bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating the Impact of Circulating miRNAs on Cardiovascular System Remodeling During Pregnancy
Authors: Khan Inzar , Raggio Max , Hetherington Isabella , Totary-Jain Hana 
Published: May 2024

During pregnancy, women undergo significant remodeling of their cardiovascular system, a complex process involving various physiological adaptations to ensure an adequate blood supply to the developing fetus. An intriguing area of research focuses on the role of circulating microRNAs, particularly the primate-specific chromosome 19 miRNA cluster (C19MC) and the rodent-specific chromosome 2 miRNA cluster (C2MC), both of which exhibit high expression levels in the placenta. Extracellular vesicles, such as exosomes, play a crucial role in intercellular communication and may carry microRNAs that contribute to the physiological changes observed during pregnancy. However, the influence of circulating C19MC and C2MC microRNAs on maternal cardiovascular system remodeling remains unexplored. We hypothesized that the increased levels of circulating C2MC or C19MC microRNAs during pregnancy might play a role in the maternal cardiovascular system adaptations. To investigate this hypothesis, we conducted a study to determine whether circulating exosomes during pregnancy lead to elevated expression levels of C19MC or C2MC microRNAs in various organs, including the heart, kidney, liver, spleen, lungs, and brain. In our investigation, we utilized three distinct mouse models: wild-type (WT) mice expressing only C2MC, C2MC knock-out (KO) mice, and a novel humanized mouse model, which combined C2MC KO with either a single or double copy of the human C19MC. We extracted total RNA from the organs of these mice and performed cDNA synthesis. Subsequently, we measured the expression levels of two representative microRNAs, miR-517a and miR-466a, corresponding to C19MC and C2MC, respectively, in the organs of pregnant and non-pregnant mice using TaqMan RT-qPCR. Our results indicated no significant differences in the expression levels of miR-517a and miR-466a when normalized to the housekeeping gene snoRNA-202 across different organs in pregnant and non-pregnant mice. To comprehensively assess the expression patterns of all microRNAs within the C19MC and C2MC clusters in various organs of pregnant and non-pregnant mice, further investigation with a larger sample size and small RNA-Seq analysis is warranted. This approach will enable us to explore a broader spectrum of microRNAs and potentially identify specific candidates that may play a crucial role in the essential physiological process of maternal cardiovascular system remodeling. This study is supported by USF Cardiovascular Summer Undergraduate Research Fellowship (SURF) sponsored by the American Heart Association. 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.
SERCA mediated thermogenesis during contraction-relaxation cycle in rat skeletal muscle in vivo
Authors: Tabuchi Ayaka , Tanaka Yoshinori , C Poole David , Kano Yutaka 
Published: May 2024

BACKGROUND: Across the lifespan, body temperature homeostasis is tightly regulated and impacts various physiological phenomena. In skeletal muscle, heat is produced via contraction-dependent (shivering) and independent (nonshivering) mechanisms, regulating the body temperature and muscle physiology including contractile properties. PURPOSE: In this study, we aimed to reveal the intracellular temperature dynamics in skeletal muscle in vivo during the contraction-relaxation cycle. Additionally, we tested the hypothesis that calcium ion (Ca2+) handling mediated by sarcoplasmic reticulum Ca2+ ATPase (SERCA) is involved in the thermogenesis process during contraction-relaxation cycle in skeletal muscle fibers. METHOD: The spinotrapezius muscle of anesthetized adult male Wistar rats (n = 18) was exteriorized and subjected to microinjection of fluorescent probe Cellular Thermoprobe for Fluorescence Ratio (49.3 μM) for intracellular temperature imaging in vivo. The fluorescence ratio (R: 580 nm / 515 nm) was measured in vivo during temperature increases induced by an external heater for thermoprobe calibration. R was also measured following Ca2+ injection (3.9 nL, 2.0 mM), and Ca2+ injection with SERCA inhibition by cyclopiazonic acid (CPA, 100 μM). RESULTS: The fluorescence ratio linearly increased with the increase of the muscle surface temperature from 25 °C to 40 °C (r2 = 0.97, P < 0.01). The intracellular temperature in muscle was increased and sustained following the Ca2+ injection and this thermogenetic response was significantly suppressed with SERCA inhibition (Ca2+: 38.3 ± 1.4 °C vs Ca2++CPA: 28.3 ± 2.8 °C, P < 0.01 at 1 min following injection). Importantly, elevated muscle temperature occurred predominantly in the muscle relaxation phase that followed the muscle shortening: That shortening occurred immediately and transiently after the Ca2+ injection. CONCLUSION: In this investigation, we demonstrated a novel technique for in vivo intracellular temperature imaging of skeletal muscle. Herein we demonstrate that substantial heat is generated concomitantly with SERCA mediated Ca2+ handling and muscle relaxation. This work was supported by JSPS KAKENHI Grant Numbers 20H04074, 19K22800. 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.
Sex-dependent impairment of kidney function in megalin knockout mice
Authors: Youm Elynna , Albalawy Wafaa N. , Marciszyn Allison , Rbaibi Youssef , Shipman Katherine , Boyd-Shiwarski Cary , Tan Roderick 
Published: May 2024

Megalin ( Lrp2) is a multiligand receptor that drives endocytic flux in the kidney proximal tubule (PT) and is necessary for the recovery of albumin and other filtered proteins that escape the glomerular filtration barrier. We previously found that knocking out Lrp2 in the opossum kidney (OK) PT cell line leads to differential expression of genes involved in mitochondrial and metabolic function. Additionally, we observed large reductions in sodium glucose co-transporter 2 (Sglt2) transcript (>80%) and protein (~40%) expression levels. While Sglt2 transcript and protein levels in Lrp2 KO in mice were more modestly reduced, male and female KO mice fed regular chow or a Western diet (WD) had increased tolerance to a high glucose challenge compared with control mice. Surprisingly, male Lrp2 KO mice fed a WD developed substantial kidney injury, while female KO mice had significantly less injury. In metabolic studies, Lrp2 KO mice preferentially utilized fatty acid oxidation compared to control mice. We hypothesize that compromised endocytic flux in Lrp2 KO mice impairs mitochondrial and metabolic function to worsen kidney damage in a sex-dependent manner. Current studies are focused on a variety of approaches to test how reduced endocytic capacity impacts mitochondrial function and metabolism in Lrp2 KO cells and control OK cells. We will confirm our findings in age-matched male and female control and Lrp2 KO mice. These studies will help to determine the role of megalin expression and function on PT metabolism, function, and overall health. National Institutes of Health: T32DK061296, T32AG021885-20, RO1 DK125049, RO1 DK118726, S10 OD028596, U54 DK137329. 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.
Proteomic profiling of Botryllus schlosseri, an emerging model organism
Authors: Dong Weizhen , Luu Brenda , Lin Mandy , Enriquez Isabel , Hamar Jens , Kültz Dietmar 
Published: May 2024

Botryllus schlosseri is a colonial chordate species that exhibits robust stem cell-mediated regeneration capacities throughout life. It grows through a process of colonial budding known as blastogenesis, in addition to its sexual reproduction mode, embryogenesis. In natural conditions, colony growth peaks in the summer and drastically decreases in the winter due to various seasonal factors. We have established and optimized a method to rear B. schlosseri animals in landlocked laboratories where the controlled conditions allow colonies to grow continuously and exponentially through asexual reproduction under constant temperature, salinity, light, and nutrient conditions. During the weekly blastogenic cycle, all asexually derived parental zooids synchronously regress within one day and are replaced by a new generation. To enable comprehensive molecular phenotyping of this species we established a quantitative proteomics workflow and spectral library for Liquid chromatography/Tandem mass spectrometry (LCMS) data-independent acquisition (DIA). In this study, we quantified the relative abundances of several thousand proteins representing molecular phenotypes of B. schlosseri. This workflow enables us to use proteomics to characterize zooid development during its regenerative cycle, including the short critical period of the takeover stage, during which degenerating zooids undergo massive apoptosis while succeeding buds quickly mature and migrate into place. From this data, protein networks associated with regeneration and degeneration can be created, offering insights into tissue developmental pathways in vivo and future cell immortalization strategies in vitro. Furthermore, the establishment of quantitative proteomics workflows for B. schlosseri coupled with its unique life cycle features promotes the use of this model organism for the study of phenotypic plasticity and evolution of aging, stem cells, and mechanisms of regeneration and cell differentiation. This project is funded by NSF Grant MCB — 2127516. 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.
Use of Function Diagrams in Physiology Education: Nessie the Nephron and Navigating the Lochs
Authors: Wilson Thad , Jackson Brian , Sawaya B. Peter 
Published: May 2024

Function diagrams focus on physiological concepts rather than associated structures and can serve as elaboration tools and mnemonic aids. A function diagram prototype of the gastrointestinal system was recently described (Wilson & Barrett, Adv Physiol Educ, 45:264–268, 2021). Currently, a functional diagram of the glomerulus, nephron, urinary system, and bladder is proposed. Colloquially named “Nessie the Nephron” to loosely capture the looping structure and illusive understanding of renal blood flow, glomerular filtration, and epithelial transport for the student, not to mention the nearly mythical countercurrent multiplier. “Navigating the Lochs” references Nessie’s possible habitat and more importantly the movement and storage of the modified ultrafiltrate from the nephron. The primary analogies that form the structure of this function diagram are: Rain Barrel, Soaker Hose, & Hose Nozzle (afferent and efferent blood flow and filtration pressure); Water Purification System (glomerular filtration barrier forming multiple step filtration process involving the capillary, basement membrane, and podocytes); Mixed Recycling Machine (proximal tubule individual, co-, and bulk transport); Desiccator & Briner (thin descending limb removal of water and thin/thick ascending limb movement of salt); Conveyor Belt Picker (distal nephron selective ion transport); and Concentrator (collecting duct water and urea transport). The primary analogies that elaborate “Navigating the Lochs” are Aqueduct & Cistern System (fluid movement and collection); and Pressure Gauge, Syringe Bulb, and Two-valve Plumbing (bladder storage and micturition). Complimenting these analogies is the rich potential for inclusion of clinical and comparative applications and examples to link previous knowledge and strengthen memories for future retrieval. University of Kentucky College of Medicine. 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.
Alteration of Piezo1 signaling in type 2 diabetic mice: Focus on endothelium and BKca channel
Authors: Haam Chae Eun , Choi Sooyeon , Oh Eun Yi , Byeon Seonhee , Choi Soo-Kyoung , Lee Young-Ho 
Published: May 2024

Aim: Piezo1, a mechanosensitive ion channel, plays a significant role in vascular physiology and disease. This study aimed to elucidate the altered signaling elicited by Piezo1 activation in the arteries of type 2 diabetes. Methods: Ten-to 12-week-old male C57BL/6 (control) and type 2 diabetic mice (db−/db−) were used. The second-order mesenteric arteries (~150 mm) were used for isometric tension experiments. Western blot analysis and immunofluorescence staining were performed to observe protein expression. Results: Piezo1 was significantly decreased in mesenteric arteries of type 2 diabetic mice compared to control mice, as analyzed by western blot and immunofluorescence staining. Piezo1 agonist, Yoda1, concentration-dependently induced relaxation of mesenteric arteries in both groups. Interestingly, the relaxation response was significantly greater in control mice than in db−/db− mice. The removal of endothelium reduced relaxation responses induced by Yoda1, which was greater in control mice than db−/db− mice. Furthermore, the relaxation response was reduced by pre-treatment with various types of K+ channel blockers in endothelium-intact arteries in control mice. In endothelium-denuded arteries, pre-incubation with charybdotoxin, an Ca2+-activated K+ channel (BKCa channel) blocker, significantly attenuated Yoda1-induced relaxation in db−/db− mice, while there was no effect in control mice. Co-immunofluorescence staining showed more structural coupling between Piezo1 and BKCa channel was observed in db−/db− mice than in control mice. Conclusions: The present study is the first report on the distinct aspects of vascular response induced by Piezo1 activation in the mesenteric resistance arteries in type 2 diabetic mice. National Research Foundation of Korea (RS-2023-00272628). 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.
Targeting Melanocortin 4 Receptor to Treat Sleep-Disordered Breathing
Authors: Amorim Mateus R. , Aung O , Anokye-Danso Frederick , de Deus Junia L. , Xiong Jiali , Dergacheva Olga , Bevans-Fonti Shannon 
Published: May 2024

There is no effective pharmacotherapy for sleep-disordered breathing (SDB). A melanocortin receptor 4 (MCR4) agonist, setmelanotide (SET), is used to treat genetic obesity caused by abnormal melanocortin and leptin signaling. We hypothesized that SET can treat SDB in diet-induced obese mice. We performed a proof-of-concept randomized crossover trial of a single dose of SET vs vehicle and a two-week daily SET vs vehicle trial in obese mice. We also examined co-localization of Mcr4 mRNAs with a marker of CO2 sensing neurons PHOX2b in the brainstem and performed chemogenetic studies expressing Cre-dependent designer receptors exclusively activated by designer drugs (DREADD) in Mcr4-Cre mice. SET increased minute ventilation across sleep/wake states, greatly enhanced the hypercapnic ventilatory response (HCVR), and abolished apneas during sleep. PHOX2b+ neurons in the nucleus of the solitary tract (NTS) and the parafacial region expressed Mc4r. Chemogenetic stimulation of the MC4R+ neurons in the parafacial region, but not in the NTS, augmented the HCVR without any changes in metabolism. Parafacial MC4R neurons projected to the respiratory pre-motor neurons expressing cholera toxin B after C3-C4 spinal cord injections. In conclusion, MC4R agonists enhance the HCVR and treat SDB by acting on the parafacial MC4R+ neurons. NIH (R01 HL128970, R01 HL133100, and R01 HL138932), AHA (#915167). 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.
Modulation of Endothelial Cell Mitochondrial Phenotype and Angiogenesis by TRPV4
Authors: Dalal Kesha , Katari Venkatesh , Kondapalli Narendra , Paruchuri Sailaja , Thodeti Charles 
Published: May 2024

Transient receptor potential vanilloid type 4 (TRPV4) is a mechanically activated ion channel implicated in the regulation of endothelial cell (EC) proliferation, migration, and angiogenesis. However, the molecular mechanism(s) by which TRPV4 regulates EC functions remains underexplored. Here, we investigated if TRPV4 channels mediate endothelial function via modulation of mitochondria. Confocal microscopy showed a peri-nuclear localization of mitochondria in normal EC (NEC), while they were localized throughout the cell in TRPV4 knockout EC (KOEC). Furthermore, transmission electron microscopy confirmed clear round mitochondria in NEC compared to elongated mitochondria with distinct cristae in KOEC. Importantly, we found increased distribution of mitochondria in KOEC with increasing stiffness, when cultured on extracellular matrix (ECM) gels of varying stiffness that mimic the stiffness of matrix in pathophysiological conditions such as tumor or heart failure (0.2, 8, and 50 kPa). Mechanistically, western blot analysis showed increased fusion/fission protein ratio (Optic Atrophy 1 (OPA1)/mitochondrial fission factor (MFF)), in KOEC compared to NEC. Seahorse flux analyzer analysis demonstrated increased basal oxygen consumption rate (OCR), maximal OCR, ATP-linked OCR, and spare capacity in KOEC compared to NEC, which were significantly attenuated by a small molecule inhibitor of OPA1, MYLS22. Finally, MYLS22 normalized TRPV4-knockout mediated abnormal proliferation, migration, and angiogenesis ex vivo. Taken together, these findings indicate that mechanosensitive TRPV4 channels regulate mitochondrial phenotype and function during angiogenesis through OPA1. This work was supported by the National Institutes of Health (and R01HL148585 and AHA-TPA-971237) to CKT. 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.
Protection from hypertension phenotype by a mitochondrial division inhibitor in mice infused with angiotensin II
Authors: Nakayama Yuki , J. Preston Kyle , Kawai Tatsuo , Torimoto Keiichi , Eguchi Satoru 
Published: May 2024

Mitochondrial dysfunction has been implicated in various types of cardiovascular diseases including hypertension. Mitochondrial fission fusion balance is critical for mitochondrial quality control, whereas enhanced fission has been reported in several models of cardiovascular diseases. However, limited information is available regarding the contribution of mitochondrial fission in hypertension. Here, we have tested our hypothesis that inhibition of mitochondrial fission attenuates development of hypertension and associated vascular remodeling. C57BL6 mice were infused with angiotensin II for 2 weeks with or without treatment of mitochondrial fission inhibitor mdivi1. Cultured vascular endothelial cells and adventitial fibroblasts from rat aortas were stimulated with angiotensin II in the presence or absence of mdivi1. In C57BL6 mice infused with angiotensin II for 2 weeks, co-treatment of mitochondrial fission inhibitor mdivi1 significantly inhibited angiotensin II-induced development of hypertension assessed by telemetry. Histological assessment of hearts and aortas demonstrated that mdivi1 inhibited vessel fibrosis and hypertrophy induced by angiotensin II. This was associated with attenuation of angiotensin II-induced decline in mitochondrial aspect ratio seen in both endothelium and media of aortas. Mdivi1 also mitigated angiotensin II-induced cardiac hypertrophy assessed by heart weight body weight ratio as well as by echocardiogram. Proteomic analysis on endothelial cell culture media with angiotensin II and/or mdivi1 treatment revealed that mdivi1 inhibited endothelial cell hypersecretory phenotype induced by angiotensin II. In addition, mdivi1 attenuated angiotensin II-induced protein induction of periostin, a myofibroblast marker in cultured vascular fibroblasts. In conclusion, these data suggest that mdivi1 prevented angiotensin II-induced hypertension and cardiovascular remodeling via multicellular mechanisms in the vasculature. 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.