bluuebunny/crossref_metadata_2025_split huggingface dataset:
LRRC8A-VRAC modulates the contractile response by managing the superoxide anion influx in diabetic vasculogenic erectile dysfunction
Authors: Vieira Dos Santos Cintia , Rodrigues dos Passos Rinaldo , Choi Hyehun , Panja Sourav , Wilczynski Stephanie , Carneiro Fernando , Lamb Fred 
Published: May 2024

Introduction: Erectile dysfunction (ED) may be an early marker for cardiovascular diseases, and it is often associated with an hypercontractility of the corpus cavernosum (CC) and pudendal artery (PA) because of increased reactive oxygen species (ROS). Leucine Rich Repeat Containing 8 (LRRC8) Volume Regulated Anion Channels (VRACs) regulates Nox1 and modulates the influx of extracellular superoxide anion (O2•-), contributing to the creation of an oxidized domain, enhancing calcium sensitivity of the smooth muscle which promotes contraction. Objective: We hypothesize that downregulation of NOX1 or LRRC8A would decrease the contractile responses to phenylephrine (PE) and electrical field stimulation (EFS) in the CC, PA and mesenteric resistance artery (MRA) of diabetic mice (dbdb−/−). Methods: The CC and PA of diabetic (dbdb−/−) mice were mounted in myographs. The contraction elicited by PE or EFS was performed in the presence of apocynin (non-selective NOX inhibitor) and GKT137831 (NOX1/4 inhibitor). In LRRC8A KO dbdb−/− mice, contractions to PE and EFS were obtained in the absence or in the presence of GKT137831.Results: In the CC, the maximal contraction to PE was increased in dbdb−/− animals, and in the presence of 3 mM of apocynin, the contractile response was markedly diminished in both control and dbdb−/−. Incubation with GKT137831 reduced the contraction elicited by PE only in the dbdb−/− group (68 ± 9% of the maximal contraction), whereas in the control group this reduction was not significant (82 ± 14% of the PE-maximal contraction). In the PA, the potency of PE was increased in the dbdb−/− group, and apocynin 1mM restored the contraction to normal levels. In the LRRC8A KO dbdb−/− mice, the contraction to PE in the MRA and PA was reduced by 30% compared to dbdb−/−. The response to EFS in CC was similar to dbdb−/−, however, GKT137831 reduced the contraction to EFS with lesser magnitude of inhibition in the LRRC8A KO dbdb−/− mice (35% of inhibition) compared to dbdb−/− mice (50% of inhibition), suggesting that the participation of O2•- in the contractile response was reduced by the lack of functional LRRC8A. Conclusion: LRRC8A modulates the contractile response by managing the influx of reactive oxygen species (ROS) in smooth muscle cells. Inhibition of LRRC8A may be a therapeutic target to prevent hypercontractility of arteries and CC in conditions where there are marked increases in ROS production, such as diabetes. NIH – R01 132948; Institute on Cardiovascular Disease Research, University of South Carolina. 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.
The Influence of Resting Retrograde Shear Rate on Endothelial Function as Assessed by Flow Mediated Dilation
Authors: Alhalimi Taha A. , Trotter Claire E. , Velusamy Prema , Nandadeva Damsara , Fadel Paul J. 
Published: May 2024

Shear stress profiles are an important determinant of endothelial function. Unidirectional blood flow enhances mean shear and protects endothelial function, whereas increased retrograde and oscillatory shear favors a proatherogenic environment. In this regard, acutely increasing retrograde shear has been shown to impair endothelial function. Also, previous studies have reported an elevation in retrograde shear in older adults that has been suggested to contribute to impaired endothelial function with age. However, the impact of having elevated retrograde shear at rest on endothelial function remains unclear. Therefore, we aimed to assess the associations between resting shear patterns and endothelial function, as measured by flow-mediated dilation (FMD) in a cohort of young and older adults. We hypothesized that higher retrograde shear rate and oscillatory shear index at rest would be related to a lower FMD value. Method: A total of 60 participants, 30 young adults (24 ± 5 years) and 30 older adults (62 ± 9 years), were studied. Resting brachial artery blood flow was measured using duplex Doppler ultrasound and retrograde shear rate and oscillatory shear index were calculated. Brachial artery FMD was used as a measure of endothelial function. Pearson correlations were used to investigate the associations between FMD, resting shear patterns, and age. Result: FMD was significantly lower in older compared to young adults (4.9 ± 2.7% vs. 7.6 ± 3.2%, p < 0.01). Both retrograde shear rate and oscillatory shear index tended to be greater in older adults (-20.7 ± 15.1 s−1 vs. -15.2 ± 17 s−1, p = 0.062, and 10.7 ± 8% vs. 7.9 ± 8.0%, p = 0.056, respectively). FMD was not correlated with retrograde shear rate (r = -0.18, p = 0.17), or oscillatory shear index (r = -0.21, p = 0.11) in the entire cohort or in the young and older group alone. However, FMD, retrograde shear rate, and oscillatory index were moderately correlated with age: FMD (r = -0.45, p < 0.01), retrograde shear rate (r = -0.32, p = 0.012), and oscillatory shear index (r = 0.33, p < 0.01). Conclusion: These preliminary results suggest that resting retrograde shear and oscillatory shear index are not associated with reduced endothelial function in a cohort of young and old adults. Nevertheless, age-associated reductions in endothelial function and elevated retrograde shear were observed. This project was supported by the College of Nursing and Health Innovation. 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.
Carotid body-mediated chemoreflex drive predicts the development of HFpEF in mice
Authors: Pereyra Katherin 
Published: May 2024

Heart failure with preserved ejection fraction (HFpEF) is a prevalent pathophysiological condition affecting millions of people worldwide. Several factors have been pointed out to play a role in the development of HFpEF; however, there are no molecular/physiological variables that can predict the incidence of HFpEF. Interestingly, carotid body (CB) chemoreceptors have been implicated in worse outcomes in reduced ejection fraction HF. Then, we hypothesized that CB chemoreflex sensitivity may offer prognostic value in HFpEF. Accordingly, we aimed to study whether high chemoreflex drive predicts the development of HFpEF in mice. A longitudinal study was performed in adult C57BLJ6 mice (P90) that underwent 16 weeks treatment with a high fat diet (60% high fat diet, HFD) and a nitric oxide synthase blocker (L-NAME 0.6 g/L) to induce HFpEF. Mice were recorded for cardiac/hemodynamic and ventilatory function before the onset of HFD and L-NAME treatment by using 2D-echocardiography, tissue doppler imaging, blood pressure and whole-body plethysmography, respectively. At 16 weeks after HFD+L-NAME all mice were recorded again. CB-chemoreflex drive was assessed by the hypoxic ventilatory response (HVR, FiO2»10%). We found that »50% of total mice (n=24) develop HFpEF after 16 weeks of HFD+L-NAME as evidenced by a significant (p<0.05) increase in the E/A ratio (1.60±0.09 vs. 1.30±0.01 mmHg, HFpEF vs. nonHFpEF), blood pressure (MAP: 98.7±1.9 vs. 88.4±1.4 mmHg, HFpEF vs. nonHFpEF) and body weight (31±1 vs. 29±0 g, HFpEF vs. nonHFpEF). Remarkably, a higher HVR before the onset of HFD+L-NAME was closely associated with the prevalence of HFpEF. Indeed, (4/5) mice that displayed a high HVR chemoreflex (³0.15 ΔVE/FiO2%) develop HFpEF after 16 weeks of HFD+L-NAME treatment. Our results showed for the first time that CB-mediated chemoreflex sensitivity predicts the development of HFpEF and support the notion that peripheral chemoreflex drive may be useful to evaluate the risk of developing HFpEF. Supported by Fondecyt 1220950. 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.
Hypoxia Exposure Fine-Tunes Mitochondrial Function in Primary Dermal Fibroblasts Derived from Loggerhead Sea Turtles
Authors: Arango B. Gabriela , Ensminger David C. , Godard-Codding Celine , Vázquez-Medina Jose Pablo 
Published: May 2024

Sea turtles are constantly exposed to changes in oxygen tension derived from extended breath-hold diving, but the cellular-level response to such changes is not completely understood. Most studies in hypoxia-tolerant reptiles have focused on the freshwater turtle Trachemys scripta, which responds to anoxia by inducing metabolic rewiring and preserving mitochondrial integrity, facilitating effcient mitochondrial respiration during reoxygenation. Here, we derived primary dermal fibroblasts from loggerhead sea turtles and western fence lizards to study the bioenergetic cellular response to hypoxia exposure in diving and non-diving reptiles. Cells from both species stained positive for the fibroblast markers vimentin and PDGFRb and responded to hypoxia exposure (0.1% O2) by accumulating HIF-1α. We measured oxygen consumption rates (OCR) in intact cells using Seahorse technology. We found that basal, maximal, and spare respiratory capacity was lower in lizard than in loggerhead cells at 26oC under normoxic (room air) conditions (p < 0.0001). Exposure to short (1h) and long-term hypoxia (24h) altered mitochondrial function in both species. Maximal and spare respiratory capacity were lower in loggerhead than in lizard cells (p < 0.01) after 1h hypoxia followed by 1h reoxygenation. In contrast, basal and maximal respiratory capacity was higher in loggerhead compared to lizard cells after 24h hypoxia (p < 0.04). Nonetheless, the overall OCR after 24h hypoxia in both species was lower than that observed after 1h hypoxia. Overall, there was a significant reduction in cellular respiration in both species from short-term to long-term hypoxia exposure. In lizard cells, basal OCR decreased by a factor of three while maximal OCR decreased by a factor of 4.5. In loggerhead cells, both the basal and maximal OCR decreased by a factor of two. Our results demonstrate species-specific regulation of cellular respiration after hypoxia exposure. Remarkably, loggerhead cells show a steady downregulation of cellular respiration in response to hypoxia exposure and faster recovery after extended hypoxia (24h) than lizard cells, aligning with the remarkable hypoxic tolerance exhibited by sea turtles, which can endure up to 7 hours of breath-holding underwater. Understanding the cellular mechanisms that drive hypoxic tolerance in diving animals can provide insights for treating human conditions characterized by hypoxia signaling. Ford Foundation. 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.
Investigation of the Role of Aging on Pulmonary Microvascular Endothelial Cell Barrier Function During Mechanical Ventilation
Authors: Manji Aminmohamed , Mehta Sanjay , Wang Lefeng , Pape Cynthia , McCaig Lynda , Veldhuizen Ruud , Gill Sean 
Published: May 2024

Elderly individuals have substantially elevated morbidity and mortality following pulmonary insult that require mechanical ventilation (MV) to sustain respiratory function. It is not known if an altered response to MV contributes to the worsened outcomes in the elderly. MV is associated with injury to pulmonary microvascular endothelial cells (PMVEC), leading to a compromised vascular barrier, and fluid and protein leakage within the tissue. However, the precise impact that age has on the vascular endothelium during MV is unknown. We hypothesized that aging augments PMVEC barrier dysfunction during MV. To address this hypothesis, young and aged mice were ventilated at a tidal volume of 20 mL/kg for 3 hours. To assess microvascular permeability, lungs were lavaged and abundance of the serum protein, immunoglobulin M, within the lavage fluid was measured. Lung tissue was dissociated into single cells and RNA was collected for single-cell RNA sequencing (scRNAseq). Subsequent analysis was performed using the Seurat package in R to give insight into the role of specific cell types, with a particular emphasis on microvascular endothelial cells. To directly assess molecular mechanisms directly in the cells, PMVEC were isolated from a separate cohort of non-ventilated young and aged mice and cultured in vitro. Cells were grown to confluency, then assessed for barrier integrity by Evans blue-labelled albumin leak across monolayers and immunofluorescence staining of cell junctional adherens and tight junction proteins, VE-cadherin and claudin-5. Compared to young, aged-ventilated animals had a significant increase in immunoglobulin M in their lavage fluid. Analysis of scRNAseq data revealed more robust activation and inflammation in the endothelial cells from aged animals following MV. Endothelial monolayers from aged animals in vitro exhibited a significant increase in albumin flux, which was associated with poor VE-cadherin and claudin-5 junction formation. In conclusion, PMVEC from aged mice exhibit compromised barrier function, leading to augmented permeability following MV. The age-dependent loss in barrier function appears to be due to an impaired ability to re-establish functional cell-cell junctions. These findings suggest that the aged vascular barrier is more susceptible to injury from MV, due to impaired PMVEC cell-cell junction integrity. Our results may highlight molecular pathways involved in predisposing aged individuals to worsened outcomes during MV, which can help in developing targeted therapeutics. Funded by Lawson Health Research Institute, CIHR, the Ontario Graduate Scholarship, and Western University. 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.
Influence of Commonly-Encountered Participant Behavior on Cardiovascular Measures during Physiological Testing
Authors: McLaurin Natalie , Alhalimi Taha , Ramos Andrea , Trevino George , Tanaka Hirofumi 
Published: May 2024

Objective: When conducting laboratory testing, it is essential for participants to rest quietly in the supine posture without much movement. This is to establish a stable baseline to minimize external interference and distractions that could affect physiological measures. However, it is rather common that some participants start talking to investigators, fall asleep, or use cell phones for texting during the resting period. It is also common to observe some participants change their posture to side laying to make themselves more comfortable. The extent to which these common laboratory encounters influence cardiovascular outcome measures such as blood pressure and arterial stiffness has not yet been studied. Methods: A total of 55 adults (16 men and 39 women, 36±15 years) were studied under the following seven conditions: 1) quiet supine rest, 2) pretending to sleep, 3) while and 4) after talking to investigators, 5) during and 6) after cell phone use for texting, and 7) lying on the side. Each condition was separated by 5 minutes. The order of the conditions was randomized. Systolic and diastolic blood pressure (BP), heart rate, brachial-ankle pulse wave velocity (baPWV), and carotid-femoral PWV (cfPWV) were measured during these conditions. Results: Compared with quiet rest (61±10 bpm), heart rate was elevated (p<0.05) when the participants were talking to the investigators (65±10 bpm) and texting on cell phones (69±15 bpm). Both systolic and diastolic BP were 3-4 mmHg greater when they were talking to the investigators but 4-5 mmHg lower in the ‘side lying’ position compared with quiet rest. In the ‘side lying’ condition, baPWV was not affected but cfPWV was not able to be measured in 16 participants resulting in a 38% failure rate. baPWV was greater (p<0.01) while and after the participants were talking to investigators. cfPWV was not able to be measured during talking but was not affected when it was assessed after talking. Pretending to sleep and texting on a cell phone did not significantly influence any of the BP and PWV measures. Conclusions: Talking during the testing period significantly increases all the cardiovascular measures assessed in the present study. However, pretending to sleep and cell phone texting do not appear to influence them. There was no funding source for this study. 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.
Vagal nerve and sympathetic nerve activity in response to glucagon-like peptide-1 (GLP-1) receptor stimulation in conscious rats
Authors: Miki Kenju , Ikegame Shizuka , Yoshimoto Misa 
Published: May 2024

GLP-1 (Glucagon-Like Peptide-1) is a type of gastrointestinal hormone that plays an integral role in regulating glucose homeostasis and appetite control. GLP-1 receptors are expressed throughout the body, and it has been suggested that GLP-1 can be detected by vagal afferent nerve activity, leading to changes in sympathetic nerve activity. However, the details of the effects of GLP-1 receptor stimulation on autonomic nerve activity have not been reported. Therefore, this study investigated the effects of different sites of GLP-1 receptor stimulation on autonomic nerve activity by administering GLP-1 receptor agonists via three routes: intravenous (IV), intraportal vein (iport), and intraperitoneal (iperi). Male Wistar rats were chronically implanted with electrodes, catheters for measuring cervical vagal activity, renal and lumbar sympathetic nerve activity, electroencephalogram, electromyogram, electrocardiogram, arterial pressure, sensors for tissue fluid glucose concentration, and catheters for drug administration in the vein, portal vein, and abdominal cavity. Exendin-4, a GLP-1 receptor agonist, was administered to conscious rats via one of the following routes: intravenous, intra-portal vein, or intra-abdominal. Cervical vagal activity was increased in all routes of Exendin-4 administration. Renal sympathetic nerve activity was rapidly decreased by Exendin-4 administration and gradually recovered to pre-administration levels. There were no significant differences in renal sympathetic nerve activity among the different routes of Exendin-4 administration. On the other hand, lumbar sympathetic nerve activity increased slowly after Exendin-4 administration through the iperi and iport routes, while it decreased initially, then gradually increased following administration through the IV route. These results demonstrate that stimulation of GLP-1 receptors by Exendin-4 increases vagal nerve activity, decreases renal sympathetic nerve activity, and produces regionally different responses in lumbar sympathetic nerve activity depending on the site of stimulation. JST (JPMJMS2023). 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.
Estrogen Metabolites Modulate Airway Hyperreactivity in a Murine Model of Asthma
Authors: Kumar Ashish , Reza Mohammad Irshad , Ambhore Nilesh , Balraj Premanand , Sathish Venkatachalem 
Published: May 2024

Objective: Airway hyperreactivity (AHR) and remodeling are the key contributors to airway changes in asthma resulting in airway narrowing and resistance to airflow. Sex-steroid signaling, especially estrogen’s differential role in asthma undoubtedly questions its prime involvement in regulating airway structure and function in context to asthma. Evidence from cardiovascular (CV) and reproductive systems suggests that estrogen metabolites particularly 2-hydroxyestradiol (2HE) and 16α-hydroxyestradiol (16αHE2) influence a multitude of cellular functions. Accordingly, the aim of this study is to determine how estrogen metabolites regulate AHR and remodeling using a mouse model of asthma. Methods: WT C57BL/6J (male and female) mice were procured from Jackson Laboratory. Experimental animals were administered with PBS, 2-HE (2 mg/kg), 16αHE2 (2 mg/kg) with/without MA intranasally on alternate days for 28 days. On day 29, mice were anesthetized and subjected to SCIREQ flexiVent to measure Lung mechanics like airway resistance (Rrs), elastance (Ers), and compliance (Crs). Following this, broncho-alveolar lavage (BAL) was performed for differential leukocyte count (DLC) and lung tissue samples processed for histology using hematoxylin and eosin (H&E) staining and Sirius-red and fast-green (SRFG). Results: MA-challenged group increased airway Rrs and reduced Crs in response to methacholine (MCh) in both male and female mice with profound effects in female mice. Animals exposed to MA and administered with 16αHE2 showed significant increase the Rrs while 2-HE downregulated the MA effect. The exacerbated effect of 16αHE2 on Rrs was significantly higher in MA-challenged female mice compared to male mice. Histology study including H&E and SRFG stained lung sections show increased ASM mass in 16αHE2 exposed mixed MA challenged mice. Whereas 2HE reversed MA induced effect. DLC in BAL showed increased neutrophils and eosinophils in MA challenged mice, this was attenuated by 2HE. Conclusion: This study highlights the distinct role of estrogen metabolites in regulating airway hyperresponsiveness and remodeling in the context of asthma. Thus, providing possible therapeutic potential for observed sex differences in asthma. Acknowledgment: Supported by NIH grant R01-HL146705 (Sathish). 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.