have tested this in our investigation. Through our in vivo and in vitro studies, we have determined a novel interaction between Col-8 and elastin. Mice deficient in Col-8 (Col8−/−) had reduced baseline blood pressure and increased arterial compliance, indicating an enhanced Windkessel effect in conducting arteries. Differences in both the ECM composition and VSMC activity resulted in Col8−/− carotid arteries that displayed increased crosslinked elastin and functional distensibility, but enhanced catecholamine-induced VSMC contractility. In vitro studies revealed that the absence of Col-8 dramatically increased tropoelastin mRNA and elastic fiber deposition in the ECM, which was decreased with exogenous Col-8 treatment. These findings suggest a causative role for Col-8 in reducing mRNA levels of tropoelastin and the presence of elastic fibers in the matrix. Moreover, we also found that Col-8 and elastin have opposing effects on VSMC phenotype, the former promoting a synthetic phenotype, whereas the latter confers quiescence. These studies further our understanding of Col-8 function and open a promising new area of investigation related to elastin biology.

Damage detection of composite overwrapped pressure vessels using ARX models

After the Columbia accident, aged composite overwrapped pressure vessels (COPVs) employed for space missions are being subjected to various examination and monitoring techniques to identify different failure modes. As an innovative approach, this paper explores the capability of Auto-Regressive model with eXogenous input (ARX) model analysis method to detect damages/flaws in COPVs utilizing the pressure as the input and the corresponding strains as the response data. Different levels of pressure were applied to the instrumented COPVs; both pressure and strains were simultaneously recorded, and later were analyzed to detect anomalies. Also investigated is the possibility of obtaining indices/features related to the performance of COPVs. It was discovered that varying strain measurements were recorded of damage induced COPVs while consistent strain measurements were recorded of intact COPVs. Furthermore, a Damage Feature (DF) was identified to compare the existing conditions of COPVs. A deviation of the DF values from an established threshold level was apparent for damage-induced COPVs while other COPVs were below the threshold level.

Endothelin B receptor dysfunction mediates elevated myogenic tone in cerebral arteries from aged male Fischer 344 rats

The human brain requires adequate cerebral blood flow to meet the high demand for nutrients and to clear waste products. With age, there is a chronic reduction in cerebral blood flow in small resistance arteries that can eventually limit proper brain function. The endothelin system is a key mediator in the regulation of cerebral blood flow, but the contributions of its constituent receptors in the endothelial and vascular smooth muscle layers of cerebral arteries have not been well defined in the context of aging. We isolated posterior cerebral arteries from young and aged Fischer 344 rats, as well as ETB receptor knock-out rats and mounted the vessels in plexiglass pressure myograph chambers to measure myogenic tone in response to increasing pressure and targeted pharmacological treatments. We used an ETA receptor antagonist (BQ-123), an ETB receptor antagonist (BQ-788), endothelin-1, an endothelin-1 synthesis inhibitor (phosphoramidon), and vessel denudation to dissect the roles of each receptor in aging vasculature. Aged rats exhibited a higher myogenic tone than young rats, and the tone was sensitive to the ETA antagonist, BQ-123, but insensitive to the ETB antagonist, BQ-788. By contrast, the tone in the vessels from young rats was raised by BQ-788 but unaffected by BQ-123. When the endothelial layer that is normally enriched with ETB1 receptors was removed from young vessels, myogenic tone increased. However, denudation of the endothelial layer did not influence vessels from aged animals. This indicated that endothelial ETB1 receptors were not functional in the vessels from aged rats. There was also an increase in ETA receptor expression with age, whereas ETB receptor expression remained constant between young and aged animals. These results demonstrate that in young vessels, ETB1 receptors maintain a lower myogenic tone, but in aged vessels, a loss of ETB receptor activity allows ETA receptors in vascular smooth muscle cells to raise myogenic tone. Our findings have potentially important clinical implications for treatments to improve cerebral perfusion in older adults with diseases characterized by reduced cerebral blood flow.

Aging Impairs Mitochondrial Function and Mitophagy and Elevates Interleukin 6 Within the Cerebral Vasculature.

BackgroundThe blood‐brain barrier (BBB) is critical for cerebrovascular health. Although aging impairs the integrity of the BBB, the mechanisms behind this phenomenon are not clear. As mitochondrial components activate inflammation as mitochondria become dysfunctional, we examined how aging impacts cerebrovascular mitochondrial function, mitophagy, and inflammatory signaling; and whether any alterations correlate with BBB function.Methods and ResultsWe isolated cerebral vessels from young (2–3 months of age) and aged (18–19 months of age) mice and found that aging led to increases in the cyclin‐dependent kinase inhibitor 1 senescence marker with impaired mitochondrial function, which correlated with aged mice exhibiting increased BBB leak compared with young mice. Cerebral vessels also exhibited increased expression of mitophagy proteins Parkin and Nix with aging. Using mitophagy reporter (mtKeima) mice, we found that the capacity to increase mitophagy from baseline within the cerebral vessels on rotenone treatment was reduced with aging. Aging within the cerebral vessels also led to the upregulation of the stimulator of interferon genes and increased interleukin 6 (IL‐6), a cytokine that alters mitochondrial function. Importantly, exogenous IL‐6 treatment of young cerebral vessels upregulated mitophagy and Parkin and impaired mitochondrial function; whereas inhibiting IL‐6 in aged cerebral vessels reduced Parkin expression and increased mitochondrial function. Furthermore, treating cerebral vessels of young mice with mitochondrial N‐formyl peptides upregulated IL‐6, increased Parkin, and reduced Claudin‐5, a tight junction protein integral to BBB integrity.ConclusionsAging alters the cerebral vasculature to impair mitochondrial function and mitophagy and increase IL‐6 levels. These alterations may impair BBB integrity and potentially reduce cerebrovascular health with aging.

ASK1 Mediates Apoptosis and Autophagy during oxLDL-CD36 Signaling in Senescent Endothelial Cells.

Vessel damage by oxidized low-density lipoprotein (oxLDL) increases reactive oxygen species (ROS) and the membrane receptor cluster of differentiation 36 (CD36), involving various vascular pathological processes. In this study, the role of apoptosis signal-regulating kinase 1 (ASK1) as a cellular effector via the oxLDL-CD36 signaling axis, and its related mechanism as a downstream responder of CD36, was investigated in senescent human aortic endothelial cells (HAECs). To inhibit oxLDL-triggered vascular damage, HAECs and monocytes were treated with the CD36-neutralizing antibody or the ASK1 inhibitor NQDI-1. The oxLDL-triggered increases in ROS and CD36 elevated active ASK1 in the senescent HAECs. The ROS increase induced apoptosis, whereas CD36 neutralization or ASK1 inhibition protected against cell death. The blocking of CD36 increased senescent HAEC autophagy. In monocytes, oxLDL also induced CD36 expression and autophagy, the latter of which still occurred following ASK1 inhibition but not after CD36 neutralization. These findings suggest that oxLDL exposure activates ASK1, as a CD36 downstream responder, to accelerate apoptosis, particularly in senescent HAECs. ASK1's involvement in monocytic autophagy was due to endoplasmic reticulum stress resulting from the oxLDL load, suggesting that oxLDL loading on aged vessels causes atherosclerotic endothelial dysfunction mediated by active ASK1.

MFG-E8 mediates arterial aging by promoting the proinflammatory phenotype of vascular smooth muscle cells

BackgroundAmong older adults, arterial aging is the major factor contributing to increased risk for cardiovascular disease–related morbidity and mortality. The chronic vascular inflammation that accompanies aging causes diffuse intimal–medial thickening of the arterial wall, thus increasing the vulnerability of aged vessels to vascular insults. Milk fat globule–epidermal growth factor 8 (MFG-E8) is a biomarker for aging arteries. This integrin-binding glycoprotein, induced by angiotensin II, facilitates vascular smooth muscle cell (VSMC) proliferation and invasion in aging vasculatures. This study investigated whether MFG-E8 directly mediates the initial inflammatory responses in aged arteries or VSMCs.MethodsA model of neointimal hyperplasia was induced in the common carotid artery (CCA) of aged mice to exacerbate age-associated vascular remodeling. Recombinant MFG-E8 (rMFG-E8) was administered to the injured artery using Pluronic gel to accentuate the effect on age-related vascular pathophysiology. The MFG-E8 level, leukocyte infiltration, and proinflammatory cell adhesion molecule (CAM) expression in the arterial wall were evaluated through immunohistochemistry. By using immunofluorescence and immunoblotting, the activation of the critical proinflammatory transcription factor nuclear factor (NF)-κB in the injured CCAs was analyzed. Immunofluorescence, immunoblotting, and quantitative real-time polymerase chain reaction were conducted using VSMCs isolated from the aortas of young and aged mice to assess NF-κB nuclear translocation, NF-κB-dependent gene expression, and cell proliferation. The extent of intimal–medial thickening in the injured vessels was analyzed morphometrically. Finally, Transwell migration assay was used to examine VSMC migration.ResultsEndogenous MFG-E8 expression in aged CCAs was significantly induced by ligation injury. Aged CCAs treated with rMFG-E8 exhibited increased leukocyte extravasation, CAM expression, and considerably increased NF-κB activation induced by rMFG-E8 in the ligated vessels. Exposure of early passage VSMCs from aged aortas to rMFG-E8 substantially increased NF-κB activation, proinflammatory gene expression, and cell proliferation. However, rMFG-E8 attenuated VSMC migration.ConclusionsMFG-E8 promoted the proinflammatory phenotypic shift of aged VSMCs and arteries, rendering the vasculature prone to vascular diseases. MFG-E8 may constitute a novel therapeutic target for retarding the aging processes in such vessels.

Pathophysiology of aged lymphatic vessels.

Lymphatic vessels maintain body homeostasis by recirculation of fluid and cells. Cell senescence induces lymphatic dysfunction. Impaired contractile function is caused by low muscle cell investiture and decrease of nitric oxide in aged lymphatic collectors, leading to poor drainage of lymph. Aging-induced loss of endothelial glycocalyx and production of inflammatory cytokines increases permeability of lymphatic vessels. In addition, aging-associated basal activation of mast cells delays immune response. In this review, we summarize the structural and pathological changes of aged lymphatic vessels, and discuss the underlying molecular mechanisms.

Nicotinamide mononucleotide (NMN) supplementation promotes anti-aging miRNA expression profile in the aorta of aged mice, predicting epigenetic rejuvenation and anti-atherogenic effects.

Understanding molecular mechanisms involved in vascular aging is essential to develop novel interventional strategies for treatment and prevention of age-related vascular pathologies. Recent studies provide critical evidence that vascular aging is characterized by NAD+ depletion. Importantly, in aged mice, restoration of cellular NAD+ levels by treatment with the NAD+ booster nicotinamide mononucleotide (NMN) exerts significant vasoprotective effects, improving endothelium-dependent vasodilation, attenuating oxidative stress, and rescuing age-related changes in gene expression. Strong experimental evidence shows that dysregulation of microRNAs (miRNAs) has a role in vascular aging. The present study was designed to test the hypothesis that age-related NAD+ depletion is causally linked to dysregulation of vascular miRNA expression. A corollary hypothesis is that functional vascular rejuvenation in NMN-treated aged mice is also associated with restoration of a youthful vascular miRNA expression profile. To test these hypotheses, aged (24-month-old) mice were treated with NMN for 2weeks and miRNA signatures in the aortas were compared to those in aortas obtained from untreated young and aged control mice. We found that protective effects of NMN treatment on vascular function are associated with anti-aging changes in the miRNA expression profile in the aged mouse aorta. The predicted regulatory effects of NMN-induced differentially expressed miRNAs in aged vessels include anti-atherogenic effects and epigenetic rejuvenation. Future studies will uncover the mechanistic role of miRNA gene expression regulatory networks in the anti-aging effects of NAD+ booster treatments and determine the links between miRNAs regulated by NMN and sirtuin activators and miRNAs known to act in the conserved pathways of aging and major aging-related vascular diseases.

Age-related changes of the human retinal vessels: Possible involvement of lipid peroxidation

BackgroundAging of the human retina is accompanied by oxidative stress that exerts profound changes in the retinal neurons. It is unknown if oxidative stress influences the cellular components of the retinal vessels in some ways. MethodsWe examined changes in retinal vessels in human donor eyes (age: 35–94 years; N=18) by light and transmission electron microscopy, TUNEL and immunohistochemistry for biomarkers of vascular smooth muscle cells (SMC; actin), oxidative stress (4-hydroxy 2-nonenal [HNE] and nitrotyrosine), microglia (Iba-1) and vessels (isolectin B4). ResultsThe earliest changes in the endothelium and pericytes of capillaries are apparent from the seventh decade. With aging, there is clear loss of organelles and cytoplasmic filaments, and a progressive thickening of the endothelial and pericyte basal lamina. Loss of filaments, accumulation of lipofuscin and autophagic vacuoles are significant events in aging pericytes and SMC. Actin immunolabelling reveals discontinuity in arterial SMC layers during eighth decade, indicating partial degeneration of SMC. This is followed by hyalinization, with degeneration of the endothelium and SMC in arteries and arterioles of the nerve fibre layer (NFL) and ganglion cell layer in ninth decade. Iba-1 positive microglia were in close contact with the damaged vessels in inner retina, and their cytoplasm was rich in lysosomes. HNE immunoreactivity, but not of nitrotyrosine, was detected in aged vessels from seventh decade onwards, suggesting that lipid peroxidation is a major problem of aged vessels. However, TUNEL positivity seen during this period was limited to few arteries and venules of NFL. ConclusionThis study shows prominent age-related alterations of the pericytes and SMC of retinal vessels. These changes may limit the energy supply to the neurons and be responsible for age-related loss of neurons of the inner retina.

Endothelial cells on an aged subendothelial matrix display heterogeneous strain profiles in silico

Within the artery intima, endothelial cells respond to mechanical cues and changes in subendothelial matrix stiffness. Recently, we found that the aging subendothelial matrix stiffens heterogeneously and that stiffness heterogeneities are present on the scale of one cell length. However, the impacts of these complex mechanical micro-heterogeneities on endothelial cells have not been fully understood. Here, we simulate the effects of matrices that mimic young and aged vessels on single- and multi-cell endothelial cell models and examine the resulting cell basal strain profiles. Although there are limitations to the model which prohibit the prediction of intracellular strain distributions in alive cells, this model does introduce mechanical complexities to the subendothelial matrix material. More heterogeneous basal strain distributions are present in the single- and multi-cell models on the matrix mimicking an aged artery over those exhibited on the young artery. Overall, our data indicate that increased heterogeneous strain profiles in endothelial cells are displayed in silico when there is an increased presence of microscale arterial mechanical heterogeneities in the matrix.

Aging-associated alterations in lymphatic vessels and mast cells in perilymphatic tissues

Abstract Aging alters lymphatic vessel structure (by increasing the size of low muscle cell investiture zones), ultrastructure (through loss of the glycocalyx), and proteome composition causing a concomitant increase in lymphatic permeability. Our recent studies have shown that the contractile function of aged lymphatic vessels is depleted with abolished role of nitric oxide and an increased role of lymphatic-born histamine in flow-dependent regulation of lymphatic phasic contractions and tone. Thus, aging-related reduced vessel functionality and increased oxidative stress of the lymphatic vasculature facilitate the spread of pathogens into perilymphatic tissues. In addition, aging causes the basal activation of the perilymphatic mast cells, which, in turn, restricts the recruitment/activation of MHCII+ -positive cells and eosinophils in perilymphatic tissues. This aging-associated basal activation of perilymphatic mast cells limits proper functioning of the mast cell/histamine/NF-kB axis that is essential for the regulation of lymphatic vessel transport and barrier functions as well as for both the interaction and trafficking of immune cells near and within lymphatic collecting vessels. Cumulatively these alterations play crucial roles in the progression of aging-related pathogenesis in inflammation and immunity.

Intermittent PTH 1-34 administration improves the marrow microenvironment and endothelium-dependent vasodilation in bone arteries of aged rats.

Inflammation coincides with diminished marrow function, vasodilation of blood vessels, and bone mass. Intermittent parathyroid hormone (PTH) administration independently improves marrow and vascular function, potentially impacting bone accrual. Currently, the influence of marrow and intermittent PTH administration on aged bone blood vessels has not been examined. Vasodilation of the femoral principal nutrient artery (PNA) was assessed in the presence and absence of marrow. Furthermore, we determined the influence of PTH 1-34 on 1) endothelium-dependent vasodilation and signaling pathways [i.e., nitric oxide (NO) and prostacyclin (PGI2)], 2) endothelium-independent vasodilation, 3) cytokine production by marrow cells, and 4) bone microarchitecture and bone static and dynamic properties. Young (4-6 mo) and old (22-24 mo) male Fischer-344 rats were treated with PTH 1-34 or a vehicle for 2 wk. In the absence and presence of marrow, femoral PNAs were given cumulative doses of acetylcholine, with and without the NO and PGI2 blockers, and diethylamine NONOate. Marrow-derived cytokines and bone parameters in the distal femur were assessed. Exposure to marrow diminished endothelium-dependent vasodilation in young rats. Reduced bone volume and NO-mediated vasodilation occurred with old age and were partially reversed with PTH. Additionally, PTH treatment in old rats restored endothelium-dependent vasodilation in the presence of marrow and augmented IL-10, an anti-inflammatory cytokine. Endothelium-independent vasodilation was unaltered, and PTH treatment reduced osteoid surfaces in old rats. In conclusion, the marrow microenvironment reduced vascular function in young rats, and PTH treatment improved the marrow microenvironment and vasodilation with age. NEW & NOTEWORTHY This study investigated the influence of the marrow microenvironment on bone vascular function in young and old rats. An inflamed marrow microenvironment may reduce vasodilator capacity of bone blood vessels, diminishing delivery of blood flow to the skeleton. In young rats, the presence of the marrow reduced vasodilation in the femoral principal nutrient artery (PNA). However, intermittent parathyroid hormone administration (i.e., a treatment for osteoporosis) improved the marrow microenvironment and vasodilator capacity in old PNAs.

Dermatoporosis: a further step to recognition.

Skin ageing has long been considered only as a cosmetic issue. However, with increasing lifespan, we experience a functional dimension of skin ageing which extends beyond cosmetics and appearance. Ten years ago, we proposed the neologism dermatoporosis to cover different characteristics of a chronic cutaneous insufficiency/fragility syndrome, to understand underlying molecular mechanisms and to develop preventative or therapeutic strategies.

Comparison of applicability of current transition temperature shift models to SA533B-1 reactor pressure vessel steel of Korean nuclear reactors

Abstract The precise prediction of radiation embrittlement of aged reactor pressure vessels (RPVs) is a prerequisite for the long-term operation of nuclear power plants beyond their original design life. The expiration of the operation licenses for Korean reactors the RPVs of which are made from SA533B-1 plates and welds is imminent. Korean regulatory rules have adopted the US Nuclear Regulatory Commission's transition temperature shift (TTS) models to the prediction of the embrittlement of Korean reactor pressure vessels. The applicability of the TTS model to predict the embrittlement of Korean RPVs made of SA533B-1 plates and welds was investigated in this study. It was concluded that the TTS model of 10 CFR 50.61a matched the trends of the radiation embrittlement in the SA533B-1 plates and welds better than did that of Regulatory Guide (RG) 1.99 Rev. 2. This is attributed to the fact that the prediction performance of 10 CFR 50.61a was enhanced by considering the difference in radiation embrittlement sensitivity among the different types of RPV materials.