bluuebunny/crossref_metadata_2025_split huggingface dataset:
FK506‐binding protein 51 plays a role in pulmonary endothelial cell phenotype switching
Authors: Brown Jonathan R. , Morrow Rebekah L. , Morrow K. Adam , Vasauskas Audrey A. 
Published: June 2021

It is well‐established that endothelial cells exhibit heterogeneity. Indeed, in the pulmonary vasculature, pulmonary artery endothelial cells (PAECs) and pulmonary microvascular endothelial cells (PMVECs) exhibit a many differences, including differences in proliferation rate and growth inhibition. PMVECs have a greater proliferative potential than PAECS and do not exhibit contact inhibition of growth in culture. Additionally, PMVECs express higher levels of FK506‐binding protein 51 (FKBP51) than PAECs, a trait that confers resistance to the store‐operated calcium current, Isoc. Here, we asked whether FKBP51 affects endothelial cell phenotype. Pulmonary arterial hypertension is marked by endothelial dysfunction and vascular remodeling, and it has been suggested that phenotype switching via endothelial‐to‐mesenchymal transition or resident stem cells may contribute to disease progression. We investigated the role of FKBP51 in phenotype switching using an FKPB51‐overexpressing PAEC cell line. FKBP51‐overexpressing PAECs showed a two‐fold increase in doubling time compared to wild type PAECs. PAECs grow in islands, exhibiting a cobblestone appearance and contact‐dependent growth inhibition. On the other hand, FKBP51‐overexpressing PAECs have a PMVEC‐like phenotype, wherein cells take on a spindle‐like morphology when sub‐confluent and are not growth inhibited at confluence. In addition, FKBP51‐overexpressing PAECs show increased smooth muscle actin, an indicator of endothelial cell dedifferentiation, as compared to wild‐type PAECs. Taken together, these data suggest that FKBP51 may play an important role in phenotype switching in PAECs.Support or Funding InformationAmerican Heart Association #17AIREA33680155This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sympathetic Innervation Promotes Bone Marrow Homing of Specific CD8+ Effector Memory T Cells in Hypertension
Authors: Xiao Liang , Itani Hana A. , Foss Jason D. , Chen Wei , Harrison David G. 
Published: June 2021

We have recently identified a critical role of hypertension‐specific effector memory T lymphocytes (TEM cells) in the blood pressure elevation and renal dysfunction caused by repeated hypertensive stimuli. Formed during an initial immune challenge, TEM cells reside in the bone marrow (BM) in a quiescent state for prolonged periods, and can be reactivated upon re‐exposure to the hypertensive stimulus. Hypertension is associated with increased sympathetic outflow. We therefore hypothesized that sympathetic nerves regulate accumulation and reactivation of hypertension‐specific TEM cells in the BM. We performed unilateral superior cervical ganglionectomy (SCGx) in wild‐type C57BL/6 mice, causing selectively sympathectomy of the forelimb on the surgical side. After recovery, mice received Ang II infusion for two weeks. To determine the changes of T cells in the BM that were specific to hypertension, 5×106 BM cells were isolated from either the SCGx or control limbs, loaded with proliferation marker CFSE, and co‐cultured with 0.5×106 splenic dendritic cells isolated from another Ang II‐infused mouse. We found 30% less CD8+ T cell proliferation in the SCGx BM compared to control side (1.9±0.2 vs. 2.8±0.1×104, p<0.001), but no difference in CD4+ T cells. To further study the effect of sympathetic nerves on BM T cell homing, 1×107 pan T cells were isolated from CD45.2+ wild‐type mice after Ang II infusion and adoptively transferred to CD45.1 mice that had previously undergone unilateral SCGx. Flow cytometry indicated that 7 days after transfer, 25% fewer CD8+ TEM cells from the hypertensive donors homed to the SCGx BM compared to the innervated BM (5.3±0.8 vs. 8.1±1.5 per 104 total T cells, p<0.05), suggesting that sympathetic nerves regulate CD8+ TEM homing in the bone marrow at baseline condition. To study enhanced local sympathetic nerve activity in BM observed in hypertension, excitatory DREADD (designed receptor exclusively activated by designed drug) was expressed in the SCG on one side of mice by microinjection of adeno‐associated viral vector. Two weeks later, the animals received pan‐T cells adoptively transferred from hypertensive donors, and the specific ligand clozapine‐N‐oxide for DREADD was given in drinking water for 7 days. In contrast to denervation, augmenting sympathetic nerve activity increased CD8+ TEM homing by ~50% compared to the baseline level (14.9±2.7 vs. 9.3±2.3 per 104 total T cells, p<0.01). These data define a novel role of sympathetic nerves in regulation of memory T cell trafficking in hypertension. Adrenergic blockade may be beneficial in disrupting survival of these injurious T cells, and thus might provide protection against repeated hypertensive stimuli known cause their reactivation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Reduced bone marrow adrenergic receptor signaling is protective against weight gain and high fat‐induced hypertension
Authors: Ahmari Niousha , Yang Tao , Malphurs Wendi , Martyniuk Christopher J. , Zubcevic Jasenka 
Published: June 2021

INTRODUCTIONNeurogenic hypertension (HTN) is characterized by activation of immune system (IS) in part via elevated sympathetic nerve activity (SNA) to the bone marrow (BM). We have previously shown that chronic increase in BM SNA is linked with heightened release of inflammatory cells (ICs) in rodent models of HTN. Conversely, specific genetic ablation of BM beta adrenergic receptors results in a decrease in circulating ICs and reduces blood pressure (BP). Considering the role of both elevated SNA and IS in obesity, we hypothesized that reduction of SNA effects on BM ICs will dampen the inflammation and BP responses to high fat diet.METHODSBM mouse chimera was created by reconstituting sub‐lethally irradiated male C57BL/6J mice (6 weeks old) with whole BM cells isolated from either the adrenergic beta 1 and beta 2 receptor knock out (Adrb1.b2KO) mice (Jax Labs stock#003810), to generate BM C57‐Adrb1.b2 KO chimera, or the wild type C57BL/6J mice, to generate BM C57‐C57 control chimera. Success of reconstitution was confirmed by PCR for beta 1 and 2 adrenergic receptors in circulating cells following a 3 month recovery. Mice were placed on either control (10 kcal fat) or high fat diet (60 kcal fat) ad libitum for two weeks. Weight and food intake were measured twice weekly in all mice. BP measurements were taken using tail cuff at baseline, and thereafter three times a week throughout the study. Visceral fat pads were collected and weighed at the conclusion of the study. Flow cytometry was used to quantify circulating ICs (T cells, neutrophils, macrophages) and endothelial progenitor cells at endpoint.RESULTSBoth the BM C57‐C57 control chimera and BM C57‐Adrb1.b2 KO chimera mice had a statistically significant increase in total body weight following two weeks of high fat diet (by 5.33 g on average; P<0.05 vs control). However, only BM C57‐C57 control chimera mice had a significant increase in perirenal, epidymul, and retroperitoneal fat following high fat diet feeding (P<0.05). While mice on control diet had comparable BP values between the two groups, we observed a significantly elevated BP in BM C57‐C57 control chimera mice compared to the BM C57‐Adrb1.b2 KO chimera on high fat diet (mean systolic BP: 126.0 mmHg vs 105.7mmHg; p<0.05). However, no significant changes were observed in quantity of circulating CD4 T‐cells, macrophages, neutrophils or endothelial progenitors between the two mouse groups.CONCLUSIONReduced responsiveness of the BM hematopoietic cells to SNA is protective against high fat diet‐induced visceral fat gain and HTN, without significant changes in overall weight gain or circulating inflammatory cells.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Early blood pressure response to isometric exercise is attenuated in obese individuals who have undergone bariatric surgery
Authors: Guo Winston , Joyner Michael J. , Curry Timothy B. , Limberg Jacqueline K. 
Published: June 2021

ObjectiveBlood pressure (BP) reactivity to stress is predictive of the development of cardiovascular disease. Cardiovascular reactivity is attenuated in individuals after bariatric surgery; however, the underlying mechanisms are not completely understood. We hypothesized the BP response at the onset of isometric handgrip exercise would occur earlier and to a lesser degree in individuals who underwent bariatric surgery when compared to obese adults and the reliance on total peripheral resistance (TPR) would be attenuated.MethodsTwenty‐six individuals [7 non‐obese (28±3 yrs, 23±1 kg/m2), 11 obese (33±2 yrs, 39±1 kg/m2), 8 post‐bariatric surgery (35±2 yrs, 29±1 kg/m2)] completed isometric handgrip exercise (40% maximum voluntary contraction) to exhaustion. Heart rate (HR, ECG) and arterial BP (brachial catheter) were measured continuously. Stroke volume was estimated from the pressure waveform and cardiac output (CO) and TPR were calculated. Peak change, time to peak, and rate of rise in BP were assessed during the first 30‐s of exercise.ResultsCompared to non‐obese controls, obese adults exhibited a slower initial rise in BP (9.3± 3.9 vs 21.7±2.5 s) and higher peak BP change (Δ6.7±2.1 vs Δ11.9±2.1 mmHg) at the onset of isometric handgrip exercise (p<0.05). Peak BP and the rate of rise were not different between individuals who underwent bariatric surgery (14.0±4.1 s, Δ5.6±1.3 mmHg) and non‐obese controls (p>0.05). Non‐obese controls exhibited an exercise‐mediated increase in CO whereas obese adults increased TPR (p<0.05). The increases in CO and TPR were less apparent in individuals who underwent bariatric surgery (p>0.05). Low cardiac baroreflex sensitivity (BRS) and heart rate variability (HRV: SDNN, standard deviation of normal to normal R‐R intervals) at rest were related to smaller increases in CO (BRS: R=0.47, p<0.01; SDNN: R=0.57, p<0.01) and greater increases in TPR (BRS: R=−0.49, p=0.01; SDNN: R=−0.60, p<0.01) during exercise.ConclusionsIn contrast to obese adults, individuals who underwent bariatric surgery exhibit a rapid rise in BP at the onset of isometric handgrip exercise. This rapid increase in BP is associated with a fall in TPR and results in lower peak BP at the onset of isometric exercise. These data suggest bariatric surgery attenuates BP reactivity to physical stress via improvements in the time‐course of hemodynamic responses and reflex autonomic adjustments.Support or Funding InformationNIH HL130339, NIH HL083947, NIH DK82424, NIH UL1 RR024150, Mayo Clinic Department of Anesthesiology, Mayo Foundation for Medical Education and ResearchThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Leptin‐mediated Sympatho‐excitation in Obese Rats: Role for Astrocyte‐Neuron Crosstalk in the Arcuate Nucleus
Authors: Liu Xuefei , Li Yulong , Patel Kaushik P. , Zheng Hong 
Published: June 2021

Accumulated evidence indicates that enhanced sympathetic activation is associated with obesity. Hypothalamic leptin‐mediated signaling may contribute to the exaggerated sympatho‐excitation in obesity. The present study was conducted to investigate “neuron‐astrocyte” interactions regulating leptin signaling within the arcuate nucleus (ARCN) of hypothalamus in obese rats. High‐fat diet (42% fat for 12 weeks) induced hyperlipidemia and hyperleptinemia in Sprague Dawley rats. In anaesthetized condition, microinjections of leptin (5ng~100ng) and N‐methyl‐D‐aspartate (NMDA 50–200pmol) into the ARCN induced increases in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) in both control and obese rats. Pre‐inhibition of astrocytes with astrocytic metabolic inhibitor fluorocitrate reduced leptin‐induced, but not NMDA‐induced RSNA and MAP within the ARCN. In the ARCN, leptin/leptin receptor is localized in both neurons and astrocytes. In obese rats, leptin and leptin receptor were increased in the ARCN, particularly increased more in the astrocytes than in the neurons. Furthermore, we found that the expressions of glutamate transporter GLT1 and excitatory amino acid transporter‐2 (EAAT‐2) which are major glutamate transporters expressed predominantly in astrocytes were decreased within the ARCN in obese rats. Consistent with these in‐vivo observations, in cultured astrocytic C6 cells, GLT1 and EAAT‐2 levels decreased with leptin (100 ng/ml) treatment for 24 hours. Taken together, these results suggest leptin signaling via neuron‐astrocytes interactions in the ARCN may contribute to the exaggerated sympatho‐excitation observed in obese rats. This effect maybe mediated by the action of leptin regulating glutamate transporters in the astrocytes within the ARCN of the hypothalamus.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Environmental Enrichment Reverses Chronic Stress‐Induced Brain‐Gut Axis Dysfunction
Authors: Love James , Johnson Anthony , Ligon Casey , Meerveld Beverley Greenwood‐Van 
Published: June 2021

Stress‐induced visceral hyperalgesia is a contributing factor in irritable bowel syndrome (IBS), a highly prevalent brain‐gut disorder characterized by chronic visceral pain. Previously we showed that repetitive daily exposure to a water avoidance stressor (WAS) for 1 hr/day for 7 days induced visceral and somatic hyperalgesia in a rodent model. A positive environment enrichment (EE) is known to have a critical role in brain development and stress reactivity, however it is unknown whether EE is capable of reversing stress‐induced viscero‐somatic hypersensitivity.MethodsExperiments were performed on male F344 rats that were housed in either standard housing (SH) or in large cages filled with toys and food treats for EE. The effect of EE (7–14 days) before and/or during the WAS or sham stress (SHAM) induced visceral and somatic hypersensitivity was investigated (n=4/group). Visceral sensitivity was assessed via a visceromotor response (VMR) to graded pressure (0–60 mmHg) of isobaric colorectal distension (CRD). Somatic sensitivity was measured via von Frey filaments applied to the hind paw. Results were analyzed with one‐ or two‐way ANOVA with a Bonferroni's correction.ResultsCompared to male rats placed in SH, we found that EE for 14 days before and during the 7 days of WAS produced a significant attenuation in visceral (60 mmHg, WAS+EE=19.8±4.0 vs. WAS+SH=28.5±4.1 abdominal contractions, p<0.05) and somatic hypersensitivity (WAS+EE=85.7±7.4 vs. WAS+SH=65.6±4.5 g withdrawal threshold, p<0.01). In a similar fashion, rats housed with EE for only 7 days before and during the WAS procedure also demonstrated a significant reduction in visceral hypersensitivity and somatic allodynia. However, when rats were not pre‐exposed to EE and only housed in an EE during the time of the WAS procedure, there was no significant inhibition of WAS‐induced visceral hypersensitivity (60mmHg, WAS+EE=27.7±11.0 abdominal contractions) or somatic allodynia (WAS+EE=59.3±5.1 g).Summary and ConclusionsOur data reveal that pre‐exposure of adult animals to short‐term EE prevents visceral and somatic hypersensitivity induced by chronic repetitive stress. Future experiments are designed to understand the basic underlying molecular mechanisms responsible for the positive effects of EE on stress‐induced visceral and somatic hyperalgesia and its implications in the treatment of brain‐gut axis dysfunction.Support or Funding InformationDr. Greenwood‐Van Meerveld would like to acknowledge the funding provided by her Department of Veterans Affairs Merit Grant – I01BX002188. Dr. Greenwood‐Van Meerveld is the recipient of a Senior Research Career Scientist award (1IK6BX003610) from the Department of Veterans Affairs.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Visceral Organ Cross‐Sensitization in a Rodent Model of Early Life Stress
Authors: May Jeffery , Mohammadi Ehsan , Johnson Anthony C. , Meerveld Beverly Greenwood‐Van 
Published: June 2021

INTRODUCTION AND OBJECTIVEBladder pain syndrome (BPS) and irritable bowel syndrome (IBS) exhibit a high comorbidity, show a female predominance, and patients often report a history of early life stress (ELS). However, whether ELS serves as a risk factor for visceral organ cross‐sensitization remains to be determined. Our previous work suggests that multi‐organ visceral hypersensitivity results from visceral organ crosstalk. In this study, we test the novel hypothesis that ELS induces chronic visceral pain in adults through bladder‐colon crosstalk.METHODSNeonatal female Long Evans rats were exposed to an odor attachment learning model of ELS produced by classical conditioning. On postnatal (PN) days 8 to 12 neonatal female rats (n=27) were separated into: Group 1: odor with an unpaired shock [Unpredictable ELS], Group 2: odor only. In adulthood (PN 90) dilute protamine sulfate (PS) (1mg/ml) was infused into the bladder via intravesical infusion. Colon sensitivity was assessed 24 hr. post PS in freely moving animals as a visceromotor response (VMR) to graded pressures (0–60mmHg) of isobaric colorectal distension and quantified as the number of abdominal contractions over 10 min. Rats receiving no PS infusion served as controls.RESULTSIn adults PS infusion into the bladder significantly increased colonic sensitivity in all groups (VMR at 60mmHg: Odor Only=21.4±1.7 (n=5) vs Odor Only plus PS=36.0±1.8 (n=10) [p<0.0001], Unpredictable ELS=38.7±3.6 (n=6) vs Unpredictable ELS plus PS=52.7±1.7 (n=6) [p<0.0001] abdominal contractions). The crosstalk‐induced increase in colonic hypersensitivity was similar between the odor only and unpredictable ELS groups (ΔVMR at 60mmHg (plus PS – no PS): Odor Only=14.6±1.7 vs Unpredictable ELS=14.0±3.6 [p=0.90]).SUMMARY & CONCLUSIONSOur data revealed that in adulthood intravesical infusion of PS into the bladder in female rats previously exposed to ELS as neonates induces colonic hyperalgesia, however the magnitude of the PS‐induced colonic hyperalgesia did not differ between groups. These findings, in a rodent model, suggest that unpredictable ELS does not augment acute visceral organ cross sensitization in adulthood.Support or Funding InformationIn‐house funding from the Greenwood‐Van Meerveld lab was used to support this project.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Inulin/FOS‐rich diet alters gut microbiota, brain activity and cardiovascular responses in the SHR
Authors: Silva Carla Grazielle Bueno , Yang Tao , Malphurs Wendi L. , Magee Kacy L. , Larkin Riley M. , Febo Marcelo , Vickroy Thomas W. , Zubcevic Jasenka 
Published: June 2021

It is well established that hypertension is associated with autonomic dysfunction and gut dysbiosis. Here, we show that chronic inulin/FOS‐rich diet alters gut microbiota, promotes autonomic dysfunction, and increases BP in conscious unrestrained spontaneously hypertensive rat (SHR), as well as the SHR submitted to restraint stress. These alterations were accompanied by activation of cardioregulatory brain regions, namely the paraventricular nucleus (PVN) of hypothalamus and solitary tract nucleus (NTS), as measured by manganese‐enhanced magnetic resonance imaging (MEMRI). BP was also significantly increased in the inulin/FOS diet‐fed Wistar‐Kyoto (WKY) rat submitted to restraint stress, albeit to a lesser extent.MethodsMale 4 weeks old WKY and SHR were placed on either the inulin/fructooligosaccharides (FOS)‐rich diet (fiber, n=6), or its calorie‐matched control diet (ctl, n=6) (Research Diets, Inc.) for 14 weeks. BP was measured weekly by tail cuff and telemetry, and during 20 minutes of restraint stress. Spectral analysis of BP waveform signal was performed to derive autonomic variables. MEMRI was performed in SHR at tenth week on diet.ResultsInulin/FOS‐rich diet caused significant shifts in gut bacterial profiles in WKY and SHR as an increase in Bifidobacterium population (WKY: 0.006624 ± 0.0018 vs. 0.4989 ± 0.1745 arbitrary unit; p=0.0073, n=6. SHR: 0.03099 ± 0.0127 vs. 0.2134 ± 0.0656 arbitrary unit; p=0.0258, n=6). We observed no change in BP in conscious unrestrained WKY; however, conscious unrestrained SHR fed with inulin/FOS diet had significantly higher mean BP compared to control (163.8 ± 1.6 vs. 169.6 ± 1.3 mmHg; p=0.0083, n=6). Restraint stress produced a small but significant increase in BP in inulin/FOS‐fed WKY compared to control (104.5 ± 7.45 vs. 116.3 ± 3.19 mmHg; p=0.0411, n=6). This effect was more pronounced in the SHR on inulin/FOS compared to control diet (189.6 ± 2.1 vs. 198.9 ± 1.9 mmHg; p=0.0024, n=6). These responses were associated with a trend in increase in LF/HF (vasovagal) balance in the diet‐fed WKY (1.99 ± 1.43 vs. 3.04 ± 1.46; p=0.09, n=6), and with significant increase in LF/HF in the diet‐fed SHR (6.49 ± 0.47 vs. 8.16 ± 0.59, p=0.0306, n=6). MEMRI showed increased activation of the PVN (−0.6514 ± 0.07 vs 0.05026 ± 0.06 % of baseline; p=0.0018, n=3) and NTS (0.1194 ± 0.05 vs. 0.3817 ± 0.09 % of baseline; p=0.0409, n=3) in diet‐fed SHR.ConclusionGut microbiota plays an important role in brain‐gut communication in hypertension. This pathway may present a novel therapeutic target for treatment of this condition.Support or Funding InformationFAPESP : Fundação de Amparo à Pesquisa do Estado de São PauloThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.