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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 73 records · Page 4
All sourcesNASA NTRSDOE OSTI
DOE OSTI2014

Atorvastatin ameliorates arsenic-induced hypertension and enhancement of vascular redox signaling in rats

Chronic arsenic exposure has been linked to elevated blood pressure and cardiovascular diseases, while statins reduce the incidence of cardiovascular disease predominantly by their low density lipoprotein-lowering effect. Besides, statins have other beneficial effects, including antioxidant and anti-inflammatory activities. We evaluated whether atorvastatin, a widely used statin, can ameliorate arsenic-induced increase in blood pressure and alteration in lipid profile and also whether the amelioration could relate to altered NO and ROS signaling. Rats were exposed to sodium arsenite (100 ppm) through drinking water for 90 consecutive days. Atorvastatin (10 mg/kg bw, orally) was administered once daily during the last 30 days of arsenic exposure. On the 91st day, blood was collected for lipid profile. Western blot of iNOS and eNOS protein, NO and 3-nitrotyrosine production, Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation, lipid peroxidation and antioxidants were evaluated in thoracic aorta. Arsenic increased systolic, diastolic and mean arterial blood pressure, while it decreased HDL-C and increased LDL-C, total cholesterol and triglycerides in serum. Arsenic down-regulated eNOS and up-regulated iNOS protein expression and increased basal NO and 3-nitrotyrosine level. Arsenic increased aortic Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation and lipid peroxidation. Further, arsenic decreased the activities of superoxide dismutase, catalase, and glutathione peroxidase and depleted aortic GSH content. Atorvastatin regularized blood pressure, improved lipid profile and attenuated arsenic-mediated redox alterations. The results demonstrate that atorvastatin has the potential to ameliorate arsenic-induced hypertension by improving lipid profile, aortic NO signaling and restoring vascular redox homeostasis. - Highlights: • Arsenic increased systolic, diastolic and mean arterial blood pressure and caused dyslipidemia. • Arsenic increased both oxidative and nitrosative stress in thoracic aorta. • Atorvastatin regularized blood pressure, improved lipid profile and restored redox homeostasis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

The imperatorin derivative OW1, a new vasoactive compound, inhibits VSMC proliferation and extracellular matrix hyperplasia

Chronic hypertension induces vascular remodeling. The most important factor for hypertension treatment is reducing the risk of cardiovascular disease. OW1 is a novel imperatorin derivative that exhibits vasodilative activity and antihypertensive effects in two-kidney one-clip (2K1C) renovascular hypertensive rats. It also inhibited vascular remodeling of the thoracic aorta in a previous study. Here, the inhibitory effects and mechanisms of OW1 on arterial vascular remodeling were investigated in vitro and in 2K1C hypertensive rats in vivo. OW1 (20 μM, 10 μM, 5 μM) inhibited Ang II-induced vascular smooth muscle cells (VSMCs) proliferation and ROS generation in vitro. OW1 also reversed the Ang II-mediated inhibition of α-SMA levels and stimulation of OPN levels. Histology results showed that treatment of 2K1C hypertensive rats with OW1 (20, 40, and 80 mg/kg per day, respectively for 5 weeks) in vivo significantly decreased the number of VSMCs, the aortic cross-sectional area (CSA), the media to lumen (M/L) ratio, and the content of collagen I and III in the mesenteric artery. Western blot results also revealed that OW1 stimulated the expression of α-SMA and inhibited the expression of collagen I and III on the thoracic aorta of 2K1C hypertensive rats. In mechanistic studies, OW1 acted as an ACE inhibitor and affected calcium channels. The suppression of MMP expression and the MAPK pathway may account for the effects of OW1 on vascular remodeling. OW1 attenuated vascular remodeling in vitro and in vivo. It could be a novel candidate for hypertension intervention. - Highlights: • OW1, an imperatorin derivative, attenuates vascular remodeling caused by hypertension. • OW1 inhibits VSMC proliferation and media layer hypertrophy. • OW1 acts as an ACE inhibitor and affects calcium channels. • Suppression of MMPs expression and MAPK pathway may account for the effects of OW1 on vascular remodeling.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Aluminum exposure for one hour decreases vascular reactivity in conductance and resistance arteries in rats

Aims: Aluminum (Al) is an important environmental contaminant; however, there are not enough evidences of Al-induced cardiovascular dysfunction. We investigated the effects of acute exposure to aluminum chloride (AlCl{sub 3}) on blood pressure, vascular reactivity and oxidative stress. Methods and results: Male Wistar rats were divided into two groups: Untreated: vehicle (ultrapure water, ip) and AlCl{sub 3}: single dose of AlCl{sub 3} (100 mg/kg,ip). Concentration-response curves to phenylephrine in the absence and presence of endothelium, the nitric oxide synthase inhibitor L-NAME, the potassium channel blocker tetraethylammonium, and the NADPH oxidase inhibitor apocynin were performed in segments from aortic and mesenteric resistance arteries. NO released was assessed in aorta and reactive oxygen species (ROS), malondialdehyde, non-protein thiol levels, antioxidant capacity and enzymatic antioxidant activities were investigated in plasma, aorta and/or mesenteric arteries. After one hour of AlCl{sub 3} exposure serum Al levels attained 147.7 ± 25.0 μg/L. Al treatment: 1) did not affect blood pressure, heart rate and vasodilator responses induced by acetylcholine or sodium nitroprusside; 2) decreased phenylephrine-induced vasoconstrictor responses; 3) increased endothelial modulation of contractile responses, NO release and vascular ROS production from NADPH oxidase; 4) increased plasmatic, aortic and mesenteric malondialdehyde and ROS production, and 5) decreased antioxidant capacity and affected the antioxidant biomarkers non-protein thiol levels, glutathione peroxidase, glutathione-S-transferase, superoxide dismutase and catalase enzymatic activities. Conclusion: AlCl{sub 3}-acute exposure reduces vascular reactivity. This effect is associated with increased NO production, probably acting on K{sup +} channels, which seems to occur as a compensatory mechanism against Al-induced oxidative stress. Our results suggest that Al exerts toxic effects to the vascular system. - Highlights: • One hour of aluminum exposure decreases vascular reactivity. • Vascular imbalance after aluminum exposure is related to increased oxidative stress. • Enhanced NO release is the first step against the effects of Al at vascular system.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

MiR-375 silencing attenuates pro-inflammatory macrophage response and foam cell formation by targeting KLF4

Macrophage mediated inflammation and foam cell formation play crucial roles in the development of atherosclerosis. MiR-375 is a small noncoding RNA that significantly implicated in multiple tumor regulation and has been emerged as a novel biomarker for type 2 diabetes. However, the exact role of miR-375 on macrophage activation remains unknown. In the present study, we observed that miR-375 expression showed an up-regulated expression in atherosclerotic aortas, as well as in bone marrow derived macrophages (BMDMs) and mouse peritoneal macrophages (MPMs) isolated from ApoE deficiency mice and was gradually increased followed the Ox-LDL treated time. Functionally, miR-375 inhibition significantly decreased foam cell formation accompanied by up-regulated genes expression involved in cholesterol efflux but reduced genes expression implicated in cholesterol influx. Moreover, miR-375 silencing increased resolving M2 macrophage but reduced pro-inflammatory M1 macrophage markers expression. Such above effects can be reversed by miR-375 overexpression. Mechanistically, we noticed that miR-375 knockdown promoted KLF4 expression which was required for the ameliorated effect of miR-375 silencing on macrophage activation. Importantly, the consistent results in mRNA expression of M1 and M2 markers were observed in vivo, and miR-375{sup −/−}ApoE{sup −/−} mice significant decreased atherosclerotic lesions in the whole aorta and aortic sinus. Taken together, these evidences suggested that miR-375 knockdown attenuated macrophage activation partially through activation of KLF4-dependent mechanism.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Fatty acid binding protein 3 deficiency limits atherosclerosis development via macrophage foam cell formation inhibition

Highlights: • We firstly indicated that FABP3 was highly expressed in the aorta of HFD-fed ApoE{sup −/-} mice. • Silencing FABP3 attenuated atherosclerosis due to inhibited macrophage foam cell formation. • FABP3 knockdown decreased foamy macrophage formation partly by inhibiting the PPARγ signal pathway. Atherosclerosis is the underlying contributing factor of cardiovascular disease, which is a process of inflammation and lipid-rich lesion. Macrophage-derived foam cell is a key hallmark of atherosclerosis and connected with various factors of lipid metabolism. Here, we showed that fatty acid binding protein 3 (FABP3) was upregulated in the aorta of ApoE{sup −/-} mice with high-fat-diet (HFD) feeding. Knockdown of FABP3 in HFD-fed ApoE{sup −/-} mice notably facilitated cholesterol efflux, inhibited macrophage foam cell formation, and thus prevented atherogenesis. Furthermore, FABP3 silencing decreased the expression of peroxisome proliferator-activated receptor γ (PPARγ). Mechanistic studies had disclosed the involvement of PPARγ signaling in balancing cholesterol uptake and efflux and diminishing foam cell formation. These findings firstly revealed an anti-atherogenic role of FABP3 silencing in preventing foamy macrophage formation partly through PPARγ, which might be a beneficial approach for therapying atherosclerosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Polyhydroxybutyrate/valerate/polycaprolactone small-diameter vascular graft: Experimental study of integration into organism

We prepared polyhydroxybutyrate/valerate (PHBV)/polylcaprolactone (PCL) small-diameter vascular grafts using electrospinning. Surface structure was assessed by scanning electron microscopy whilst physicomechanical properties were investigated by longitudinal uniaxial tension testing. Patency of grafts implanted into the rat abdominal aorta was evaluated using a Doppler ultrasonography at 2 week, 1 month and 12 month postimplantation. In addition, we assessed local histological features, along with IL-1β, IL-2, IL-4, IL-10, TNFa, TGF-β1, and VEGF serum levels. We revealed that only 2 (25%) grafts were not thrombosed at 2 week and 1 month postimplantation. However, at 12 month postimplantation a satisfactory histological pattern was observed in 50% of all cases, and we detected a monolayer of endothelial cells on the inner graft surface in half the cases. Regarding other grafts, we revealed minor connective tissue hyperplasia in 41.7% of the grafts and an inflammatory infiltrate in the part of the arterial wall in 8.3% of the grafts. We found that the IL-1β serum level was 3.5-fold higher in the group of experimental rats at 12 month postimplantation (p < 0.01). In addition, the IL-2 and IL-4 serum levels at 12 month postimplantation were 2- and 2.8-fold higher as compared to short-term implantation (2 weeks and 1 month) and control rats (p < 0.05) whilst the IL-10 serum level at 1 and 12 month postimplantation was more than 100-fold higher in comparison with 2 week postimplantation and control rats (p < 0.001). Serum VEGF was detected only at 12 month postimplantation. All in all, we created a biocompatible PHBV/PCL small-diameter vascular graft with a high surface area to volume ratio. A long-term patency of biodegradable vascular grafts after implantation into the rat abdominal aorta and the absence of a considerable immune response confirmed a high biocompatibility of such construct and the possibility of its use as a vascular graft.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗
DOE OSTI2016

Unsteady fluid flow in a slightly curved pipe: A comparative study of a matched asymptotic expansions solution with a single analytical solution

The present work is motivated by the fact that blood flow in the aorta and the main arteries is governed by large finite values of the Womersley number α and for such values of α there is not any analytical solution in the literature. The existing numerical solutions, although accurate, give limited information about the factors that affect the flow, whereas an analytical approach has an advantage in that it can provide physical insight to the flow mechanism. Having this in mind, we seek analytical solution to the equations of the fluid flow driven by a sinusoidal pressure gradient in a slightly curved pipe of circular cross section when the Womersley number varies from small finite to infinite values. Initially the equations of motion are expanded in terms of the curvature ratio δ and the resulting linearized equations are solved analytically in two ways. In the first, we match the solution for the main core to that for the Stokes boundary layer. This solution is valid for very large values of α. In the second, we derive a straightforward single solution valid to the entire flow region and for 8 ≤ α < ∞, a range which includes the values of α that refer to the physiological flows. Each solution contains expressions for the axial velocity, the stream function, and the wall stresses and is compared to the analogous forms presented in other studies. The two solutions give identical results to each other regarding the axial flow but differ in the secondary flow and the circumferential wall stress, due to the approximations employed in the matched asymptotic expansion process. The results on the stream function from the second solution are in agreement with analogous results from other numerical solutions. The second solution predicts that the atherosclerotic plaques may develop in any location around the cross section of the aortic wall unlike to the prescribed locations predicted by the first solution. In addition, it gives circumferential wall stresses augmented by approximately 100% with respect to the matched asymptotic expansions, a factor that may contribute jointly with other pathological factors to the faster aging of the arterial system and the possible malfunction of the aorta.

42 ENGINEERING↗
DOE OSTI2014

Measurement of cardiac output from dynamic pulmonary circulation time CT

Purpose: To introduce a method of estimating cardiac output from the dynamic pulmonary circulation time CT that is primarily used to determine the optimal time window of CT pulmonary angiography (CTPA). Methods: Dynamic pulmonary circulation time CT series, acquired for eight patients, were retrospectively analyzed. The dynamic CT series was acquired, prior to the main CTPA, in cine mode (1 frame/s) for a single slice at the level of the main pulmonary artery covering the cross sections of ascending aorta (AA) and descending aorta (DA) during the infusion of iodinated contrast. The time series of contrast changes obtained for DA, which is the downstream of AA, was assumed to be related to the time series for AA by the convolution with a delay function. The delay time constant in the delay function, representing the average time interval between the cross sections of AA and DA, was determined by least square error fitting between the convoluted AA time series and the DA time series. The cardiac output was then calculated by dividing the volume of the aortic arch between the cross sections of AA and DA (estimated from the single slice CT image) by the average time interval, and multiplying the result by a correction factor. Results: The mean cardiac output value for the six patients was 5.11 (l/min) (with a standard deviation of 1.57 l/min), which is in good agreement with the literature value; the data for the other two patients were too noisy for processing. Conclusions: The dynamic single-slice pulmonary circulation time CT series also can be used to estimate cardiac output.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2015

SU-E-J-129: Atlas Development for Cardiac Automatic Contouring Using Multi-Atlas Segmentation

Purpose: To develop a set of atlases for automatic contouring of cardiac structures to determine heart radiation dose and the associated toxicity. Methods: Six thoracic cancer patients with both contrast and non-contrast CT images were acquired for this study. Eight radiation oncologists manually and independently delineated cardiac contours on the non-contrast CT by referring to the fused contrast CT and following the RTOG 1106 atlas contouring guideline. Fifteen regions of interest (ROIs) were delineated, including heart, four chambers, four coronary arteries, pulmonary artery and vein, inferior and superior vena cava, and ascending and descending aorta. Individual expert contours were fused using the simultaneous truth and performance level estimation (STAPLE) algorithm for each ROI and each patient. The fused contours became atlases for an in-house multi-atlas segmentation. Using leave-one-out test, we generated auto-segmented contours for each ROI and each patient. The auto-segmented contours were compared with the fused contours using the Dice similarity coefficient (DSC) and the mean surface distance (MSD). Results: Inter-observer variability was not obvious for heart, chambers, and aorta but was large for other structures that were not clearly distinguishable on CT image. The average DSC between individual expert contours and the fused contours were less than 50% for coronary arteries and pulmonary vein, and the average MSD were greater than 4.0 mm. The largest MSD of expert contours deviating from the fused contours was 2.5 cm. The mean DSC and MSD of auto-segmented contours were within one standard deviation of expert contouring variability except the right coronary artery. The coronary arteries, vena cava, and pulmonary vein had DSC<70% and MSD>3.0 mm. Conclusion: A set of cardiac atlases was created for cardiac automatic contouring, the accuracy of which was comparable to the variability in expert contouring. However, substantial modification may need for auto-segmented contours of indistinguishable small structures.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Image-derived and arterial blood sampled input functions for quantitative PET imaging of the angiotensin II subtype 1 receptor in the kidney

Purpose: The radioligand {sup 11}C-KR31173 has been introduced for positron emission tomography (PET) imaging of the angiotensin II subtype 1 receptor in the kidney in vivo. To study the biokinetics of {sup 11}C-KR31173 with a compartmental model, the input function is needed. Collection and analysis of arterial blood samples are the established approach to obtain the input function but they are not feasible in patients with renal diseases. The goal of this study was to develop a quantitative technique that can provide an accurate image-derived input function (ID-IF) to replace the conventional invasive arterial sampling and test the method in pigs with the goal of translation into human studies. Methods: The experimental animals were injected with [{sup 11}C]KR31173 and scanned up to 90 min with dynamic PET. Arterial blood samples were collected for the artery derived input function (AD-IF) and used as a gold standard for ID-IF. Before PET, magnetic resonance angiography of the kidneys was obtained to provide the anatomical information required for derivation of the recovery coefficients in the abdominal aorta, a requirement for partial volume correction of the ID-IF. Different image reconstruction methods, filtered back projection (FBP) and ordered subset expectation maximization (OS-EM), were investigated for the best trade-off between bias and variance of the ID-IF. The effects of kidney uptakes on the quantitative accuracy of ID-IF were also studied. Biological variables such as red blood cell binding and radioligand metabolism were also taken into consideration. A single blood sample was used for calibration in the later phase of the input function. Results: In the first 2 min after injection, the OS-EM based ID-IF was found to be biased, and the bias was found to be induced by the kidney uptake. No such bias was found with the FBP based image reconstruction method. However, the OS-EM based image reconstruction was found to reduce variance in the subsequent phase of the ID-IF. The combined use of FBP and OS-EM resulted in reduced bias and noise. After performing all the necessary corrections, the areas under the curves (AUCs) of the AD-IF were close to that of the AD-IF (average AUC ratio =1 ± 0.08) during the early phase. When applied in a two-tissue-compartmental kinetic model, the average difference between the estimated model parameters from ID-IF and AD-IF was 10% which was within the error of the estimation method. Conclusions: The bias of radioligand concentration in the aorta from the OS-EM image reconstruction is significantly affected by radioligand uptake in the adjacent kidney and cannot be neglected for quantitative evaluation. With careful calibrations and corrections, the ID-IF derived from quantitative dynamic PET images can be used as the input function of the compartmental model to quantify the renal kinetics of {sup 11}C-KR31173 in experimental animals and the authors intend to evaluate this method in future human studies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Automatic coronary calcium scoring using noncontrast and contrast CT images

Purpose: Calcium scoring is widely used to assess the risk of coronary heart disease (CHD). Accurate coronary artery calcification detection in noncontrast CT image is a prerequisite step for coronary calcium scoring. Currently, calcified lesions in the coronary arteries are manually identified by radiologists in clinical practice. Thus, in this paper, a fully automatic calcium scoring method was developed to alleviate the work load of the radiologists or cardiologists. Methods: The challenge of automatic coronary calcification detection is to discriminate the calcification in the coronary arteries from the calcification in the other tissues. Since the anatomy of coronary arteries is difficult to be observed in the noncontrast CT images, the contrast CT image of the same patient is used to extract the regions of the aorta, heart, and coronary arteries. Then, a patient-specific region-of-interest (ROI) is generated in the noncontrast CT image according to the segmentation results in the contrast CT image. This patient-specific ROI focuses on the regions in the neighborhood of coronary arteries for calcification detection, which can eliminate the calcifications in the surrounding tissues. A support vector machine classifier is applied finally to refine the results by removing possible image noise. Furthermore, the calcified lesions in the noncontrast images belonging to the different main coronary arteries are identified automatically using the labeling results of the extracted coronary arteries. Results: Forty datasets from four different CT machine vendors were used to evaluate their algorithm, which were provided by the MICCAI 2014 Coronary Calcium Scoring (orCaScore) Challenge. The sensitivity and positive predictive value for the volume of detected calcifications are 0.989 and 0.948. Only one patient out of 40 patients had been assigned to the wrong risk category defined according to Agatston scores (0, 1–100, 101–300, >300) by comparing with the ground truth. Conclusions: The calcified lesions in the noncontrast CT images can be detected automatically by using the segmentation results of the aorta, heart, and coronary arteries obtained in the contrast CT images with a very high accuracy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-F-I-45: An Automated Technique to Measure Image Contrast in Clinical CT Images

Purpose: To develop and validate an automated technique for measuring image contrast in chest computed tomography (CT) exams. Methods: An automated computer algorithm was developed to measure the distribution of Hounsfield units (HUs) inside four major organs: the lungs, liver, aorta, and bones. These organs were first segmented or identified using computer vision and image processing techniques. Regions of interest (ROIs) were automatically placed inside the lungs, liver, and aorta and histograms of the HUs inside the ROIs were constructed. The mean and standard deviation of each histogram were computed for each CT dataset. Comparison of the mean and standard deviation of the HUs in the different organs provides different contrast values. The ROI for the bones is simply the segmentation mask of the bones. Since the histogram for bones does not follow a Gaussian distribution, the 25th and 75th percentile were computed instead of the mean. The sensitivity and accuracy of the algorithm was investigated by comparing the automated measurements with manual measurements. Fifteen contrast enhanced and fifteen non-contrast enhanced chest CT clinical datasets were examined in the validation procedure. Results: The algorithm successfully measured the histograms of the four organs in both contrast and non-contrast enhanced chest CT exams. The automated measurements were in agreement with manual measurements. The algorithm has sufficient sensitivity as indicated by the near unity slope of the automated versus manual measurement plots. Furthermore, the algorithm has sufficient accuracy as indicated by the high coefficient of determination, R2, values ranging from 0.879 to 0.998. Conclusion: Patient-specific image contrast can be measured from clinical datasets. The algorithm can be run on both contrast enhanced and non-enhanced clinical datasets. The method can be applied to automatically assess the contrast characteristics of clinical chest CT images and quantify dependencies that may not be captured in phantom data.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1995

'Non-hypotensive' hypovolaemia reduces ascending aortic dimensions in humans

1. The notion that small, 'non-hypotensive' reductions of effective blood volume alter neither arterial pressure nor arterial baroreceptor activity is pervasive in the experimental literature. We tested two hypotheses: (a) that minute arterial pressure and cardiac autonomic outflow changes during hypovolaemia induced by lower body suction in humans are masked by alterations in breathing, and (b) that evidence for arterial baroreflex engagement might be obtained from measurements of thoracic aorta dimensions. 2. In two studies, responses to graded lower body suction at 0 (control), 5, 10, 15, 20 and 40 mmHg were examined in twelve and ten healthy young men, respectively. In the first, arterial pressure (photoplethysmograph), R-R interval, and respiratory sinus arrhythmia amplitude (complex demodulation) were measured during uncontrolled and controlled breathing (constant breathing frequency and tidal volume). In the second, cross-sectional areas of the ascending thoracic aorta were calculated from nuclear magnetic resonance images. 3. Lower body suction with controlled breathing resulted in an increased arterial pulse pressure at mild levels (5-20 mmHg; ANOVA, P < 0.05) and a decreased arterial pulse pressure at moderate levels (40 mmHg; ANOVA, P < 0.05). Both R-R intervals and respiratory sinus arrhythmia were negatively related to lower body suction level, whether group averages (general linear regression, r > 0.92) or individual subjects (orthogonal polynomials, 12 of 12 subjects) were assessed. 4. Aortic pulse area decreased progressively and significantly during mild lower body suction, with 47% of the total decline occurring by 5 mmHg. 5. These results suggest that small reductions of effective blood volume reduce aortic baroreceptive areas and trigger haemodynamic adjustments which are so efficient that alterations in arterial pressure escape detection by conventional means.

NASA Discipline Cardiopulmonary↗
DOE OSTI2016

Dynamic autophagic activity affected the development of thoracic aortic dissection by regulating functional properties of smooth muscle cells

The aortic medial degeneration is the key histopathologic feature of Thoracic aortic dissection (TAD). The aim of this study was to identify the change of autophagic activity in the aortic wall during TAD development, and to explore the roles of autophagy on regulating functional properties of smooth muscle cells (SMCs). Firstly, compared with control group (n = 11), the increased expression of autophagic markers Beclin1 and LC3 was detected in the aortic wall from TAD group (n = 23) by immunochemistry and western blot. We found that more autophagic vacuoles were present in the aortic wall of TAD patients using Transmission electron microscopy. Next, autophagic activity was examined in AD mice model established by β-aminopropionitrile fumarate (BAPN) and angiotensin II. Immunochemistry proved that autophagic activity was dynamically changed during AD development. Beclin1 and LC3 were detected up-regulated in the aortic wall in the second week after BAPN feeding, earlier than the fragmentation or loss of elastic fibers. When AD occurred in the 4th week, the expression of Beclin1 and LC3 began to decrease, but still higher than the control. Furthermore, autophagy was found to inhibit starvation-induced apoptosis of SMCs. Meanwhile, blockage of autophagy could suppress PDGF-induced phenotypic switch of SMCs. Taken together, autophagic activity was dynamically changed in the aortic wall during TAD development. The abnormal autophagy could regulate the functional properties of aortic SMCs, which might be the potential pathogenesis of TAD. - Highlights: • Autophagy is up-regulated in aorta wall from thoracic aorta dissection (TAD) patient. • Autophagic activity is dynamically changed during TAD development. • Dynamically change of autophagy is associated with pathological process of TAD. • Autophagy participate in the development of TAD by regulating function of SMCs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Late Life Supplementation of 25‐Hydroxycholesterol Reduces Aortic Stiffness and Cellular Senescence in Mice

ABSTRACT Stiffening of the aorta is a key antecedent to cardiovascular diseases (CVD) with aging. Age‐related aortic stiffening is driven, in part, by cellular senescence—a hallmark of aging defined primarily by irreversible cell cycle arrest. In this study, we assessed the efficacy of 25‐hydroxycholesterol (25HC), an endogenous cholesterol metabolite, as a naturally occurring senolytic to reverse vascular cell senescence and reduce aortic stiffness in old mice. Old (22–26 months) p16‐3MR mice, a transgenic model allowing for genetic clearance of p16‐positive senescent cells with ganciclovir (GCV), were administered vehicle, 25HC, or GCV to compare the efficacy of the experimental 25HC senolytic versus genetic clearance of senescent cells. We found that short‐term (5d) treatment with 25HC reduced aortic stiffness in vivo, assessed via aortic pulse wave velocity (p = 0.002) to a similar extent as GCV. Ex vivo 25HC exposure of aorta rings from the old p16‐3MR GCV‐treated mice did not further reduce elastic modulus (measure of intrinsic mechanical stiffness), demonstrating that 25HC elicited its beneficial effects on aortic stiffness, in part, through the suppression of excess senescent cells. Improvements in aortic stiffness with 25HC were accompanied by favorable remodeling of structural components of the vascular wall (e.g., lower collagen‐1 abundance and higher α‐elastin content) to a similar extent as GCV. Moreover, 25HC suppressed its putative molecular target CRYAB, modulated CRYAB‐regulated senescent cell anti‐apoptotic pathways, and reduced markers of cellular senescence. The findings from this study identify 25HC as a potential therapy to target vascular cell senescence and reduce age‐related aortic stiffness.

Cell Biology↗
DOE OSTI2016

MO-FG-CAMPUS-JeP2-01: 4D-MRI with 3D Radial Sampling and Self-Gating-Based K-Space Sorting: Image Quality Improvement by Slab-Selective Excitation

Purpose: A recent 4D MRI technique based on 3D radial sampling and self-gating-based K-space sorting has shown promising results in characterizing respiratory motion. However due to continuous acquisition and potentially drastic k-space undersampling resultant images could suffer from low blood-to-tissue contrast and streaking artifacts. In this study 3D radial sampling with slab-selective excitation (SS) was proposed in attempt to enhance blood-to-tissue contrast by exploiting the in-flow effect and to suppress the excess signal from the peripheral structures particularly in the superior-inferior direction. The feasibility of improving image quality by using this approach was investigated through a comparison with the previously developed non-selective excitation (NS) approach. Methods: Two excitation approaches SS and NS were compared in 5 cancer patients (1 lung 1 liver 2 pancreas and 1 esophagus) at 3Tesla. Image artifact was assessed in all patients on a 4-point scale (0: poor; 3: excellent). Signal-tonoise ratio (SNR) of the blood vessel (aorta) at the center of field-of-view and its nearby tissue were measured in 3 of the 5 patients (1 liver 2 pancreas) and blood-to-tissue contrast-to-noise ratio (CNR) were then determined. Results: Compared with NS the image quality of SS was visually improved with overall higher signal in all patients (2.6±0.55 vs. 3.4±0.55). SS showed an approximately 2-fold increase of SNR in the blood (aorta: 16.39±1.95 vs. 32.19±7.93) and slight increase in the surrounding tissue (liver/pancreas: 16.91±1.82 vs. 22.31±3.03). As a result the blood-totissue CNR was dramatically higher in the SS method (1.20±1.20 vs. 9.87±6.67). Conclusion: The proposed 3D radial sampling with slabselective excitation allows for reduced image artifact and improved blood SNR and blood-to-tissue CNR. The success of this technique could potentially benefit patients with cancerous tumors that have invaded the surrounding blood vessels where radiation therapy is needed to remove tumor from those regions prior to surgical resection. This work is partially supported by NIH R03CA173273; and CTSI core voucher award.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

WE-AB-207B-01: Dose Tolerance for SBRT/SABR

Purpose: Stereotactic body radiation therapy (SBRT) / stereotactic ablative body radiotherapy (SABR) is gaining popularity, but quantitative dose tolerance has still been lacking. To improve this, the April 2016 issue of Seminars in Radiation Oncology will have normal tissue complication probability (NTCP) models for 10 critical structures: optic pathway, cochlea, oral mucosa, esophagus, chestwall, aorta, bronchi, duodenum, small bowel, and spinal cord. Methods: The project included more than 1500 treatments in 1–5 fractions using CyberKnife, Gamma Knife, or LINAC, with 60 authors from 15 institutions. NTCP models were constructed from the 97 grade 2–3 complications, predominantly scored using the common terminology criteria for adverse events (CTCAEv4). Dose volume histogram (DVH) data from each institutional dataset was loaded into the DVH Evaluator software (DiversiLabs, LLC, Huntingdon Valley, Pa) for modeling. The current state of the literature for the critical structures was depicted using DVH Risk Maps: comparative graphs of dose tolerance limits that can include estimated risk levels, reported complications, DVH data for study patients, as well as high- and low-risk dose tolerance limits. Results: For relatively acceptable toxicity like grade 1–3 rib fractures and chestwall pain, the high-risk limits have 50% risk and the low-risk limits have 5% risk. Emami et al (IJROBP 1991 May 15;21(1):109–22) used 50% and 5% risk levels for all structures, whereas this effort used clinically acceptable ranges for each: in structures like aorta or spinal cord where complications must be avoided, the high- and low-risk limits have about 3% and 1% risk, respectively, in this issue of Seminars. These statistically based guidelines can help ensure plan quality for each patient. Conclusion: NTCP for SBRT is now becoming available. Hypofractionated dose tolerance can be dramatically different than extrapolations of conventional fractionation so NTCP analysis of the SBRT/SBRT data is important to ensure safe clinical practice. Dr. Grimm, designed and holds intellectual property rights to the DVH Evaluator software tool which is an FDA-cleared product in commercial use, and was used to analyze the data.

60 APPLIED LIFE SCIENCES↗