bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of fetal cells of the nervous tissue during postresuscitational encephalopathy in rats of different sex and ages
Authors: Aitbayeva Zhaina 
Published: June 2021

The aim of the study was to examine the comparative aspect of the influence of the intraperitoneal injection of fetal cells in the nervous tissue during postresuscitational encephalopathy in rats of different sex and age. For the purposes of investigating the qualitative and quantitative composition of phospholipids lipid extraction of the cerebral cortex was produced based on the method of J. Falchion (Folch J. et al., 1957) and fractionation of phospholipids (PL) based on the thin layer chromatography on silica gel. The study revealed that the intraperitoneal injection of a suspension of fetal neural cells accelerates the rate of replenishment of neurological deficit and increases survival reanimated males of all ages.The introduction of fetal nerve cells improves the spectral composition of phospholipids in brain homogenate lively males and worsens at reanimated females. Repeated injection of cells of fetal neural tissue leads in all experimental groups to the adverse redistribution of fractions of phospholipids.
End Binding protein 3 regulates calcium signaling and permeability of the endothelial barrier
Authors: Geyer Melissa , Gu Lianzhi , Vogel Stephen M. , Malik Asrar B. , Komarova Yulia A. 
Published: June 2021

End binding (EBs) proteins bind growing microtubule (MT) plus ends and promote MT growth. We have recently shown that Vascular Endothelial (VE)‐cadherin outside‐in signaling regulates phosphorylation of EB3 to suppress MT persistent growth and thus allowing for the assembly of adherens junctions (AJs). Depletion of EB3 has no effect on either MT dynamics or formation of (AJs) in confluent endothelial monolayers. However, depletion of EB3 significantly attenuates cell shape change and permeability increase in cells subjected to pro‐inflammatory mediator thrombin. EB3 interacts with inositol 1,4,5‐thriphosphate receptor type 3 (IP3R3) and facilitates agonist‐induced clustering of IP3R3 and IP3‐dependent release of calcium from intracellular stores. Cell permeant variant of IP3R3‐derivative peptide containing EB3 consensus motif reduces the interaction between EB3 and IP3R3 and mitigates increased endothelial permeability response. Furthermore, infusion of this peptide in ex vivo murine lung preparation attenuates increase in lung vascular liquid permeability (Kf,c) in response to activation of the Protease‐Activated Receptor‐1 (PAR‐1). Intravenous injection of this peptide prevents lung injury and reduces the lethality of polymicrobial sepsis in mice. These data indicate that EB3 regulates calcium signaling in endothelium and facilitates pulmonary vascular leak in disease states.This work was supported by NIH grants R01 HL103922 and Giles F. Filley Memorial Award to Y. K.; R01 HL 45638 to A.B. M.; T32 HL07829–17 support to M. G.
Angiotensin II receptor synergism with prostaglandin E2 receptors
Authors: Palazzo Maria C. , Breyer Richard M 
Published: June 2021

Upon intravenous infusion prostaglandin E2 (PGE2) acts as a systemic vasodepressor in mice and humans. Under certain circumstances however PGE2 may act as a vasopressor. Subthreshold concentrations of vasoconstrictors such as potassium chloride or phenylephrine enhance PGE2‐mediated vasoconstriction. Here we demonstrate using wire myography that angiotensin II (Ang II), a principal effector of the renin‐angiotensin‐ aldosterone‐system, potentiates PGE2‐mediated vasoconstriction in mouse femoral arteries. Using knockout mice and pharmacological inhibitors, we have determined that this potentiation effect is mediated via the angiotensin AT1 receptor and the PGE2 EP3 receptor. Y‐27632, a Rho kinase inhibitor, blocked the Ang II‐evoked potentiation of EP3 action suggesting a role for the Rho‐ROCK pathway in the observed potentiation. Our data support the hypothesis that angiotensin II synergizes with PGE2 to induce vasoconstriction. The significance on blood pressure homeostasis and detailed mechanism of this interaction remains to be determined.This work was supported by a grant from the NIH NIDDK DK37097(RMB)
Inflammatory signaling as a therapeutic target for the treatment of breast cancer‐induced bone pain.
Authors: Sayers Nicole Marie , Symons‐Liguori Ashley M , Lozano‐Ondoua Alysia N , Vanderah Todd W 
Published: June 2021

Many common cancers, including breast, prostate, lung and kidney, have a high propensity for bone metastasis; for breast cancer, 70% of malignancies will metastasize to bone, resulting in debilitating pain and bone destruction in 75–95% of patients. Despite the prevalence of bone pain in cancer patients, the specific causes and therapeutic targets for managing bone pain are poorly understood. Breast cancer metastasis to bone results in a proinflammatory shift in the bone‐tumor microenvironment. Here we hypothesize that breast cancer‐induced bone metastasis elicits pain by the actions of pro‐inflammatory mediators at their receptors on nociceptive neurons in the bone and periosteum.In the following work, we utilize an in vivo model of breast cancer‐induced bone pain that results in both spontaneous and evoked pain behaviors. Initial studies determined that the expression of proinflammatory cytokines (tumor necrosis factor‐α, interleukin‐6) and chemokines (chemokine C‐C motif ligands 2 and 3) are enhanced in tumor‐bearing bone, but not the contralateral bone or serum. mRNA quantitation of bone marrow extrudate corroborated these findings. The attenuation of bone‐derived inflammatory mediators by cannabinoid‐receptor 2 agonists, which produce inflammatory suppression of immune cells, was associated with decreases in evoked and spontaneous pain behaviors.Furthermore, we demonstrate in vitro that inflammatory mediators are constitutively produced by a murine breast cancer cell line. Cannabinoid receptor‐2 agonists attenuated not only the production of cytokines and chemokines by cancer cells, but also attenuated interleukin‐6 or tumor necrosis factor α‐induced proliferation. The results of these data suggest that tumor‐derived inflammatory mediators may drive bone cancer pain. Targeting the inflammatory component of metastatic bone pain provides a novel therapy for pain management in breast cancer‐induced bone pain.
Impaired monoamine and organic cation uptake in choroid plexus in mice with targeted disruption of the plasma membrane monoamine transporter (Slc29a4) gene
Authors: Duan Haichuan , Wang Joanne 
Published: June 2021

The choroid plexus (CP) forms the blood‐cerebrospinal fluid (CSF) barrier (BCSFB) and protects the brain from circulating drugs and toxins. Plasma membrane monoamine transporter (PMAT, SLC29A4) is a novel polyspecific monoamine and organic cation (OC) transporter. Here we investigated the role of PMAT in CP transport of endogenous amines and xenobiotic cations. The mRNA expression of PMAT and functionally related transporters, including the classic monoamine transporters (SERT, DAT, NET) and the OC transporters (OCT1~3, MATE1/2), were measured in human and mouse CPs. The expression and membrane localization of the PMAT protein were determined by immunostaining. A mouse model with targeted deletion of the Slc29a4 gene was generated and validated. The significance of PMAT in CP uptake of monoamines/OCs was evaluated in uptake assays using CPs from wild type and Pmat−/−mice. Our results showed that PMAT is the predominant OC/monoamine transporter in the CP and is localized to the CSF‐facing apical membrane of the CP epithelium. Pmat−/−mice are viable, fertile with no overt physiological abnormalities. Importantly, Pmat−/−CPs showed much reduced (~30–40%) uptake of monoamines/OCs. There was no significant involvement of other tested transporters. Together our data demonstrated that PMAT transports monoamines/OCs from the CSF into the CP and mediates the first step of monoamine/OC brain efflux at the BCSFB.This work was supported by NIH Grants GM066233 and GM066233–07S1.
Electrophysiological recordings in rats performing the sustained attention task
Authors: Edgerton Jeremy , Neal Sarah , Harvey Brian , Kiss Tamás , Grimwood Sarah 
Published: June 2021

Cognitive impairments are associated with many brain disorders. Past efforts to develop treatments have relied heavily on rodent behavioral measures to assess drug efficacy, with little success. In response, efforts are underway to identify neural circuit activity patterns that underlie cognitive processes and that may provide more sensitive and predictive measures of drug efficacy.The goal of the present study was to begin characterizing the neural circuit activity related to directed visual attention in rats. We implanted recording electrodes into attention‐related brain areas of rats trained in the sustained attention task, and recorded local field potential (LFP) activity as the rats performed the task. The LFPs were modulated by task events including visual stimuli, lever pressing, and reward delivery, with a strong beta frequency oscillation appearing in multiple sites in response to the reward. Visual evoked potentials in posterior parietal cortex were much larger in correct trials than in error trials, suggesting that this signal is indicative of visual stimulus detection. These results support the continued development of LFP recordings in behaving rodents as a potential means to evaluate new therapeutic compounds for CNS disorders.The study was funded by Pfizer Inc.
Interleukin‐1β‐induced BBB dysfunction involves decreased claudin‐5 protein expression and is dependent on non‐muscle myosin light chain kinase
Authors: Beard Richard S. , Wu Kevin Y. , Reynolds Jason J. , Davis Stephanie M. , Haines Ricci J. , Wu Mack H. , Yuan Sarah Y. 
Published: June 2021

Aberrant elevation in the pro‐inflammatory cytokine interleukin‐1β (IL‐1β) contributes to neuroinflammatory diseases. Blood‐brain barrier (BBB) dysfunction is a hallmark phenotype of neuroinflammation, and it is known that IL‐1β directly induces BBB hyperpermeability, but the mechanisms remain unclear. Claudin‐5 (Cldn5) is a tight junction protein expressed at endothelial cell‐to‐cell contacts and is critical for maintaining BBB integrity. Non‐muscle myosin light chain kinase (nmMLCK) is a key regulator involved in endothelial permeability, and IL‐1β has been shown to modulate nmMLCK in intestinal epithelium. Considering these factors, we tested the hypothesis that IL‐1β decreases Cldn5 expression to induce BBB hyperpermeability in an nmMLCK dependent manner. Treating brain microvascular endothelial cells (BMVEC) with IL‐1β decreased trans‐endothelial electrical resistance (TER), increased monolayer permeability, and significantly decreased Cldn5 expression. However, BMVECs isolated from nmMLCK−/− mice showed attenuated TER response and unchanged Cldn5 expression upon IL‐1β challenge. In culmination, experimental autoimmune encephalomyelitis (EAE) was used as a model of neuroinflammation, and EAE‐induced BBB hyperpermeability observed in wild‐type mice was significantly reduced in nmMLCK−/− mice.Supported by NIH RO1 HL061507, GM097270, HL070752 and HL096640.
Metabolic adaptation of microvessel steady state diameters: Is oxygen sensing really needed?
Authors: Reglin Bettina E. , Secomb Timothy W. , Pries Axel R. 
Published: June 2021

BackgroundSignals related to local blood supply lead to an increase of diameter and flow in microvessels upon underperfusion, establishing a negative feedback regulation. Current concepts assume release of metabolic signaling substances in response to low oxygenation from the vessel wall, the tissue or red blood cells. Here, we investigated principles of feedback regulation in the metabolic adaptation of steady state vessel diameters.MethodsA simulation model of vascular diameter adaptation was applied to a mesenteric vascular network (576 segments) to study implications of different assumptions with respect to metabolic signaling on oxygen and blood flow distribution. Deviations of simulated parameters from measured values (velocity, diameter) were analyzed.Results1. Oxygen dependence of metabolic signaling is not needed to establish negative feedback regulation due to a ‘dilution effect’ by blood flow. 2. Oxygen dependence does not provide a negative feedback in metabolic signaling by tissue cells in case of insufficient vessel density. 3. Positive feedback and thus instability is evoked, if the amount of metabolic signal producing structures increases with vessel diameter or flow, as is the case in metabolic signaling by RBC.ConclusionSurprisingly, oxygen dependence of metabolic signaling is not needed for diameter adaptation under resting conditions in microvascular networks.
Transmission of pulsatility in the microcirculation: Where and how damping occurs?
Authors: Pan Qing , Wang Ruofan , Reglin Bettina , Yan Jing , Ning Gangmin , Pries Axel R. 
Published: June 2021

BackgroundPulsatility of blood flow plays a critical role in vascular regulation. It is prominent in arterioles but attenuated in venules, due to damping in microvascular beds. However, the damping mechanisms of flow pulsatility in microcirculation remain unclear.MethodsTo explore the damping process, we developed a mathematical model describing pulse propagation and reflection through vascular network and applied it to artificial test networks with defined properties and a mesenteric experimental network (546 segments). Pulse damping was quantified by percent change in pulsatility index (PI, pressure amplitude/mean pressure).ResultsIn passage through experimental and test networks, PI is reduced by about 30%. Possible damping mechanisms were investigated by changing modeling parameters and properties of test networks. PI damping was not affected by eliminating viscous properties of vascular wall. Upon eliminating wave reflection related to output boundaries, bifurcations, and to vascular resistance, PI damping was reduced to 27, 18, and 2%, respectively.ConclusionDamping related to vascular resistance dominates in the microcirculation and is mostly related to wave reflection. (supported by National Nature Science Foundation of China, # 81271662).
Mechanistic Studies of AVE3085 Against Homocysteine in Endothelial Protection
Authors: Yang Qin , Xue Hong‐Mei , Yu Cheuk‐Man 
Published: June 2021

The effect and mechanisms of eNOS transcription enhancer AVE3085 on homocysteine (Hcy)‐induced endothelial dysfunction were studied in porcine coronary small arteries. Myograph study of relaxation, electrochemical measurement of NO, RT‐PCR and Western blot analysis of eNOS, iNOS expression, and eNOS phosphorylation were performed. Arginase activity was determined by urea production and O2.− generation by lucigenin‐enhanced chemiluminenscence. Exposure to Hcy for 24h attenuated bradykinin‐induced relaxation and NO release, lowered eNOS mRNA, eNOS protein, and p‐eNOSSer1177 whereas elevated iNOS level. AVE3085 restored NO release and relaxation, enhanced eNOS but decreased iNOS expression. Inhibition of Akt or PI3 kinase attenuated the effect of AVE3085 on relaxation and eNOS phosphorylation. Arginase activity and O2.− production were inhibited by AVE3085 in Hcy‐exposed vessels. AVE3085 prevents Hcy‐induced endothelial dysfunction by preservation of NO and inhibition of O2.− production. The preservation of NO‐related function is attributed to upregulation and activation of eNOS and inhibition of arginase. Reduction of O2.− results from reversal of eNOS uncoupling by inhibition of arginase and iNOS. PI3 kinase/Akt pathway is involved in AVE3085‐induced eNOS activation.Supported by GRF CUHK4789/09M & 4774/12M; NSFC 81200123; Key Med. Program of Tianjin Binhai Health Bureau 2011BHKZ001.
Treadmill running improves diabetes‐induced capillary regression in skeletal muscle through activation of VEGF and angiopoietin pathways without inhibition of thrombospondin‐1
Authors: Fujino Hidemi , Kondo Hiroyo , Murakami Shinichiro , Tanaka Masayuki , Nagatomo Fumiko , Fujita Naoto , Ishihara Akihiko 
Published: June 2021

PURPOSEExercise has been shown to be an effective treatment in the prevention of some complications due to type 2 diabetes (T2DM). The purpose of this study was to investigate the effects of treadmill running on the capillary regression and associated angiogenic factors in the soleus muscle of T2DM rats.METHODSGoto‐Kakizaki (GK) and Wistar rats were randomly divided into an exercise training (T2DM+Ex, Con+Ex) and a sedentary group (T2DM, Con). The T2DM+Ex and Con+Ex rats were run at a low‐intensity on a treadmill 6 times a week for 3 weeks. The capillary in soleus muscle was visualized using 3‐D method. The expression of pro‐angiogenic factors, and anti‐angiogenic factor, thrombospondin‐1 (TSP‐1), in the soleus muscle were determined by TaqMan probe‐based PCR.RESULTSAlthough the capillary volume of the soleus muscle was lower in T2DM than in Con rats, that in T2DM+Ex and Con+Ex was higher than that in Con. VEGF and Angiopoietin pathways in the T2DM+Ex were significantly increased compared with those in other groups although TSP‐1 level increased.CONCLUSIONThese findings suggest that treadmill running improves the regression of capillary in diabetic muscle, and the pro‐angiogenic pathways in diabetic muscle could be up‐regulated by exercise. Supported by Grants‐in‐Aid for Science Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology.
Intrinsic balance of small artery active and passive diameter‐tension relations
Authors: Tuna Bilge Guvenc , Bakker Erik NTP , VanBavel Ed 
Published: June 2021

Arterial remodeling is important in the pathogenesis of vascular diseases and target organ damage. In this study we induced matrix remodeling to smaller diameters and studied active diameter‐tension relations to understand the link between active and passive biomechanics.Diameter‐tension relations were obtained in the passive state and upon full activation (125 mM K+ + 10−6 M NE) by wire myography before and after matrix cross linking by incubation with transglutaminase 2 (1, 5 hours TG2, 50μg/ml, n=6) or after low flow induced remodeling by ligation of rat mesenteric small arteries (1 day LF1, 3days LF3, n=8). The diameter for peak force capacity (Dopt, control 289±6, TG2 258±9*, LF1 258±12*, LF3 247±5*) shifted in the same direction as the passive diameter at 100 mmHg equivalent pressure (D100, control 353±9, TG2 317±17#, LF1 302±13#, LF3 301±7#), normalizing Dopt/D100 balance in vitro and in vivo. Active force at large distention fell simultaneously with increased passive force in all groups. Only LF3 vessels had increased contractile capacity at small diameters.In conclusion, active tension capacity at high distension is masked by passive tension, challenging the concept that active and passive elements are arranged simply parallel, and suggests that there is an intrinsic mechanism linking biomechanical properties of active and passive components.
Targeting of 11β‐hydroxysteroid dehydrogenase type 2 (11βHSD2) in the nucleus of the solitary tract (NTS) links salt appetite and hypertension
Authors: Evans Louise Christine , Kenyon Christopher , Mullins John , Holmes Megan , Bailey Matthew 
Published: June 2021

11βHSD2 catalyses the inactivation of cortisol to cortisone, and thus ensures aldosterone‐specific activation of MR in target tissues. Cre‐lox technology was used to selectively target hsd11b2 expression in the NTS of mice. Telemetry was used to measure blood pressure during which Cre+ and Cre− mice (n=6 per group) had free access to either H2O or H2O and 1.5% NaCl. Cre+ mice were normotensive when given access to water. When offered a choice of water or saline, Cre+ mice had a significant salt preference (68% total fluid intake was NaCl), contrasting with Cre‐mice, which had salt aversion (40% total fluid intake was NaCl). The increased salt intake resulted in significant hypertension, (P=0.0004 active period, P=0.0178 inactive period). In Cre+ mice hypertension occurred over a time period during which balance studies showed that sodium was not retained. When salt‐intake was matched in Cre+ and Cre− mice, only the mice with NTS targeting of hsd11b2 developed a salt induced hypertension.Here we have defined a role of mineralocorticoid receptors in the NTS that unifies the behavioral drive to consume sodium with the long‐term control of blood pressure. These data indicate a primary central component to the hypertension in the Cre+ mice. Funded by British Heart Foundation.
Endoplasmic reticulum stress is upstream of angiotensin‐II (Ang‐II)‐induced reactive oxygen species (ROS) formation in the subfornical organ (SFO)
Authors: Young Colin N. , Wang Gang , Iadecola Costantino , Mark Allyn L. , Davisson Robin L. 
Published: June 2021

We have demonstrated that oxidative stress and endoplasmic reticulum (ER) stress in the brain SFO mediate Ang‐II‐dependent hypertension (HTN). Whether these two mechanisms are linked remains unknown. Here we tested the hypothesis that ER stress mediates Ang‐II‐induced oxidative stress in the SFO. First, freshly dissociated murine SFO cells were treated with Ang‐II in the presence or absence of the chemical ER stress inhibitor TUDCA. Dihyroethidium (DHE) was used as the ROS indicator. Ang‐II caused a significant increase in ROS production in SFO cells and this response was abrogated by pretreatment with TUDCA (1.28±0.04 vs 1.00±0.01 fold vehicle, Ang‐II vs Ang‐II + TUDCA, p<0.05). Second, C57Bl/6 mice underwent SFO‐targeted microinjections of an adenovirus encoding the ER chaperone GRP78 (AdGRP78, n=4), an approach we have shown to reduce ER stress and prevent Ang‐II HTN. SFO‐targeted AdLacZ (n=4) served as a control. Following recovery, mice were implanted with osmominpumps for 2 wk delivery of low‐dose Ang‐II. Ang‐II caused a significant increase in DHE fluorescence in the SFO at 14 days of Ang‐II infusion. This increase in ROS formation was prevented by SFO‐selective reduction in ER stress using AdGRP78 (1.78±0.21 vs 1.02±0.03 fold untreated, AdLacZ vs AdGRP78, p<0.05). These findings demonstrate that Ang‐II‐induced ER stress is a source of SFO oxidative stress in this model of HTN.HL63887, HL96571, HL84207
Humoral immune system activation promotes the development of hypertension
Authors: Mathis Keisa W. , Wallace Kedra , Lamarca Babbette , Ryan Michael J. 
Published: June 2021

Circulating autoantibodies are elevated in patients with essential hypertension suggesting the possibility of humoral immune system activation. Whether humoral immunity underlies the pathogenesis of hypertension is unclear. We hypothesized that humoral immune suppression (B cell depletion) would prevent the development of hypertension in a mouse model of the autoimmune disease systemic lupus erythematosus (SLE). Female SLE (NZBWF1) and control mice (NZW) were treated weekly with anti‐CD20 (10 mg/kg, Genentech) or vehicle (anti‐IgG) starting at 20, 26, and 30 weeks of age and ending at 34 weeks. Anti‐CD20 treatment reduced spleen weight in all groups regardless of treatment duration. Mean arterial pressure (MAP; mmHg) was higher in SLE mice compared to controls in all groups [(20 weeks; 134±1 vs 115±3, p<0.01); (26 weeks; 139±5 vs 116±2, p<0.001); (30 weeks; 138±2 vs 117±6, p<0.001)]. Anti‐CD20 did not alter MAP in SLE mice treated from 26 (131±3) or 30 (135±4) weeks of age. However, MAP was lower in SLE mice treated with anti‐CD20 starting at 20 weeks of age (120±3; p=0.01). Anti‐CD20 did not affect MAP in any control group. These data suggest that suppression of humoral immunity early in disease progression, but not later, can prevent the development of hypertension and supports the idea of autoimmunity as an underlying mechanism.AHA4350019/5T32HL105324, HL085907/HL092284/HL085907S1/UMMC‐IRSP, HL051971