Independent Relaxation Research Articles

Red blood cells from patients with ST-elevation myocardial infarction and elevated C-reactive protein levels induce endothelial dysfunction.

Endothelial dysfunction is an early consequence of vascular inflammation and a driver of coronary atherosclerotic disease leading to myocardial infarction. The red blood cells (RBCs) mediate endothelial dysfunction in patients at cardiovascular risk, but their role in patients with acute myocardial infarction is unknown. This study aimed to investigate if RBCs from patients with ST-elevation myocardial infarction (STEMI) induced endothelial dysfunction and the role of systemic inflammation in this effect. RBCs from patients with STEMI and aged-matched healthy controls were co-incubated with rat aortic segments for 18h followed by evaluation of endothelium-dependent (EDR) and -independent relaxation (EIDR). RBCs and aortic segments were also analyzed for arginase and oxidative stress. The patients were divided into groups depending on C-reactive protein (CRP) levels at admission. RBCs from patients with STEMI and CRP levels >2 mg/L induced impairment of EDR, but not EIDR, compared to RBCs from STEMI and CRP <2 mg/L and healthy controls. Aortic expression of arginase 1 was increased following incubation with RBCs from patients with STEMI and CRP >2, and arginase inhibition prevented the RBC-induced endothelial dysfunction. RBCs from patients with STEMI and CRP >2 had increased reactive oxygen species compared to RBCs from patients with CRP <2 and healthy controls. Vascular inhibition of NADPH oxidases and increased dismutation of superoxide improved EDR. RBCs from patients with STEMI and low-grade inflammation induce endothelial dysfunction through a mechanism involving arginase 1 as well and increased RBC and vascular superoxide by NADPH oxidases.

Fitting Quality of NMR Relaxation Data to Differentiate Asphalt Binders

Asphalt binder performance grades (PGs) are important metrics in designing pavements for effective transportation infrastructure. The PG system relies on the binder’s stiffness and is determined through energy- and time-intensive physical testing. Physical properties, like stiffness, can also be determined by spin–lattice NMR relaxometry, a non-destructive chemical method. NMR relaxometry can quantify the molecular mobility of materials by determining relaxation times from exponential decays of excited nuclear magnetization. While relaxation times have been used to determine physical properties of materials, a quantitative relation to the PG grades of asphalt binder is yet to be established. In this study, T1 NMR relaxation analyses were used to differentiate between solid asphalt binders and determine the fastest yet still-reliable method of modeling exponential decay data. Algorithms that fit exponential decay relaxation data using one, two, or three independent relaxation times were compared with a 128-coefficient discrete inverse Laplace transformation to determine the best mathematical fit for a comparative analysis. The number of data points was then reduced from 256 to 64 to 16 and finally to 8 data points on a relaxation curve to reduce the testing time and determine the minimum number of data points needed for comparison. Two batches of PG 64-22 asphalt binder, along with samples of PG 76-22 and 94-10 binders, were investigated. The best compromise between measuring time and data reliability was found by acquiring 64 data points and then using a biexponential model to fit the experimental data. The PG 64-22 sources provided similar results, indicating similar physical properties. The PG 64-22 and PG 76-22 binders could also be compared via monoexponential data fits, but the PG 94-10 samples required an additional relaxation parameter for comparison. To differentiate all three binder grades, the primary relaxation times, along with their relative ratios, were utilized.

"Evaluation of the effects of pioglitazone on perivascular adipose tissue function, properties and structure in a rat model of type-2 diabetes."

Perivascular adipose tissue (PVAT) plays an important role in many physiological and pathological processes, such as regulation of vascular tone. The aim of this study is to evaluate the effects of pioglitazone on functional, structural, and biochemical properties of PVAT in an experimental model of type-2 diabetes (T2DM). T2DM was induced by high-fat-diet/low-dose-streptozotocin (HFD/STZ) in rats, and pioglitazone (20mg/kg/p.o.) was administered for 6 weeks. Changes in biochemical parameters, PVAT-mass, vascular-reactivity in thoracic-aorta as well as PVAT adipocytokine and PPARG-expression levels, and histopathology were evaluated. Pioglitazone administration improved blood glucose and lipid profiles in T2DM. Pioglitazone did not change the anticontractile effect of PVAT on aortic contractile reactivity and besides, had no influence on endothelium-dependent and -independent relaxation responses. Pioglitazone administration increased PVAT-mass and TNF-α levels while adiponectin, leptin, and IL-6 levels were unchanged. Also, a prominent increase was observed in PPARG-expression in T2DM-Pio group. Moreover, pioglitazone decreased liver steatosis, aortic wall thickening and myocardial damage whereas increased adipocyte size and adiposity in PVAT. Overall, pioglitazone treatment changed the mass and in part the inflammatory profile of PVAT but did not modify vasoreactivity in T2DM. This study provides novel findings in relationship with the adipogenic effect of pioglitazone and PVAT function.

Differences in endothelial function between patients with Type 1 and Type 2 diabetes: effects of red blood cells and arginase.

The mechanisms underlying endothelial dysfunction in Type 1 and Type 2 diabetes (T1DM and T2DM) are unresolved. The red blood cells (RBCs) with increased arginase activity induce endothelial dysfunction in T2DM, but the implications of RBCs and the role of arginase inhibition in T1DM are unexplored. We aimed to investigate the differences in endothelial function in patients with T1DM and T2DM, with focus on RBCs and arginase. Thirteen patients with T1DM and twenty-six patients with T2DM, matched for HbA1c and sex were included. In vivo endothelium-dependent and -independent vasodilation (EDV and EIDV) were assessed by venous occlusion plethysmography before and after administration of an arginase inhibitor. RBCs were co-incubated with rat aortic segments for 18h followed by evaluation of endothelium-dependent (EDR) and -independent relaxation (EIDR) in isolated organ chambers. In vivo EDV, but not EIDV, was significantly impaired in patients with T2DM compared with patients with T1DM. Arginase inhibition resulted in improved EDV only in T2DM. RBCs from patients with T2DM induced impaired EDR but not EIDR in isolated aortic segments, whereas RBCs from patients with T1DM did not affect EDR nor EIDR. The present study demonstrates markedly impaired EDV in patients with T2DM in comparison with T1DM. In addition, it highlights the divergent roles of RBCs and arginase in mediating endothelial dysfunction in T1DM and T2DM. While endothelial dysfunction is mediated via RBCs and arginase in T2DM, these phenomena are not prominent in T1DM thereby indicating distinct differences in underlying mechanisms.

Dimethyl Fumarate Prevents the Development of Chronic Social Stress-Induced Hypertension in Borderline Hypertensive Rats.

This study investigated the effects of chronic crowding-induced social stress and dimethyl fumarate (DMF) on borderline hypertensive rats, focusing on the transcription nuclear factor (erythroid-derived 2)-like 2 (NRF2) gene Nfe2l2, on the expression of selected NFR2-mediated gene expressions in the heart, and on vascular function. Rats were exposed to chronic crowding, DMF treatment (30 mg/kg/day, p.o.), or a combination of both for six weeks. Blood pressure (BP) was measured non-invasively, gene expressions were analysed using RT-qPCR, and vascular function was assessed by measuring noradrenaline (NA)-induced vasoconstriction and endothelium-dependent and -independent relaxations in the femoral arteries using a wire myograph. Chronic stress increased BP, Nfe2l2 expression, and NA-induced vasoconstriction, though it did not affect relaxation responses nor the left heart ventricle-to-body weight (LHV/BW) ratio. DMF elevated Nfe2l2 expression (as the main effect) in the heart but did not alter BP and vascular functions vs. control when administered alone. Interestingly, DMF increased the LHV/BW ratio, supposedly due to reductive stress induced by continuous NRF2 activation. When combined with stress, DMF treatment prevented stress-induced hypertension and mitigated NA-induced vasoconstriction without altering relaxation functions. In addition, the combination of stress and DMF increased Tnf and Nos2 expression and the expressions of several genes involved in iron metabolism. In conclusion, these findings suggest that DMF can prevent chronic stress-induced hypertension by reducing vascular contractility. Moreover, DMF itself may produce reductive stress in the heart and induce inflammation when combined with stress. This indicates a need for the careful consideration of long-term DMF treatment considering its impact on the heart.

Abstract We129: Endothelium-Targeted MiR-122 Inhibition Improves Vascular Endothelial Function In a High-Fat Diet Fed mice

Background: MicroRNA-122-5p (miR-122), a liver-specific miR, levels are increased in the blood during obesity and diabetes and is taken-up by the extra-hepatic tissues including vascular endothelium. Despite miR-122’s role in maintaining hepatic homeostasis, its uptake (from circulation) by other tissues disrupts their function and increases the risk of cardiovascular disorders. Hence, inhibiting extra-hepatic miR-122 is a viable approach to mitigate vascular disorders associated with diabetes. Hypothesis: Endothelium-targeted miR-122 inhibitor selectively targets miR-122 in endothelial cells and improves vascular endothelial function in high-fat-diet (HFD) fed pre-diabetic mice. Methods: To selectively inhibit miR-122 in the endothelial cells, we synthesized gamma-peptide nucleic acid miR-122 inhibitor (γP-122 I) tagged with vascular cell adhesion molecule 1 (VCAM1) targeted peptide (e-γP-122 I). The purity was assessed using HPLC. Pre-diabetic condition was induced by feeding mice with a HFD (for 8 weeks) and e-γP-122-I was injected to the HFD-fed mice (2 weeks after dietary intervention; 5 mg/kg/day, i.p., 6 weeks). MiR-122 expression was measured by real-time PCR. The vascular endothelial function was assessed by determining endothelium-dependent and independent relaxation of phenylephrine-induced precontracted aortic rings. Results were expressed as mean ± s.e.m. Results: The e-γP-122-I was &gt;95% pure. The HFD-fed mice show higher levels of serum and aortic miR-122 expression and impaired vascular endothelial function. e-γP-122-I treatment selectively inhibited aortic miR-122 expression while it has no effect on other organs (heart, kidney etc.) and improved vascular endothelial function and inflammation. Conclusions: e-γP-122-I selectively inhibits miR-122 in the endothelium and improves endothelial function in pre-diabetic mice.

Polaron-mediated transport and relaxation phenomena in the lead zinc niobate (PZN) modified bismuth ferrite solid solution

To investigate the dielectric and conductivity properties of PZN modified BF solid solution high temperature mixed oxide technique is employed. The material is subjected to analysis using XRD, SEM, and impedance spectroscopy. A polycrystalline PZN-BF sample with an average crystallite size of 63.3 nm has been formed. The scanning electron micrographs show that the grains and grain boundaries are distributed suitably. dielectric characteristics of the 0.1PZN-0.9BF compound are studied at frequencies ranging from 1 kHz to 1 MHz and temperatures ranging from ambient temperature to 400 °C. The confined mobility of charge carriers causes nearly continuous loss (NCL) behavior at low temperatures (<200 °C). High-temperature relaxation resulting from charge carrier hopping induces maximum loss and elevated conductivity. Rendering to the Overlapping Large Polaron Tunnelling (OLPT) model of conductivity, the transport mechanism in this modified BiFeO3 (BF) compound is facilitated by the short-range hopping of polarons. The NTCR behavior from Arrhenius plot of ac conductivity and temperature independent conductivity relaxation from loss modulus (M'') analysis are demonstrated. Sensors, actuators, and optoelectronic devices can benefit from the PZN-modified BF compound's electrical and dielectric characteristics, which have been studied in detail.

PDGFRALPHA ACTIVATION LEADS TO BLOOD PRESSURE INCREASE AND SMALL ARTERIES MEDIAL HYPERTROPHY IN MALE MICE

Objective: Arterial remodeling is associated with vascular function alteration and with hypertension development. This remodeling is due to cells reorganization within the vascular wall and in some cases to smooth muscle cells proliferation. PDGF (Platelet-derived Growth Factor) is a major regulator of arterial remodeling and some studies suggest that PDGFRα, one of its receptors, could be activated during hypertension. Our aim is to determine the role of PDGFRα and of PDGFRα-expressing progenitor cells in vascular remodeling. Design and method: We used a tamoxifen-inducible genetic mouse model of PDGFRα constitutive activation. Blood pressure was measured by the tail-cuff method and by carotid catheter. Small mesenteric arteries reactivity was studied using ex vivo arteriography. Vascular remodeling was analyzed by immunofluorescence. Results: PDGFRα constitutive activation for 6 weeks led to a 25% increase in blood pressure (p&lt;0.05) and a 25% decrease in cardiac output in male mice (p&lt;0.05), without changes in other cardiac parameters. In these mice, small mesenteric arteries showed no alteration in contractility or endothelium-dependent and independent relaxation but an increase of media thickness, whereas larger vessels did not show structure or function alteration. Echo-doppler analyses showed an increased resistivity index of the renal artery (+13% p&lt;0.05) but not of the aorta suggesting an increased resistance of small renal arteries. The remodeling of small mesenteric arteries was characterized by an early proliferation of perivascular cells at 4 days but not of medial cells followed by the production of new smooth muscle cells after 2 weeks. Female mice did not show blood pressure increase following induction of PDGFRα constitutive activation for 6 weeks. Small mesenteric arteries showed a reduced contractility with alteration of endothelium-dependent and independent relaxation. Conclusions: These results suggest that PDGFRα activation could participate in arterial hypertension development by leading to increased media thickness and stiffness in small arteries in males. Our results suggest that in females the increased resistance of small vessels is compensated by a decreased contractility.

Smooth Muscle-Specific Knockout of LRRC8A Anion Channels Improves Vasodilation in Renal Arteries from Diabetic Mice

Leucine Rich Repeat Containing 8 (LRRC8) family proteins (LRRC8A, B, C, D and E) comprise volume-regulated anion channels (VRACs). We previously have shown that knockout (KO) or block of LRRC8A anion channel attenuates reactive oxygen species (ROS) production by Nox1, impairs TNFα-induced inflammation, and increases vascular relaxation in mesenteric arteries. These changes are associated with reduced RhoA activation. Diabetic (db/db−/−) mice have previously been shown to develop vascular dysfunction that is characterized by increased ROS production and enhanced RhoA activation. Diabetic nephropathy causes chronic renal disease and can lead to end-stage renal failure. Oxidative stress plays a role in both the initiation and progression of this process. We hypothesized that LRRC8A KO would protect vascular function in db/db−/− mice and promote vascular relaxation in renal arteries. Smooth-muscle specific LRRC8A KO mice were created in a db/db−/− background. Renal arteries were isolated from db/db−/− WT and db/db−/− LRRC8A KO mice vascular contraction and relaxation were measured. Contractile responses to phenylephrine (PE) were unaltered in LRRC8A KO compared to WT vessels. However, both endothelium-dependent (acetylcholine, ACh) and -independent (sodium nitroprusside, SNP) relaxation were increased in LRRC8A KO compared to WT rings that were contracted with PE (Emax ACh: WT 76.8 ± 5.5 vs. KO 92.2 ± 3.3 %, LogEC50 SNP: WT -7.6 ± 0.14 vs. KO -8.4 ± 0.14, n = 4-5, * p&lt;0.05). These data demonstrate preserved vasodilation in smooth muscle-specific LRRC8A KO blood vessels. This may lead to increased renal blood flow in the setting of db/db−/−-related diabetes. Ongoing work will determine if improved vasodilation is associated with preserved renal function in these animals. If so, VRAC inhibition may provide a novel therapeutic approach to the prevention and treatment of diabetes-induced renal dysfunction. This work was supported by DK132948 and HL160975. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Regular transient limb ischemia improves endothelial function and inhibits endothelial cell apoptosis to prevent atherosclerosis in rabbit

AimsRegular transient limb ischemia (RTLI) can prevent atherosclerosis (AS) progression in hypercholesterolemic rabbits. This study aimed to investigate the minimum effective intensity and possible mechanisms of RTLI for preventing atherosclerosis.MethodsEighty rabbits were divided into eight groups: normal (N), high cholesterol (H), three RTLI [three RTLI cycles every other day (R3qod), three RTLI cycles daily (R3qd), and six RTLI cycles daily (R6qd), each cycle of RTLI included 5 min of limb ischemia followed by 5 min limb reperfusion], and three correlated sham RTLI [sham ischemia for 30 min once every other day (S3qod), sham ischemia for 30 min once daily (S3qd), and sham ischemia for 60 min once daily (S6qd)]. Rabbits in group N were kept normally, while the others were fed 1% cholesterol diet for 12 weeks. The RTLI and sham RTLI groups were received RTLI or sham RTLI procedure, respectively. The plaque area in the thoracic aorta was determined by oil red O staining, and quantifying the ratio of plaque area to intimal area (PA/IA). Endothelium-dependent and -independent relaxation were also determined. Endothelial cell were isolated from abdominal aorta of rabbits, and the apoptosis ratio was detected using flow cytometry.ResultsThe PA/IA and early apoptotic cell ratio was significantly lower as well as the endothelium-dependent relaxation response was higher in group R6qd than those in groups H and S6qd, while those in the R3qod group was not significantly different from those in groups H and S3qod, as well as those in the R3qd group showed no significant difference compared to those in groups H and S3qd.ConclusionsSix cycles of RTLI daily was the optimal effective intensity to prevent AS progression in rabbits. Endothelial function improvement and apoptosis inhibition might contribute to the anti-AS effects.

Impaired vascular relaxation in type 2 diabetes: A systematic review and meta-analysis.

Type 2 diabetes (T2D) significantly increases the risk of vascular complications (12-32 %), which are a major cause of death (over 50 %) in T2D patients. In T2D, both endothelial (ET) and vascular smooth muscle (VSM) cells are impaired, which act as independent risk factors for cardiovascular disease. Thus, the question of this systematic review and meta-analysis is: Do ET-dependent and -independent VSM relaxation impair in T2D? We systematically searched PubMed and Scopus databases until March 2024; 44 eligible clinical trial studies (68, 16, 30, and 50 study arms for acetylcholine (ACh), methacholine (MTH), sodium nitroprusside (SNP), and glyceryl trinitrate (GTN)) published were included. ET-dependent VSM relaxation in response to ACh (overall ES = -28.9 %, 95 % CI: -35.2, -22.7; p<0.001) and MTH (overall ES = -55.3 %, 95 % CI: -63.6, -47.1; p<0.001) decreased in T2D patients compared to controls. ET-independent VSM relaxation in response to SNP (overall ES = -17.2 %, 95 % CI: -35.2, -22.7; p<0.001) and GTN (overall ES = -63.2 %, 95 % CI: -81.0, -45.5; p<0.001) decreased in T2D patients compared to controls. Our meta-analysis showed reductions in both ET-dependent (~40 %) and ET-independent (~25 %) VSM relaxation. The decrease was more pronounced for MTH (~55 %) compared to ACh (~30 %) and for GTN (~63 %) compared to SNP (~17 %). These findings suggest that dysfunction of both ET and VSM contributes to impaired VSM relaxation in T2D patients. See also the graphical abstract(Fig. 1).

Aging related decreases in NM myosin expression and contractility in a resistance vessel.

Introduction: Vasodilatation in response to NO is a fundamental response of the vasculature, and during aging, the vasculature is characterized by an increase in stiffness and decrease in sensitivity to NO mediated vasodilatation. Vascular tone is regulated by the activation of smooth muscle and nonmuscle (NM) myosin, which are regulated by the activities of myosin light chain kinase (MLCK) and MLC phosphatase. MLC phosphatase is a trimeric enzyme with a catalytic subunit, myosin targeting subunit (MYPT1) and 20kDa subunit of unknown function. Alternative mRNA splicing produces LZ+/LZ- MYPT1 isoforms and the relative expression of LZ+/LZ- MYPT1 determines the sensitivity to NO mediated vasodilatation. This study tested the hypothesis that aging is associated with changes in LZ+ MYPT1 and NM myosin expression, which alter vascular reactivity. Methods: We determined MYPT1 and NM myosin expression, force and the sensitivity of both endothelial dependent and endothelial independent relaxation in tertiary mesenteric arteries of young (6mo) and elderly (24mo) Fischer344 rats. Results: The data demonstrate that aging is associated with a decrease in both the expression of NM myosin and force, but LZ+ MYPT expression and the sensitivity to both endothelial dependent and independent vasodilatation did not change. Further, smooth muscle cell hypertrophy increases the thickness of the medial layer of smooth muscle with aging. Discussion: The reduction of NM myosin may represent an aging associated compensatory mechanism to normalize the stiffness of resistance vessels in response to the increase in media thickness observed during aging.

Perfluorooctane Sulfonate Exposure Induces Cardiovascular Dysfunction in Female Rats: Role of Ovaries.

Per- and polyfluoroalkyl substances (PFAS) are pervasive environmental pollutants frequently detected in drinking water worldwide. Reports linking PFAS exposure to cardiovascular disease have increased significantly in recent years. Furthermore, women appear to be more susceptible to the adverse effects of PFAS. However, the potential role of ovaries in the increased vulnerability of females to PFAS-related health effects remains unknown. In this study, we investigated the impact of perfluorooctane sulfonate (PFOS), a prominent PFAS, on the cardiovascular function in female rats with intact ovaries and ovariectomized (OVX) females. Bilateral OVX or sham surgeries were performed in 8-week-old female SD rats. Following recovery from surgeries, the rats were given drinking water containing 50 μg/mL of PFOS for 3 weeks. Control groups received PFOS-free water. PFOS exposure significantly reduced body weight but increased blood pressure similarly in both intact and OVX rats. Echocardiography analysis revealed that PFOS exposure decreased cardiac output, end-systolic volume, and end-diastolic volume in intact but not OVX rats. Vascular function studies demonstrated that PFOS equally reduced endothelium-dependent and -independent relaxation responses in intact and OVX rats. The endothelium-independent contractile responses were more pronounced in both intact and OVX rats. eNOS protein levels were similarly decreased in both intact and OVX rats. In conclusion, PFOS affects cardiac function through hormone-dependent mechanisms, while vascular function is impaired independent of ovarian status, indicating an intricate interplay between PFOS exposure, ovarian status, and cardiovascular function.

Exponential distribution functions for positivity-preserving lattice Boltzmann schemes: Application to 2D compressible flow simulations

A family of positivity-preserving lattice Boltzmann methods (LBMs) is proposed for compressible flow simulations in the continuum regime. It relies on the efficient collide-and-stream algorithm with a collision step based on exponential distribution functions. The latter serves as a generalization of Grad's post-collision distribution functions for which here (1) the linearized non-equilibrium contributions are replaced by their exponential forms and (2) the number of these contributions can be chosen arbitrary. In practice, post-collision moments of our exponential formulation are enforced through an iterative moment-matching approach to recover any macroscopic physics of interest, with or without external forces. This methodology directly flows from the extended framework on numerical equilibria [J. Latt et al., Philos. Trans. R. Soc. A 378, 20190559 (2020)] and goes one step further by allowing for the independent relaxation of hydrodynamic and high-order modes in a given moment space, notably, making the Prandtl number freely adjustable. The model is supplemented by a shock-capturing technique, based on the deviation of non-equilibrium moments from their equilibrium counterparts, to ensure good numerical properties of the model in inviscid and under-resolved conditions. A second exponential distribution accounts for extra degrees of freedom of molecules and allows for the simulation of polyatomic gases. To validate this novel approach and to quantify the accuracy of different lattices and moment closures, several 2D benchmark tests of increasing complexity are considered: double shear layer, linear wave decay, Poiseuille flow, Riemann problem, compressible Blasius flow over a flat plate, and supersonic flow past an airfoil. Corresponding results confirm the accuracy and stability properties of our approach for the simulation of compressible flows with LBMs. Eventually, the performance analysis further highlights its efficiency on general purpose graphical processing units.

Erythrocyte-derived extracellular vesicles from type 2 diabetes patients induce endothelial dysfunction through arginase 1

Abstract Background The mechanisms driving the development of cardiovascular injury in type 2 diabetes (T2D) remain incompletely understood. We recently demonstrated that red blood cells (RBCs) from patients with T2D (T2D-RBCs) act as mediators of endothelial dysfunction, but the mechanisms underlying this interaction are not clarified. We found that RBCs via upregulation of arginase 1 attenuate nitric oxide bioavailability and endothelial function. It is increasingly clear that extracellular vesicles (EVs) are actively secreted by practically all cell types, including RBCs, and represent a novel mechanism of intercellular communication. Purpose This study aimed to determine whether EVs derived from T2D-RBCs are involved as mediators in vascular injury through the signalling of arginase 1. Methods T2D-RBCs and RBCs from age-matched healthy controls (H-RBCs) were isolated and incubated with Krebs-Henseleit buffer (20% haematocrit). Following 18h incubation, the conditioned medium was collected for EV isolation using sequential ultracentrifugation and membrane affinity column. EV concentration was measured by nanoparticle tracking analysis. Aortas isolated from wild-type mice were incubated with EVs derived from T2D-RBCs and H-RBCs for 18h. Endothelium-dependent and -independent relaxations (EDR and EIDR, respectively) of the aortae were evaluated in a wire myograph. The involvement of arginase was investigated by the addition of the arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) either to the 18h co-incubation of EVs with the aortic segments to selectively investigate the contribution of EV-derived arginase (ABH, 10 mM) or to the aortae following the 18h co-incubation to selectively target vascular arginase (ABH, 100 µM). All animal experiments were performed according to the principles of laboratory animal care (NIH Publication no. 85-23 revised 1985) and human procedures according to the declaration of Helsinki and approved by the Swedish Ethical Review Authority. Results T2D-RBCs had a ten times lower EV concentration compared to H-RBCs. T2D-RBC-derived EVs isolated using both methods significantly impaired EDR (Fig. 1A-C), whereas EIDR was not affected. This effect was observed irrespective of if the same volume or concentration of EVs were administered. Inhibition of arginase with ABH during the co-incubation with EVs derived from T2D-RBCs completely prevented the impairment of EDR induced by the EVs (Fig. 1D). Administration of ABH to the aortae following the co-incubation also attenuated the impairment of EDR. Immunohistochemical staining revealed upregulation of arginase 1 (Fig. 2A-B) but not arginase 2 (Fig. 2C-D) in the vasculature following incubation with EVs from T2D-RBCs. Conclusion EVs derived from T2D-RBCs induce endothelial dysfunction, and arginase 1 derived from these EVs mediates this endothelial dysfunction. These results shed new important light on the mechanism underlying vascular injury mediated by RBCs in T2D.

Adding SGLT2 Cotransporter Inhibitor to PPARγ Activator Does Not Provide an Additive Effect in the Management of Diabetes-Induced Vascular Dysfunction

Introduction: Endothelial dysfunction (ED) plays a key role in the pathogenesis of diabetic vascular complications. In monotherapy, dapagliflozin (Dapa) as well as pioglitazone (Pio) prevent the progression of target organ damage in both type 1 (T1DM) and type 2 diabetes. We investigated whether the simultaneous PPAR-γ activation and SGLT2 cotransporter inhibition significantly alleviate ED-related pathological processes and thus normalize vascular response in experimental T1DM. Methods: Experimental diabetes was induced by streptozotocin (STZ; 55 mg/kg, i.p.) in Wistar rats. Dapa (10 mg/kg), Pio (12 mg/kg), or their combination were administrated to the STZ rats orally. Six weeks after STZ administration, the aorta was excised for functional studies and real-time qPCR analysis. Results: In the aorta of diabetic rats, impaired endothelium-dependent and independent relaxation were accompanied by the imbalance between vasoactive factors (eNos, Et1) and overexpression of inflammation (Tnfα, Il1b, Il6, Icam, Vcam) and oxidative stress (Cybb) markers. Pio monotherapy normalized response to vasoactive substances and restored balance between Et1-eNos expression, while Dapa treatment was ineffective. Nevertheless, Dapa and Pio monotherapy significantly reverted inflammation and oxidative stress markers to normal values. The combination treatment exhibited an additive effect in modulating Il6 expression, reaching the effect of Pio monotherapy in other measured parameters. Conclusion: Particularly, Pio exerts a vasoprotective character when used in monotherapy. When combined with Dapa, it does not exhibit an expected additive effect within modulating vasoreactivity or oxidative stress, though having a significant influence on IL6 downregulation.

Short-term Effects of Cadmium Exposure on Blood Pressure and Vascular Function in Wistar Rats.

Chronic cadmium exposure is known to be associated with vascular changes and increased blood pressure, but its short-term effects on the cardiovascular system remain poorly understood. This study aimed to investigate the pressoric and vascular effects of a 7-day exposure to CdCl2 in Wistar rats. The rats were divided in control group (Ct), which received tap water, and the Cd group, which received a 100mg/L CdCl2 solution via drinking water for 7days. We analyzed body weight, plasma Cadmium concentration, systolic blood pressure (SBP), and vascular responses. Despite relatively low plasma Cadmium concentration, the Cd group exhibited elevated SBP and increased contractile response to phenylephrine. Endothelium removal and NOS inhibition increased contractions in both groups. In the Cd group's aorta, we observed enhanced levels of phospho-eNOS (Ser1177) and basal NO release. Cd group showed reduced Catalase expression and increased basal release of H2O2, with catalase reducing the contractile response. In arteries pre-contracted with phenylephrine, Cd group showed impaired endothelium-dependent (Acetylcholine) and independent (sodium nitroprussiate-SNP) relaxation responses. However, responses to SNP were similar after pre-contraction with KCl in both groups. These data suggest early effects of Cadmium on blood pressure and aortic function, indicating impaired H2O2-scavenging by catalase. Increased H2O2 due to Cadmium exposure might explain heightened responses to phenylephrine and weakened relaxation responses mediated by the NO-K+-channels pathway. Our findings shed light on Cadmium's short-term impact on the cardiovascular system, providing insights into potential mechanisms underlying its effects on blood pressure regulation and vascular function.

Impact of Age on Endothelial Function of Saphenous Vein Grafts in Coronary Artery Bypass Grafting.

An intact and functionally preserved endothelial layer in the graft is crucial for myocardial perfusion and graft patency after coronary artery bypass grafting (CABG). We hypothesized that old age is a risk factor for decreased endothelial function of bypass grafts. Thus, we investigated the impact of age in patients treated with CABG on endothelial function in saphenous vein grafts. We mounted the saphenous vein graft segments of CABG patients < 70 (n = 33) and ≥70 (n = 40) years of age in organ bath chambers and exposed them to potassium chloride (KCl) and phenylephrine (PE) to test the receptor-independent and -dependent contractility, followed by exposure to acetylcholine (ACh) and sodium nitroprusside (SNP) to test the endothelial-dependent and -independent relaxation. The maximal contraction induced by KCl (2.3 ± 1.8 vs. 1.8 ± 2 g) was stronger in patients ≥ 70 years of age. The relative contraction induced by PE in % of KCl (167 ± 64 vs. 163 ± 59%) was similar between groups. Patients aged < 70 years showed a higher endothelial-dependent relaxation induced by acetylcholine than patients ≥ 70 years (51 ± 27 vs. 42 ± 18%). The relaxation induced by SNP was similar between both groups. The endothelial function of saphenous vein bypass grafts decreases during aging. Thus, age should be considered when improving graft maintenance.

Dielectric, thermal and gamma shielding characteristics of PbO–TeO2–V2O5–CoO glasses

For the first time the lead vanado-tellurite glasses with varied concentrations of CoO were prepared and investigated for dielectric, thermal and gamma shielding properties. Density found increased and molar volume decreased, glass transition temperature and thermal stability increased with increase of CoO mole fractions. Dielectric and impedance spectra have been studied for temperature range 300K–500K and frequency range 50 Hz - 20 MHz. Dielectric constant is found to vary in the range from 10.10 × 102 to 5.56 × 102 and dielectric loss 1.42–1.55 × 104. With increase of frequency, both dielectric constant and loss decreased, and increased with increase of temperature. A single semiconducting phase is revealed by cole-cole plots. The dc conductivity deduced form impedance data and its activation energy is found increased with CoO content. Dielectric relaxation period and thermal activation energy for impedance and modulus were determined. These results are in close agreement with one another. Electric moduli master curves revealed temperature independent relaxation mechanism. Utilizing Phy-X/PSD software γ-radiation attenuation characteristics were determined. Mass and linear attenuation coefficients are found to be greater and, half and tenth value layer values smaller than those reported for several commercial glasses and rocks. Exposure build up factor and energy absorption build up factor were found to be smaller and fast neutron removal cross section values greater than those reported for various concretes, glasses and rocks in the literature. Present glasses through the evaluated characteristics, showed better gamma and neutron shielding efficiency compared to various systems quoted in the literature.

Ultrafast electron dynamics in Au/Fe/MgO(001) analyzed by Au- and Fe-selective pumping in time-resolved two-photon photoemission spectroscopy: Separation of excitations in adjacent metallic layers

The transport of optically excited, hot electrons in heterostructures is analyzed by femtosecond, time-resolved two-photon photoelectron emission spectroscopy (2PPE) for epitaxial Au/Fe/MgO(001). We compare the temporal evolution of the 2PPE intensity upon optically pumping Fe or Au, while the probing occurs on the Au surface. In the case of Fe-side pumping, assuming independent relaxation in the Fe and Au layers, we determine the hot electron relaxation times in these individual layers by an analysis of the Au layer thickness dependence of the observed, effective electron lifetimes in the heterostructure. We show in addition that such a systematic analysis fails for the case of Au-side pumping due to the spatially distributed optical excitation density, which varies with the Au layer thickness. This work extends a previous study [Beyazit et al., Phys. Rev. Lett. 125, 076803 (2020)] by new data leading to reduced error bars in the determined lifetimes and by a non-linear term in the Au-thickness dependent data analysis which contributes for similar Fe and Au film thicknesses.