bluuebunny/crossref_metadata_2025_split huggingface dataset:
Severe Cerebrovascular Dysfunction in a Hypertensive Heart Failure Model
Authors: Brooks Steven , Stanley Shyla , Chantler Paul , Brock Robert , Frisbee Jefferson 
Published: June 2021

The spontaneously hypertensive, heart failure‐prone rat (SHHF) is a preclinical model of heart failure, and is available in both lean/hypertensive (SHHF‐L) and obese/hypertensive (SHHF‐Ob) strains. While cardiac mechanics have been studied extensively in this model, vascular reactivity of conduit and small arteries has not been evaluated. The aim of this study was to assess vasoreactivity in aortic rings, isolated middle cerebral arteries (MCA), and gracilis arterioles (GA) of adult male SHHF‐L and SHHF‐Ob animals.At 37‐40 weeks of age, vessels were harvested from SHHF animals for evaluation. Aortic rings were placed in a myobath, and MCA and GA into isolated microvessel chambers. Vascular reactivity to dilator/constrictor stimuli was measured by tension myograph or video micrometer. Vasodilation to ACh was significantly impaired in aortic rings and GA of SHHF‐L (70% compared to non‐hypertensive lean control) and SHHF‐Ob (60‐70% to control). However, dilation to ACh in MCAs was reduced more than 50 % to control in the SHHF‐L, and nearly ablated in SHHF‐Ob. Both GA and MCA of SHHF‐L and SHHF‐Ob were hyperconstrictive to adrenergic stimuli. Myogenic reactivity was significantly impaired in MCA of both SHHF‐L and SHHF‐Ob, even compared to GA from the same animals.Our findings reveal severe cerebrovascular dysfunction in both lean and obese SHHFs. SHHF rats are severely hypertensive (MAP>175 mmHg), which impacts vascular tone; however, the difference in reactivity between GA and MCA indicates a more complex pathology. Further investigation is needed to determine the physiological mechanisms of vascular dysfunction in this preclinical animal model.
Cerebrovascular Abnormalities Supporting the Selfish Brain Hypothesis of Human Hypertension
Authors: Hart E , Rodrigues J , Ratcliffe L , Burchell A , Manghat N , Wise R , Nightingale A , Paton J 
Published: June 2021

The selfish brain hypothesis of hypertension suggests that brainstem hypoperfusion triggers increased sympathetic activity (SNA) and blood pressure (BP) as a mechanism to maintain cerebral perfusion. We assessed: 1) prevalence of anatomical variations in the posterior cerebral circulation, which may cause brainstem hypoperfusion, 2) relationships of SNA to cerebral vascular resistance (CVR) in hypertensive (HTN) vs normotensive (NTN) humans. The vertebral arteries (VA) and Circle of Willis (CoW) were imaged in 121 HTN (MR angiography). VA hypoplasia (VAH), defined as <2mm diameter, together with CoW morphology were compared to known standards in >50 NTN. In a cohort of HTN (n=50) and NTN (n=40), muscle SNA (MSNA, microneurography), blood flow in the internal carotid arteries (ICA) and VA (MR phase contrast), and BP were recorded.Prevalence of VAH and incomplete posterior CoW was higher in HTN vs NTN (51 vs 27% and 62 vs 38%, p<0.05). Of the posterior CoW variants, complete disconnection of anterior/posterior CoW was higher in HTN (31 vs 10%, p<0.05). Prevalence of having both VAH and incomplete posterior CoW variant was higher in HTN vs. NTN (38 vs 10%, p<0.05). Total CVR and CVR in VA was higher in HTN vs. NTN (2.6 ±0.1 vs 1.1±0.1 and 9.5±0.1 vs 6.7±0.1 mmHg/mL/dl.tissue/min). CVR was related to MSNA in both groups (HTN; r=0.40, NTN; r=0.38, P<0.05). CVR was more closely related to MSNA in the VA vs ICA in HTN (r=0.40 vs r=0.30, P=0.05).The higher prevalence of VAH and incomplete posterior CoW may cause the observed increase in CVR in HTN. The higher CVR in the posterior circulation was linked to higher MSNA in HTN, supporting the hypothesis of brainstem hypoperfusion as a driver of neurogenic hypertension.BHF.
The Effect of Multiple Sclerosis on Carotid Baroreflex Latencies of Arterial Blood Pressure and Heart Rate
Authors: Allen Dustin , Huang Mu , Davis Scott , Keller David 
Published: June 2021

Multiple sclerosis (MS) is marked by conduction abnormalities within the central nervous system that lead to impaired blood pressure regulation. However, the impact of these abnormalities on dynamic blood pressure control, particularly the timing of the responsiveness (i.e., latency), has not been examined. We tested the hypothesis that carotid‐cardiac and carotid‐vasomotor latency would be delayed in individuals with MS (n=5) compared to healthy controls (CON, n=5). Carotid baroreflex function was assessed using 5‐sec trials of neck pressure (NP, +40 Torr, simulated hypotension) and neck suction (NS, ‐60 Torr, simulated hypertension). Latencies (i.e., time‐to‐peak responses) were determined for both carotid‐cardiac (peak HR responses) and carotid‐vasomotor (peak MAP responses) by summing the R‐R intervals from the onset of the respective stimuli to the R wave of the cardiac cycle associated with the respective peak responses. Carotid‐cardiac latency was not different between groups for either NP (MS: 3.7±1.3 sec, CON: 3.7±1.3 sec; p=0.97) or NS (MS: 1.6±1.1 sec, CON: 1.9±0.8 sec; p=0.62). In addition, the carotid‐vasomotor latency to NP (MS: 5.7±1.7 sec, CON: 5.6±1.4 sec; p=0.90), and NS (MS: 4.7±2.3 sec, CON: 6.8±0.6 sec; p=0.08) were not different between groups. It appears MS does not markedly alter the timing of peak carotid‐cardiac and carotid‐vasomotor responses.Supported by NIH R15HL117224 and National MS Society RG4696A
Effects of A2a Receptors on the Hypoxic Ventilatory Response in Rats Exposed to Chronic Sustained Hypoxia
Authors: Basaran K , Moya Esteban , Fu Zengxing , Powell Frank 
Published: June 2021

Recent studies show that long term facilitation of phrenic nerve activity (LTF) with acute intermittent hypoxia (IH) involves two signaling pathways. In addition to the well‐known serotonergic (Gq) pathway, a Gs pathway can be activated by adenosine receptor 2 (A2a) agonists and cause LTF without IH (J Neurosci 28:2033‐42, 2008). Gs can inhibit the Gq pathway as A2a antagonists increase LTF from IH by disinhibiting Gq (J Physiol 588:255‐66, 2010). We tested the hypothesis that Gs also contributes to plasticity in ventilatory control during chronic sustained hypoxia (CH) by measuring the effects of A2a antagonists and agonists on ventilatory responses to hypoxia and hypercapnia in adult male rats before and after one week of CH (PO2 = 80 Torr in a hypobaric chamber). Ventilation measured in awake unrestrained rats with barometric pressure plethysmography increased after CH; acute ventilatory responses to hypoxia or hypercapnia increased also. Acute administration of A2a antagonist (MSX‐3, 1 mg/Kg i.p.) after CH did not change ventilation or acute ventilatory responses. A2a agonists (CGS 21680, 100 µg/Kg i.p.) before CH had no effect on ventilation or ventilatory responses, in contrast to stimulation reported for sleeping rats (J Neurosci 28:2033‐42, 2008). The results do not support a role for Gs in the increased ventilatory drive and hypoxic responses with CH, in contrast to their role in LTF in IH.Supported by NIH RO1 HL‐081823.
Tauopathy in the Ponto‐Medullary Brainstem Nuclei of Aged Tau‐P301L Mice
Authors: Stanic Davor , Bautista Tara , Jones Sarah , Dutschmann Mathias 
Published: June 2021

We recently identified key brainstem areas critically involved in coordinating swallowing and breathing: 1) Nucleus of the solitary tract (NTS), which generates a phasic or rhythmic ‘command’ to produce sequential swallowing in response to sensory stimuli; and 2) Kölliker‐Fuse nucleus (KF), which provides tonic drive for the laryngeal adductors and completely seals the trachea during, and between, swallows. Our aim was to identify whether an underlying pathology exists in the NTS and KF of an established model of neurodegeneration, the Tau‐P301 mouse, and humans that suffered from dementia, which may link dementia and swallowing dysfunction.Tauopathy and neurofibrillary tangle‐related neuropathological morphology was identified by immunohistochemistry using antisera raised against phosphorylated tau. Double‐fluorescence immunohistochemistry was performed to characterise the identity and functionality of cell bodies expressing phosphorylated tau.Cell bodies immunopositive for phosphorylated tau were distributed within the KF, and to a lesser degree, NTS, of Tau‐P301 mice, and the KF of dementia patients with a history of swallowing disorder. This coincided with an upregulated density/intensity of GABA and GAD67 immunoreactivity in fibers/terminals within the KF. Tau positive cell bodies in the KF coexpressed the transcription factor FOXP2.Respiratory‐related neurons in the brainstem are susceptible to neurodegeneration in Tau‐P301 mice and humans suffering dementia, which may disrupt the KF's control of laryngeal adductor motor neurons in the NA and lead to miscoordinated swallowing/breathing patterns.
The Diaphragm Challenged by Acid‐Base Imbalance
Authors: Fitzgerald Robert , Howell Sandra , Roussos Charis 
Published: June 2021

Respiratory and Metabolic Acidosis can result from a variety of diseases and be sensed by receptors in the respiratory control system. But acid/base imbalance also directly affects the performance of the principal muscle of respiration, the diaphragm (D). In this presentation we provide an overview of the in vitro (rat) and in vivo (dog) D responses to four challenges: Uncompensated/Compensated respiratory acidosis (HC/CHC) and Uncompensated/Compensated Metabolic Acidosis (MA/CMA). Our findings revealed that HC reduced the force of tetanic contraction (FC) in both rat and dog Ds. This phenomenon is often seen in human subjects as well. CHC also reduced the FC of the rat D but less that HC. Both MA and CMA reduced the FC in both rat and dog Ds. We found decreases in FC are due to decreases in peak twitch tensions and increases in ½ relaxation time (1/2RT). We found that in the rat D neither HC, MA, nor CMA reduced ATP or PCr. Further, we found that methylxanthines, neostigmine, isoproterenol acted to attenuate the decreases in FC, each by different mechanisms. But first a glance at how decreased pHi per se can affect striated muscle: (1)Increased binding of Ca++ by the sarcoplasmic reticulum (SR) and decreased rate of Ca++ uptake and release per impulse. The first would prolong twitch ½ RT. (2)ATPase activity is decreased and Ca++ concentration requirement for myofibril activation is increased. (3) K+ leaks from the cell, hyperpolarizing the cell and reducing membrane excitability.This work was performed when S. Howell and Ch. Roussos were at Meakins‐Christie Laboratories, McGill University.Support: NIH (HL RO1‐50712‐14; MRC, Canada, Quebec Thoracic Society.
Respiratory Function in the Mdx Mouse Model of Duchenne Muscular Dystrophy: Role of Hypoxia, Stress and Immune Factors
Authors: Burns David , Manning Jennifer , O'Malley Dervla , O'Halloran Ken 
Published: June 2021

Duchenne muscular dystrophy (DMD) is a genetic disease caused by defects in the dystrophin gene. Patients have severe progressive respiratory muscle dysfunction due to progressive weakness and fibrosis culminating in hypoxaemic periods due to hypoventilation. We examined respiratory function in young adult male Mdx (dystrophin deficient) mice (C57BL/10ScSnMdx/J, n=11) and wild type (WT) controls (C57BL/10ScSn, n=10). During normoxic breathing, Mdx mice had significantly reduced breathing frequency, tidal volume and minute ventilation compared to WT. Mdx mice had a significantly increased ventilatory response to acute hypoxic challenge. We also determined that young adult Mdx mice have reduced diaphragm functional capacity compared to WT, with significant decreases in tetanic force, work and power. Interestingly, Mdx diaphragm displayed tolerance to an acute (6hr) in vivo hypoxic stress, which was not observed in WT. In separate studies, co‐treatment with a monoclonal IL‐6 receptor antibody (MR1‐61; 0.3mg/kg) and the CRFR2 agonist, Urocortin 2 (30µg/kg) both administered by 6 subcutaneous injections over 2 weeks completely rescued Mdx diaphragm muscle force loss compared to saline treatment. Mdx mice have pronounced respiratory muscle dysfunction and impaired normoxic ventilation suggestive of hypoventilation. Enhanced hypoxic chemosensitivity and respiratory muscle tolerance of hypoxic stress are suggestive of adaptation to chronic hypoxaemia in young adult life. Hypoxia, stress and immune factors are implicated in diaphragm dysfunction in the Mdx mouse model of DMD.The MR1‐61 antibody was gifted by Chugai Pharmaceuticals, Tokyo, Japan.
Diaphragm Muscle Sarcopenia is Present in Both Male and Female Mice
Authors: Greising Sarah , Medina Juan , Stowe Jessica , Mantilla Carlos , Sieck Gary 
Published: June 2021

The diaphragm muscle (DIAm) must be able to generate sufficient forces to sustain ventilatory and non‐ventilatory behaviors throughout the lifespan. Age‐related decreases in DIAm fiber cross‐sectional area and specific force, i.e., sarcopenia, may impair the ability to generate transdiaphragmatic pressures (Pdi) necessary to accomplish expulsive, non‐ventilatory behaviors essential for airway clearance. We examined the effects of aging on DIAm function in both male and female mice at 6 and 24 months of age (n=79). Maximum DIAm specific force was 30% lower in old mice (P蠄0.001) and Pdi generated during non‐ventilatory behaviors was ~40% less in old mice (P蠄0.001). No differences in either DIAm force or Pdi were found between males and females. Collectively, these results indicate that DIAm sarcopenia is present in both sexes and significantly affects the ability to generate Pdi needed for airway clearance in old age.Supported by R01‐AG044615, T32‐HL105355, and the Mayo Clinic.
Aldosterone Upregulates Tight Junction Expression of Claudin‐4, Decreasing Paracellular Na+ Permeability in the Renal Cortical Collecting Duct
Authors: Rajagopal Madhumitha , Yu Alan 
Published: June 2021

Under conditions of low dietary salt intake, plasma aldosterone levels are upregulated, increasing Na+ reabsorption in the renal cortical collecting duct (CCD). While aldosterone is known to enhance transcellular Na+ reabsorption, its effect on paracellular transport remains unknown. Paracellular transport is mediated by tight junction (TJ) proteins called claudins. We used a murine CCD cell line, mpKCCD c14, to study the effect of aldosterone on paracellular transport. We found that aldosterone significantly increased transepithelial resistance (TER) and decreased paracellular Na+ permeability (PNa), when transcellular transport is blocked. We also found that aldosterone increased TJ expression of a Na+ barrier claudin, claudin‐4, suggesting that increased claudin‐4 expression at the TJ is responsible for the decrease in PNa. To confirm this, we stably knocked–down claudin‐4 expression using shRNAs. This diminished both baseline TER and aldosterone‐induced increases in TER, and PCl/PNa.Aldosterone is known to signal via a mineralocorticoid receptor and activate a serum glucocorticoid kinase (Sgk1) to enhance ENaC activity. We found that aldosterone induced changes in claudin‐4 expression and TER were also suppressed by treatment with RU486 (a steroid receptor blocker) and GSK650394 (aSgk1 antagonist). In summary, our data strongly suggests that aldosterone acts via a Sgk1 mediated pathway to upregulate expression of claudin‐4 at the TJ in the renal CCD, decreasing PNa, preventing back‐leak of actively reabsorbed Na+, and increasing net salt reabsorption. Consistent with our in‐vitro data, we have also shown that in mice fed a low salt diet renal claudin‐4 expression is enhanced.
Spinal Cord Injury Upregulates TRPM4 in the Urinary Bladder
Authors: Kullmann F Aura , Beckel Jonathan , Nakagomi Hiroshi , Wolf‐Johnston Amanda , Gauthier Christian , Kanai Anthony , Birder Lori 
Published: June 2021

Spinal cord injury (SCI) profoundly alters bladder function. Chronically, it induces urothelial hyperplasia, smooth muscle hypertrophy and detrusor hyperactivity, all of which prevent the bladder from properly storing and releasing urine. Transient receptor potential melastatin 4 (TRPM4) is a non‐selective cation channel activated by intracellular Ca2+ and modulated by ATP. This channel has been implicated in various pathologies including SCI, inflammation, axonal degeneration and cardiac myocyte hypertrophy. We hypothesize that TRPM4 may play a role in bladder dysfunction after SCI. Here, we evaluated the expression and function of TRPM4 in the bladder urothelium and smooth muscle after SCI.Bladders were removed from control and spinal cord transected C57Bl6 female mice (T8‐T9; 1‐42 days post SCI). The mucosa and smooth muscle were separated surgically and used for RT‐PCR, western blot analysis, urothelial cell culture and muscle strips contractility studies.TRPM4 mRNA and protein were expressed in the mucosa and detrusor and were upregulated after SCI. Expression levels peaked at 3‐7 days post SCI and remained elevated for the duration of the study (6 weeks post SCI). Peak levels coincided with urothelial hyperplasia and smooth muscle hypertrophy following SCI. The TRPM4 antagonist, 9‐Phenanthrol (0.1‐30 µM), relaxed detrusor strips pre‐contracted with prostaglandin‐E2 (1µM) or carbachol (0.1µM) and reduced spontaneous activity. After SCI, the magnitude of these effects was increased.Our data reveal that TRPM4 is expressed in the bladder mucosa and detrusor and is upregulated after SCI, supporting the hypothesis that TRPM4 is involved in the remodeling processes and/or development of detrusor overactivity following SCI.
Extracellular Ubiquitin Modulates Cardiac Fibroblast Phenotype and Function
Authors: Scofield Stephanie , Daniels Christopher , Dalal Suman , Singh Mahipal , Singh Krishna 
Published: June 2021

Stimulation of β‐adrenergic receptor (β‐AR) increases extracellular levels of ubiquitin (UB), and extracellular UB inhibits β‐AR‐stimulated apoptosis. In the heart, exogenous UB affects β‐AR‐stimulated increases in left ventricular function, and decreases myocardial apoptosis and fibrosis. Cardiac fibroblasts are vital for maintaining the normal function of the heart, and are integral in the structural remodeling of the heart in response to injury or stress. Here we used adult rat cardiac fibroblasts to test the hypothesis that UB modulates cardiac fibroblast phenotype and function, thereby decreasing myocardial fibrosis. Using FITC‐labeled UB and confocal microscopy, we first provide evidence that extracellular UB is internalized into cellular compartments within 30‐60 min. Immunocytochemical analysis using anti‐Ki‐67 antibodies showed that UB treatment inhibits the proliferation of actively growing fibroblasts within 24 h. UB treatment decreased the formation of lamellipodia and filopodia projections while increasing actin stress fiber formation as analyzed by FITC‐phalloidin and α‐smooth muscle actin staining. UB treatment reduced transforming growth factor β‐1 (TGF‐β1)‐stimulated migration of fibroblasts into the wound as examined by in vitro wound (scratch) assay. These results suggest a novel role of UB in modulation of cardiac fibroblast phenotype and function, and provide insight into the mechanism by which exogenous UB may modulate myocardial fibrosis.Supported by Department of Veterans Affairs (BX002332) and NIH.
Increased Cerebrovascular Protein Transcytosis and Amyloid‐β Deposition during Hyperfibrinogenemia Alter Short‐term Memory
Authors: Muradashvili Nino , Rodriguez Walter , Maldonado Claudio , Tyagi Suresh , Lominadze David 
Published: June 2021

Many inflammatory and cognitive disorders including g Alzheimer's disease are accompanied by elevated blood level of fibrinogen (Fg), called hyperfibrinogenemia (HFg). Previously we showed that HFg increases microvascular permeability mainly affecting the transcellular transport pathway. In the present study, we tested the hypothesis that HFg increases cerebrovascular protein crossing via caveolar transcytosis leading to an increased formation of Fg and amyloid‐β (Aβ) complex, which results in loss of short‐term memory.Changes in cerebrovascular permeability were assessed in male wild type (WT, C57BL/6J) and transgenic HFg mice using a dual‐tracer probing method. In addition, in HFg mice brain vascular protein transcytosis was assessed in the presence or absence of in vivo siRNA against Caveolin‐1, which was encapsulated in liposomes that fuse with endothelium and was delivered systemically. Formation of Fg‐Aβ plaque was assessed in mouse brain cryo‐sections by immunohistochemistry. Short‐term memory of mice was estimated by a novel object recognition test (NORT).Results indicate that increased cerebrovascular protein leakage occurs mainly through caveolar transcytosis during HFg and it is greater than what is observed in control mice. Formation of Fg‐Aβ complex was increased in HFg mice compared to that in WT animals. NORT assessment demonstrated that HFg intensifies the loss of short‐term memory in mice.In conclusion, HFg increases cerebrovascular permeability and enhances Fg‐Aβ complex formation, which intensify short‐term memory loss and suggests a functional role of Fg in vasculo‐neuronal pathology.
NFAT5 Expression in Circulating PBMCs is a Potential Biomarker of Whole‐body Dehydration and Stress
Authors: Munoz Colleen , McKenzie Amy , Bartley Jenna , Kunces Laura , Creighton Brent , Varanoske Alyssa , Armstrong Lawrence , Maresh Carl , Lee Elaine 
Published: June 2021

BackgroundOsmotic stress‐specific transcription factor NFAT5 (Nuclear Factor of Activated T cells) and heat stress‐specific factor HSF1 induce transcription of HSP70 and other protective proteins. Our previous work suggests NFAT5 as a novel cellular marker of whole‐body dehydration. We aimed to further characterize NFAT5, HSF1, and chaperone responses to progressive stress (dehydration, exercise, and heat) and recovery in humans.MethodsHealthy males (n=36) completed an overnight (16h) fluid deprivation (‐2.0±0.9% body mass) followed by 2h of cycling (146±2 bpm; 38°C, 40%RH; ‐4.2±0.9% total body mass). Subjects then partially rehydrated (1h; +1.90±0.57% body mass) and returned 24h later after continued ad libitum rehydration. We measured cellular HSF1, NFAT5, and HSP70 in PBMCs (flow cytometry) and plasma eHSP70 (ELISA).ResultsPBMC NFAT5 expression increased post overnight fluid deprivation (20.96%; p=0.056) and post exercise (additional 3.35%; p=0.026), and decreased with partial rehydration (‐4.78%; p=0.072). Cellular and plasma HSP70 responded to stress and recovery with different patterns, and without detectable changes in cellular HSF1.ConclusionPBMC NFAT5 expression responded to dehydration. Cellular and plasma HSP70 responded to stress differently and may thus have different function. Elucidating immune cell molecular chaperone responses to stress exposure and recovery will aid in defining the effect of stress on immune cell function.