bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Provoked Cardiovascular and Autonomic Effects of Endotoxemia in Ovariectomized Rats Are Distinctly Affected by Estrogen and Progesterone Supplementation
Authors: El‐Mas Mahmoud M. , El‐Lakany Mohammed A. , Fouda Mohamed A. , El‐Gowelli Hanan M. 
Published: June 2021

The female gender is protected against immunological and cardiovascular complications of sepsis. This study investigated whether gonadal hormone depletion by bilateral ovariectomy (OVX) could uncover the cardiovascular and autonomic effects of endotoxemia and whether these effects can be reversed by hormone replacement therapies. Changes in blood pressure (BP), heart rate variability (HRV), and left ventricular (LV) function caused by i.v. administration of lipopolysaccharide (LPS, 10 mg/kg) were evaluated in conscious female rats with different hormonal states. While LPS caused no specific cardiovascular effects in intact female rats, LPS‐treated OVX rats exhibited significant decreases in blood pressure (BP) and increases in spectral low‐frequency/high‐frequency ratio (LF/HF) of HRV, denoting enhanced cardiac sympathetic dominance. Moreover, LPS increased the rate of rise in LV pressure (dP/dtmax, LV contractility) without affecting the isovolumic relaxation constant (Tau, a measure of diastolic function). LPS hypotension was totally eliminated in OVX rats pretreated with estrogen but not medroxyprogesterone acetate (MPA). Prior selective activation of estrogen receptor‐α (4,4′,4″‐(4‐Propyl‐[1H]‐pyrazole‐1,3,5‐triyl)trisphenol, PPT) or estrogen receptor‐β (Diarylpropionitrile, DPN) partially counteracted LPS hypotension. Each of the abovementioned drug treatments (estrogen, MPA, PPT, or DPN) abrogated the LPS‐evoked exaggeration in cardiac sympathetic control (LF/HF ratio). By contrast, the elevated dP/dtmax in LPS‐treated rats was largely compromised by PPT only. The data suggest differential modulatory roles for gonadal hormones (estrogen and progesterone) and estrogen receptors (α and β) on endotoxic cardiovascular and autonomic manifestations in female rats.Support or Funding InformationSupported by the Science and Technology Development Fund, Egypt (STDF Grant No. 14895)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Doxorubicin Temporally Modulates Cyclooxygenase‐2 Levels in Male and Female Human Vascular Smooth Muscle Cells
Authors: Tat Trinh , Bartel Robyn , So Mei , Sweazea Karen , Gonzales Rayna J. 
Published: June 2021

Doxorubicin (Dox) is a chemotherapeutic agent that is highly effective at reducing recurrence and mortality in breast cancer patients. However, this anti‐cancer drug elicits dose‐ and time‐dependent cardiovascular toxicity. The pathogenesis of Dox is multifactorial, one of which involves the development and progression of inflammation mediated by activation of the TLR4/NFκB pathway. In a recent collaborative study, we demonstrated that intermittent bouts of Dox administered to mimic chemotherapeutic administration clinically attenuated protein levels of cyclooxygenase‐2 (COX‐2), a downstream proinflammatory mediator of the TLR4/NFκB pathway, in cerebral and peripheral vasculatures isolated from female ovariectomized rats. These findings were surprising and not in agreement with previously published data. Therefore, to address whether this Dox‐induced attenuated inflammatory response is time and dose dependent, we exposed cultured primary human female and male vascular smooth muscle cells to vehicle (saline) or Dox (0.3, 1.0, and 5.0 μM) for 6 and 24 hr. Following Dox treatment, cells were isolated, homogenized, and whole cell lysates analyzed for COX‐2 protein levels via immunoblotting. We also assessed levels of the upstream transcription factor, NFκBp65 as well as its activation. We observed that Dox dose dependently decreased levels of COX‐2 without altering NFκBp65 whole cell lysate protein levels at the 6 and 24 hr time points. However, NFκBp65 activity (6 hr time point), assessed indirectly using nuclear/cytosolic fractionation, was increased. Dox had no effect on cell morphology or density determined by light microscopy. Live versus dead cell percentages, determined using trypan blue, were also not affected by Dox suggesting that the anticancer drug did not alter cell death at 6 and 24 hr time points. In conclusion, these studies demonstrate a possible novel action for the anticancer agent eliciting both a dose‐ and time‐dependent effect on selective downstream mediators of inflammation such as COX‐2 in the female and male vasculature. Future studies are planned to evaluate the impact of acute versus chronic Dox treatment on COX‐2 at the transcriptional or translational levels to determine a mode of molecular regulation and to assess if sex differences exist.Support or Funding InformationUniversity of Arizona Sarver Heart Center Medical Student Award (MS) and the Valley Research Partnership P1 Grant (RJG).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mitochondrial modulation of calcium pulsars through oxidative stress
Authors: Berlatie Marianne , Toussaint Fanny , Blanchette Alexandre , Ledoux Jonathan 
Published: June 2021

Intracellular Ca2+ levels are central to endothelial mechanisms regulating smooth muscle contractility. Growing body of evidence suggests an important role for spatially‐restricted Ca2+ signals such as Ca2+ pulsars in endothelial‐dependent modulation of vascular tone. However, little information is available on mechanisms modulating these spontaneous Ca2+ dynamics. Recent work showed that clustered mitochondria near myoendothelial projections (MEP) regulate Ca2+ pulsars. Mitochondrial ATP production through oxidative respiration also generates reactive oxygen species (ROS). Interestingly, preliminary data suggests that ROS stimulate Ca2+ pulsars. Therefore, according to mitochondria production of ROS and organelle's clustering near MEP, it was hypothesized that mitochondria are modulators of local calcium dynamics through mitochondrial oxidative stress (mROS) in native endothelium. Intracellular Ca2+ dynamics were monitored in situ in Fluo‐4‐loaded endothelium of mesenteric arteries from mice with high‐speed confocal microscopy. Exposure to MitoTEMPO (10 μM), a mitochondria‐targeted antioxidant, decreased spontaneous Ca2+ pulsar frequency (2‐fold decrease). On the other hand, rotenone, a Complex 1 inhibitor, was used to stimulate mROS production and evaluate its impact on Ca2+ pulsars. mROS appears to stimulate Ca2+ dynamics since application of rotenone (10 μM) increased Ca2+ pulsars frequency. These results suggest that oxidative stress from mitochondrial origin (mROS) can modulate Ca2+ pulsars in native endothelium and might have a significant impact on vascular tone in pathophysiological conditions.Support or Funding InformationCanadian Institutes of Health Research and Montreal Heart Institute FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Main effects of light sources, photoperiods, and genetic strains on blood physiological variables of broilers grown to heavy weights.
Authors: Olanrewaju Hammed A. , Purswell Joseph L. , Collier Stephanie D. , Branton Scott L. 
Published: June 2021

Effects of light sources, photoperiods, and genetic strains on blood physiological variables of broilers grown to heavy weights were investigated in 2 trials. The experimental design was a 4 × 2 × 2 factorial consisting of 4 light sources [incandescent (ICD, standard), compact fluorescent (CFL), neutral light emitting diode (Neutral‐LED), and cool poultry specific filtered LED (Cool‐PSF‐LED)], 2 photoperiods (Regular/intermittent [2L:2D], and Short [8L:16D], and 2 genetic strains (Ross × Ross 708, Cobb 700). In each trial, 480 (240 males/240 females) 1‐d‐old chicks of each strain from different commercial hatcheries were equally and randomly distributed into 16 environmental control rooms (30 males + 30 females/room) at 50% RH. Each room was randomly assigned one of 16 treatments from d 1 to 56 d of age. Birds were provided similar diets. Feed and water were provided ad libitum. Venous blood samples were collected on d 14, 28, 42, and d 56 of age and analyzed immediately. Cool‐PSF‐LED light sources had significant (P ≤ 0.05) effects on BW, Hb, Hct, electrolytes, angap, and mOsm in comparison with birds reared under ICD, but all these changes were still within the normal acid‐base homeostasis and physiological ranges. Also, the short photoperiod significantly (P ≤ 0.05) reduced BW, pH level, pO2, sO2, and Ca2+, with significantly (P ≤ 0.05) elevated pCO2, Hct, Hb, and McHc concentrations. Acid‐base regulation during short photoperiod exposure had not deteriorated despite higher pCO2 that consequently decreased blood pH due to a respiratory acidosis. In addition, Cobb 700 had significantly (P ≤ 0.05) increased BW, pCO2, Hct, Hb, Ca2+, Cl−, McHc, and angap along with significantly (P ≤ 0.05) reduced pH level, pO2, HCO3−, and glucose in comparison with Ross × Ross 708. Plasma corticosterone was not affected by light sources, photoperiod, genetic strain or their interaction, indicating that exposure of broiler chickens to the short photoperiod markedly affects some physiological blood variables without inducing stress in modern broilers grown to heavy weights. It was concluded that the 3 LED light bulbs evaluated may be suitable for replacement of ICD along with the regular/intermittent photoperiod for commercial poultry facilities to reduce energy costs and optimize production efficiency without compromising the welfare of broilers grown to heavy weights.Support or Funding InformationNoneThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Role of cGMP and EDHF Pathways in Hydrogen Sulfide‐induced Vasorelaxation in the Human Artery
Authors: Yuan Chao , Hou Hai‐Tao , Chen Huan‐Xin , Wang Jun , Wang Zheng‐Qing , Chen Tie‐Nan , Novakovic Aleksandra , Marinko Marija , Yang Qin , He Guo‐Wei 
Published: June 2021

BackgroundEndogenous H2S generated by mercaptopyruvate sulfurtransferase (MPST) coupled with cysteine aminotransferase (CAT) in endothelium as a physical vasodilator and blood pressure regulator may play an important protective role in the pathogenesis of coronary heart disease. The present study aimed to investigate the role of cGMP and endothelium‐derived hyperpolarizing factor (EDHF) in H2S‐induced vasorelaxation in the human internal mammary artery (IMA).MethodsIn the human IMA segments from 54 patients undergoing coronary artery bypass grafting, the acetylcholine (ACh)‐induced relaxation and the effect of CAT inhibitor (aminooxyacetic acid [AOAA] and L‐aspartate) and KCa channel blocker or KATP channel blocker were studied in a myograph. Enzyme‐linked Immunosorbent Assay for PDE5A and western blotting analysis for eNOS and p‐eNOSser1177 were performed. Methylene blue assay was used to quantify the contents of H2S.ResultsThe maximal relaxation induced by ACh was significantly attenuated by AOAA or L‐aspartate, Iberiotixin (BKCa channel blocker) (P<0.01), or IKCa channel blocker plus SKCa channel blocker (TRAM‐34+Apamin) (P<0.01), or KATP channel blocker (Glibenclamide) (P<0.01). The H2S donor NaHS increased eNOS phosphorylation at its activating site S1177 and down‐regulated PDE5A activity. Incubation with ACh for 4 hours significantly increased the H2S concentration.ConclusionsWe for the first time demonstrated in the human IMA that endogenous H2S could be produced under the stimulation of ACh and that CAT is one of the key enzymes in production of H2S in the endothelial cell of the IMA. H2S may activate eNOS to produce NO that activates PKG and may also inhibit PDE5A activity; both enhance the cGMP pathway‐mediated relaxation. Further, H2S as a potential EDHF directly stimulates KCa channels to induce vasodilatation. These findings may provide new therapeutical targets for the treatment of vasospasm of coronary artery bypass grafting vessels and provide a pharmacological basis for the development of new vasodilator drugs.Support or Funding InformationSupported by grants from the National Natural Science Foundation of China (81170148 & 81641017), Zhejiang Provincial Natural Science Foundation (LY15H020008), & Tianjin Binhai Key Platform for Creative Research Program (2012‐BK110004), Binhai New Area Health Bureau (2012BWKZ008, 2016BWKY007, 2016BWKZ003).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cerebrovascular Regulation During an Insulin‐Glucose Challenge: Contribution of Nitric Oxide
Authors: Ward Aaron T. , Carter Katrina J. , Sauder Christina J. , Kellawan J. Mikhail , Weiben Oliver , Schrage William G. 
Published: June 2021

While it is known that cerebral blood flow (CBF) is regulated by various chemical factors, such as arterial CO2, the role of nitric oxide (NO) in this regulation is unclear. NO production can be increased via numerous stimuli, including insulin. However, the CBF response to an insulin surge has yet to be fully examined. Additionally, the potential contribution of NO to an insulin surge remains poorly understood. Therefore, we tested the hypotheses that a) an insulin‐glucose challenge will increase CBF, and b) these effects will be attenuated by NO synthase inhibition (L‐NMMA). Four healthy adults (2 male, 2 female; age 21±1 yrs, height: 175±7 cm, weight: 61±4 kg) completed two visits (saline control vs. L‐NMMA) under fasted conditions (>10 hours) in a single‐blind placebo‐controlled study. CBF was measured via 4D MRI utilizing phase‐contrast vastly‐undersampled isotropic projection reconstruction (PC VIPR) at baseline and 60 mins following ingestion of a 75g Oral Glucose Tolerance Test (OGTT). L‐NMMA was infused at 36 mg/kg/hr for 5 min prior to baseline measurements with subsequent infusion at 1 mg/kg/hr for 60 min. Saline infusion was matched to L‐NMMA infusion rates. CBF was quantified as the sum of flow from both internal carotid arteries and the basilar artery. Hemodynamics (HR, MAP, ETCO2) and glucose were monitored. Cerebrovascular conductance (CVC) was calculated as CBF÷MAP. HR, MAP, and ETCO2 were similar between conditions and between time points (all p>0.05). Plasma glucose increased significantly from baseline to 60 mins (p<0.05) and did not differ between groups (p>0.05). CBF (saline 782±120 mL/min vs. L‐NMMA 700±106 mL/min) and CVC (saline 8.7±1.4 mL/min/mmHg vs. LNMMA 8.2±1.0 mL/min/mmHg), a difference of ~11% and ~7%, respectively, did not differ at baseline (p>0.05). During OGTT, CBF (saline 723±146 mL/min vs. L‐NMMA 694±138 mL/min) and CVC (saline 8.6±1.7 mL/min/mmHg vs. LNMMA 8.0±1.6 mL/min/mmHg) were similar between conditions (p>0.05) and did not change over time (p>0.05). L‐NMMA trended to reduce CBF (p=0.087) and CVC (p=0.057) overall. These data suggest that CBF does not significantly increase following an insulin‐glucose challenge. However, NO may mediate basal CBF regulation in healthy adults, suggesting additional endothelial‐mediated regulation of the cerebrovasculature.Support or Funding InformationADA 1‐16‐ICTS‐099This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Reconstitution of Autophagy Improves Vascular Reactivity in Spontaneously Hypertensive Rats
Authors: McCarthy Cameron G. , Wenceslau Camilla F. , Martinez‐Quinones Patricia , Calmasini Fabiano B. , Webb R. Clinton 
Published: June 2021

The accumulation of misfolded‐aggregated proteins is linked to an increasing number of degenerative diseases, including hypertension. Although protein damage and misfolding are an inevitable consequence of normal cellular function, multiple proteostasis mechanisms are devoted to the repair or clearance of damaged proteins in order to prevent proteotoxicity. Autophagy is the constitutive and basally active recycling mechanism responsible for protein quality control. Previously, our data has suggested decreased autophagy in conduit and resistance arteries from spontaneously hypertensive rats (SHR); however, direct measurement of autophagic activity, as well as the proteotoxic consequences of undegraded, misfolded protein has not been performed. Furthermore, the effects of reconstituting autophagic activity on vascular reactivity are currently unknown. We hypothesized that mesenteric resistance arteries (MRA) from adult (14 weeks old) SHR would have decreased autophagic activity in lysosomes extracted from arteries and this would be associated with increased misfolded protein oligomers. Therefore, we further hypothesized that upregulation of autophagy via mammalian target of rapamycin (mTOR) inhibition would decrease contraction and improve relaxation in isolated MRA from SHR mounted on wire myographs. We observed that the activity of acid phosphatase, the major acid hydrolase in lysosomes, from arterial lysosomes (pooled mesenteric arteries and aorta) was decreased in SHR (μmol/min, Wistar: 0.51±0.06 vs. SHR: 0.24±0.02, p<0.05). This diminished arterial autophagic activity was observed in conjunction with the increased presence of insoluble protein deposition. Specifically, SHR MRA contained increased fibrillar amyloid oligomers, especially along the endothelium monolayer, as indicated by Congo red staining (Figure 1). When autophagy was reconstituted in isolated MRA via mTOR inhibition with Everolimus (EV; first generation mTOR inhibitor) for 1 hr, we observed that the maximum contraction to phenylephrine was reduced [Emax (mN), Vehicle: 19.8±0.5 vs. EV (0.1 nM): 10.7±0.5 vs. EV (0.1 μM): 8.5±1.0, p<0.05] and the contraction to high concentrations acetylcholine was prevented [LogEC50, Vehicle: −6.9±0.1 vs. EV (0.1 nM): −9.2±0.4 vs. EV (0.1 μM): −8.2±0.1, p<0.05]. Overall, these data reveal that SHR have impaired arterial lysosomal activity and this is associated with the accumulation of misfolded proteins. As a result, reconstituting arterial autophagic activity improved vascular function and could be a novel therapeutic treatment for proteotoxicity in hypertension.Support or Funding InformationNIH (K99GM118885 and P01HL134604).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Hypertension in serotonin‐deficient male rats is associated with reduced sympathetic drive to the vasculature
Authors: Magnusson Jennifer L. , Cummings Kevin J. 
Published: June 2021

Serotonin (5‐hydroxytryptamine, 5‐HT) neurons have widespread projections to autonomic regions of the brainstem and spinal cord. However, the specific role of central 5‐HT in the autonomic regulation of arterial blood pressure (BP) is unclear. We have previously shown that in quiet wakefulness (QW) and rapid‐eye‐movement (REM) sleep, adult male rats deficient in tryptophan hydroxylase 2 (TPH2−/−), and hence lacking central 5‐HT, have increased BP compared to wild‐type (WT) controls. The BP of female TPH2−/− rats is the same as WT. The current study sought to clarify the mechanism by which a loss of central 5‐HT leads to increased BP. We hypothesized that a loss of central 5‐HT increases sympathetic vascular tone. Using femoral arterial catheters along with electroencephalography and electromyography, we confirmed the elevated BP of adult (5–8 month old) male TPH2−/− rats (n=14) compared to male WT littermates (n=17), during QW (TPH2−/−: 123 vs WT: 115 mmHg; p=0.006) and REM sleep (TPH2−/−: 128 vs WT: 117 mmHg; p=0.002), but not during non‐rapid‐eye movement sleep (NREM) (TPH2−/−: 120 vs WT: 115 mmHg; p=0.068). In contrast, the BP of female TPH2−/− rats (n=15) was the same as WT littermates (n=12) (TPH2−/−: 119, 117, 123 vs WT: 112, 113, 115 mmHg in QW, NREM and REM, respectively) (p>0.05). To determine the influence of central 5‐HT on cardiac vagal drive and sympathetic vasculature tone, we injected atropine methyl nitrate (1 mg/kg; i.v.) and hexamethonium (HEX, 30 mg/kg; i.v.) into a subset of rats (n=5 male TPH2−/− and 5 WT; n= 9 female THP2−/− and 8 WT), and measured the maximum increase in heart rate (HR) and nadir in BP, respectively, during subsequent QW. The atropine‐induced increase in HR and BP experienced by male and female TPH2−/− rats was not significantly different than in WT littermates. Unexpectedly, male TPH2−/− rats had a reduced drop in BP following HEX compared to male WT (p=0.004), a phenotype not observed in female TPH2−/− rats. Our data suggest that a loss of central 5‐HT decreases sympathetic vascular tone in males only. While the mechanism(s) that contribute to the hypertension of male TPH2−/− rats remains unresolved, the potential interaction between central 5‐HT and components of the renin‐angiotensin‐aldosterone and vasopressin systems is worth exploring.Support or Funding InformationFunding for this research was provided by an American Heart Association Scientist Development Grant (14SDG18560022; PI: KJC) and a Ruth L. Kirschstein National Research Service Award (NRSA) Individual Predoctoral Fellowship (F31) to JLM.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.