bluuebunny/crossref_metadata_2025 huggingface dataset:
Antidepressant Treatment Preserves Microvascular Endothelium-Dependent Dilation in Women Who Have Had Preeclampsia
Authors: Lee Ruda , Brustkern Kaila , Pierce Gary , Santillan Mark , Stanhewicz Anna
Published: May 2024

Women with a history of preeclampsia (hxPE) demonstrate persistent microvascular endothelial dysfunction which may contribute to the progression of cardiovascular disease. Women with hxPE also have higher rates of depression compared to women with a history of healthy pregnancy. Interestingly, accumulating evidence indicates that antidepressant treatment may have vasculoprotective effects and attenuate preeclampsia risk. However, whether antidepressant treatment impacts microvascular function in these women remains unknown. Therefore, we examined the effect of chronic antidepressant use on microvascular function in women with hxPE. We hypothesized that antidepressant-treated women with hxPE would have greater endothelium-mediated microvascular vasodilation than unmedicated women with hxPE. Five women with hxPE who were currently treated with an antidepressant (hxPE+AD; 36±3 years; 26±7 months postpartum), six who were not (hxPE-AD; 34±2 years; 26±5 months postpartum), and six unmedicated women with a history of uncomplicated pregnancy (HC; 37±1 years; 35±7 months postpartum) participated in one study visit. We measured cutaneous vascular conductance (CVC=laser doppler flowmetry flux/MAP) responses to graded perfusion of acetylcholine (10−10-10−1 mM) via microdialysis in a control (lactated Ringer's) site and a site treated with 15 mM NG-nitro-L-arginine methyl ester [L-NAME; nitric oxide (NO) synthase inhibitor]. hxPE-AD had reduced endothelium-dependent dilation compared to HC (acetylcholine ³10−3 mM; P<0.03). hxPE+AD had greater endothelium-dependent dilation compared to hxPE-AD (acetylcholine 10−2 and 10−3 mM; P<0.02) and there were no differences between hxPE+AD and HC (all P>0.05). L-NAME reduced endothelium-dependent dilation in all groups (all P<0.001), and there was no difference between groups in NO-dependent dilation [area under the curve (AUC) at a control site − AUC at a L-NAME treated site; P=0.522]. These data suggest that microvascular endothelium-dependent dilation is preserved in women with a history of preeclampsia treated with an antidepressant, potentially mediated through non-NO-dependent mechanisms.

Funding: American Heart Association CDA 937990.

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.
Na/K-ATPase α1/Src Signaling Regulates Mitochondrial Metabolic Function and ROS Production in Human iPSC-derived Cardiomyocytes
Authors: Strause Sidney , Pessoa Marco , Cai Liquan , Gao Yingnyu , Banerjee Moumita , Tian Jiang , Xie Zijian
Published: May 2024

Through an isoform specific mechanism, the Na/K-ATPase (NKA) α1 polypeptide-mediated regulation of Src kinase has emerged as a novel regulator of mitochondrial function in various cell types. Mitochondrial metabolism ensures adequate myocardial performance and adaptation to physiological demand. It is also a critical cellular determinant of cardiac repair and remodeling. To investigate the importance of the proposed NKA/Src regulatory signaling on cardiac mitochondrial metabolic function independently from the classic Na/K-ATPase enzymatic function, we used a gene targeting approach in cardiomyocytes. Human induced pluripotent stem cells (hiPSC) expressing a Src-signaling null mutant (A420P) form of NKA α1 were generated using CRISPR/Cas9-mediated genome editing. NKA isoform protein expression and enzymatic activity remained unchanged. However, baseline levels of Src and ERK1/2 phosphorylation were decreased by 55% and 80%, respectively in the A420P hiPSC (n=3, p<0.05). Both the WT and A420P hiPSC differentiated into cardiomyocytes (iCM) as assessed by morphology, spontaneous cell contraction, marker gene expression, and subcellular striations. Cell metabolism assessed by Seahorse extracellular flux analysis revealed significant reductions in basal and maximal rates of mitochondrial respiration (50%), spare respiratory capacity (50%), ATP production (60%), and coupling effciency (20%) (n=4, p<0.05). ROS production was monitored in live cells by measuring the oxidation of the CM-H2DCFDA dye using a fluorescence microscope. The slope of the ROS production rate curve was dramatically reduced in A420P iCM (80%, n=3, p<0.05). Protein carbonylation levels, analyzed by ELISA as markers of oxidative damage, were also decreased in A420P iCM (n=4, p<0.05). Taken together, these data provide genetic evidence for a role of NKA α1/Src in the tonic stimulation of basal mitochondrial metabolism and ROS production in human cardiac myocytes. This has potential significance in cardiometabolic diseases and suggests that targeting the NKA α1/Src signaling axis may offer a novel approach to address mitochondrial dysfunction.

NIH Grant R15 HL145666, NIH Grant P20GM103434 to the West Virginia IDeA Network of Biomedical Research Excellence, and American Heart Association Postdoctoral Fellowship — 22POST917776 — to Marco T. Pessoa.

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.
Females Maintain Fluid Balance across Consecutive Workdays in Heat When Fluids are Readily Accessible
Authors: Leblanc Hannah , Rawlings Alexander , Kozlin Michael , Przybysz Johnathan , Cavuoto Lora , Schlader Zachary , Pryor Riana
Published: May 2024

Workers should aim to fully replace fluid losses during work in the heat to maintain work productivity and minimize risk of heat illnesses, however, fluid balance of females working during consecutive days in the heat is unknown. The purpose of this study was to test the hypothesis that females would maintain fluid balance during work across two consecutive workdays. Eight healthy females (age: 29±5, body mass: 75.3±20.1, body fat: 23±8%) completed two consecutive days (Day 1, Day 2) of heavy intensity work in a hot environment (35.9±1.2°C, 24±6% relative humidity). Work consisted of repeated 45/15 work/rest cycles of treadmill walking or cycling at 398±7 W of metabolic heat production and seated rest for 4 h. Every 20 min, participants were provided 237 mL of a sport drink to consume ad libitum. Urine flow rate (UFR) was measured before work. Urine specific gravity (USG) and nude body mass were measured before and after work. Fluid volume consumed and thirst (9-point Likert scale, 1=not thirsty at all, 9=very, very thirsty) were measured during work. Two-way repeated measures analysis of variance and paired samples t-tests were used to compare differences. Significance was set at p≤0.05. Percent body mass loss was not different between Day 1 (0.69±0.82%) and Day 2 (0.96±2.25%, p=0.935). Similarly, sweat rate was not different between Day 1 (0.57±0.12 L/h) and Day 2 (0.65±0.21 L/h, p=0.312). Participants consumed less fluid on Day 1 (64±21%, 25±10 mL/kg) compared to Day 2 (74±20%, p=0.026; 29±10 mL/kg, p=0.025). Participants consumed 68±19% and 77±20% (p=0.040) of fluid offered during work and 55±27% and 66±22% (p=0.173) of fluid offered during rest on Day 1 and Day 2, respectively. Resting thirst (Day 1: 2.1±1.1, Day 2: 1.6±0.5, p=0.096), change in thirst (Day 1: -0.5±0.9, Day 2: +0.3±1.3, p=0.111) and maximum thirst (Day 1: 3.6±1.1, Day 2: 3.6±1.4, p=1.000) were not different between days. USG was not different (p=0.839) across days before (Day 1: 1.009±0.010, Day 2: 1.009±0.010) or after (Day 1: 1.012±1.010, Day 2: 1.012±0.010) work, respectively. UFR was not different between days (Day 1: 2.2±1.4 mL/min, Day 2: 2.0±1.2 mL/min, p=0.836). Females completing heavy intensity work in heat maintained fluid balance across two consecutive days when fluids were readily accessible. Ad libitum fluid consumption may be suffcient to adequately replace fluid losses in females across consecutive days of work in heat.

This project was funded by the National Institute for Occupational Safety and Health (1K01OH012016-01A1).

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 Anorexigenic Peptide, Nesfatin-1, Dampens the B Cell Response to Receptor Mediated Stimulation
Authors: Steffen Tara L. , Stafford Joshua , Samson Willis K. , Yosten Gina L.C.
Published: May 2024

Obesity is an inflammatory condition marked by an increase in the accumulation of dysregulated B cells in adipose tissue (AT). These dysregulated B cells secrete pro-inflammatory mediators, cytokines and antibodies, that interfere with the normal function of the AT and contribute to the development of insulin resistance. Furthermore, depletion of the B cell compartment in a murine model has been shown to attenuate the metabolic aberrations associated with obesity. These data emphasize a clear role for B cell contribution to the comorbidities associated with obesity; however, the mechanism(s) regulating their accumulation and function are unknown. Therefore, discovery of targets that normalize the interaction between B cells and adipocytes has the potential to significantly reduce the burden of the inflammatory comorbidities of obesity that lead to metabolic disorders. Nesfatin-1 is a peptide hormone that is cleaved from the nucleobindin 2 (NUCB2) precursor along with two other peptides, nesfatin-2,3. Nesfatin-1 was originally described based on its anorexigenic effects in vivo, however recent reports have documented its anti-inflammatory activity. When NUCB2 is genetically deleted, there is a resultant increase in the presence of pro-inflammatory mediators in subcutaneous white AT (WAT). This is intriguing because humans with obesity have reduced serum nesfatin-1 in addition to low-grade chronic inflammation in WAT. However, the underlying mechanisms of how nesfatin-1 exerts its effects and its sites of action within the immune system have not been fully elucidated. In this study, we sought to determine a mechanism by which this peptide might directly interact with the immune system starting with a human B cell line, Raji. Here, we show that nesfatin-1 directly inhibits lipopolysaccharide (LPS) and B cell receptor (BCR) stimulated B cell proliferation while also protecting from inflammatory cell death. Furthermore, nesfatin-1 prevented stimulation induced secretion of pro-inflammatory mediators IgM and TNFa. Finally, we show that this effect is likely mediated via nesfatin-1’s ability to inhibit inflammatory pathway activation in this B cell line. Taken together, this work highlights a novel action of nesfatin-1 to directly bind to and inhibit B cell responses. These fundamental studies will serve as a springboard for the future development of nesfatin-1-based therapeutics for the treatment of obesity-associated inflammation, thus enabling potential new preventative strategies for forestalling the development of inflammation associated diseases, such as T2D.

Saint Louis 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.
Circulating Extracellular Vesicle-Mediated Immune Activation After Resuscitation From Cardiac Arrest in Swine
Authors: Zahra Sumbule , Rolland Tyler J , Cucinotta Daniel , Hudson Emily R , Young Rebeccah , Weil Brian
Published: May 2024

Objective: Systemic inflammation is a well-established contributor to morbidity and mortality in patients that are initially resuscitated from sudden cardiac arrest (SCA). However, our mechanistic understanding of immune activation in this context remains limited, impeding the development of targeted anti-inflammatory treatments. To address this knowledge gap, we tested the hypothesis that post-resuscitation immune cell activation is mediated, at least in part, by circulating extracellular vesicles (EVs). Methods: Swine (n=3) were subjected to 10 minutes of electrically-induced SCA followed by CPR with defibrillation and epinephrine (0.015 mg/kg iv) to achieve return of spontaneous circulation (ROSC). Blood samples were collected before SCA and 4-hours post-ROSC for isolation of plasma EVs from clarified plasma using 100kD filters, which were subsequently quantified by Nano-particle Tracking Analysis (ZetaView). Naïve PBMCs from healthy swine were cultured with basal media (negative control), lipopolysaccharide (LPS; positive control), or EVs isolated from pre-SCA or post ROSC plasma that were stained with lipophilic dye (DiD) to facilitate assessment of EV uptake (n=3 per group). After 24 hours in culture, PBMC activation was assessed via surface marker expression (flow cytometry) and inflammatory cytokine release (ELISA). Results: Compared with exposure to pre-SCA EVs and basal media, PBMCs exposed to post-ROSC EVs exhibited a significant shift toward an inflammatory phenotype, with enrichment of inflammatory dendritic cells (CD172+CD16+), inflammatory granulocytes (CD172+CD163-), and inflammatory macrophages (CD14+CD163+) in both DiD+ and DiD- cell populations (all p<0.05 vs. pre-SCA EVs). Although TNF-α, IFN-α, and IFN-γ were not detected after EV co-culture, a near-significant increase in IL-1β release was observed in PBMCs exposed to post-ROSC EVs vs. pre-SCA EVs (5.72±2.4 vs. 2.21±0.7 pg/mL; p=0.068). Conclusion: Our findings suggest that circulating plasma EVs may contribute to immune cell activation following systemic ischemia/reperfusion injury associated with resuscitation from SCA. Further studies to delineate mechanisms underlying EV-mediated pro-inflammatory shifts in immune cell phenotype and potentiation of IL-1β release may reveal novel therapeutic targets to mitigate post-resuscitation inflammation and improve patient outcomes following SCA.

Supported by funding from the NIH and US Department of Veteran's Affairs.

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.
Assessing the correlation between resting cerebral blood flow and three different cerebrovascular reactivity stressors
Authors: Khademi Motlagh Hedyeh , Haley Travis , Didier Kaylin , Muer Jessica , Wannebo Brett , Wieben Oliver , Al-Subu Awni
Published: May 2024

Background: Understanding the regulation of resting cerebral blood flow (CBF) is crucial in the realm of brain health as previous studies indicate reduced CBF is associated with an increased risk of several neurological and cerebrovascular conditions. Concurrently, cerebrovascular reactivity (CVR), which assesses the ability of blood vessels to respond to stimuli, is a valuable indicator of cerebrovascular health, as reduced CVR to increased CO2 is associated with increased stroke, cognitive decline, and mortality risk. Thus, evaluating CVR may serve as a useful tool to understand pathologic brain conditions. In this study, we sought to address these intricacies by examining how the brain responds to different physiological stressors, such as hypercapnia, hyperoxia, and hypoxia. We tested the hypothesis that a) lower resting CBF is associated with reduced CVR-CO2, b) lower resting CBF is associated with reduced CVR-hyperoxia c) lower resting CBF is associated with reduced CVR-hypoxia. Methods: 51 young, healthy adults (19F) were included (23±4 yr). Females were not taking hormonal birth control and studied on days 1-7 of the menstrual cycle. Participants completed a magnetic resonance imaging (MRI) scan and CBF was quantified using arterial spin labeling (ASL). CVR was evaluated using a resting normoxia compared to: hypercapnia (5% CO2; 32M/19F), isocapnic-hyperoxia (100% O2; 8M/7F) and isocapnic hypoxia (80-85±1% oxygen saturation (SpO2); 12M/2F). Relative CVR was calculated by the ratio of %ΔCBF/ΔEnd tidal CO2 (ETCO2) for hypercapnia, %ΔCBF/ΔSpO2 for hypoxia, and hyperoxic reactivity was analyzed as relative CBF change (%Δ). Data were analyzed using correlation with significance set at p<0.05 and are displayed as mean ± SD. Results: ETCO2 increased from 35±3 to 42±3 mmHg during hypercapnia (p<0.05), but did not change significantly during hyperoxia or hypoxia conditions (p>0.05 for both). SpO2 decreased from 98±1% to 84±2 % during hypoxia (p<0.05). There was no significant correlation between resting CBF and CVR-CO2 (r2=0.02, p=0.23), as well as CVR-hyperoxia (r2=0.07, p=0.3). However, lower CVR-hypoxia was significantly correlated with lower resting CBF (r2=0.27; p=0.05). Conclusion: These findings suggest there is an association between resting CBF and hypoxic reactivity, but not hypercapnic or hyperoxic reactivity indicating a single measure of vascular health may not be suffcient to understand cerebrovascular function in health. Further studies with larger and more diverse populations may provide deeper insights into these intricate interactions.

Funding NIH R01 HL 150361.

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.
Chronic Unpredictable Stress Induces Mitochondrial Dysfunction in Hypothalamic Pituitary Adrenal Axis Regions
Authors: Hollis Fiona , Frambes Noelle , Churillo Amelia , Mullaly Alaina , Doster James , Stegmann Kyle , Priviero Fernanda
Published: May 2024

Background: Stress elicits physiological and behavioral responses via adaptive responses like the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) activation. Under chronic stress, however, these responses become dysfunctional leading to pathological changes in behavior and health. Mitochondria are dynamic organelles that provide cellular energy, activate immune responses, and synthesize glucocorticoids in the adrenal glands in response to stress. Thus, the mitochondrion is a key candidate linking the effects of chronic stress and health, however, the effects of chronic stress on mitochondrial function in the HPA axis, particularly with respect to sex differences, are largely unexplored. Hypothesis: Chronic unpredictable stress (CUS) decreases mitochondrial function and dynamics in key regions within the HPA axis. Methods: Adult male and female C57Bl6/J mice were exposed to 28 consecutive days of CUS or handling (non-CUS) with weekly weighing. Mice were euthanized 24h after the last stress exposure and the brain and adrenal glands dissected and weighed. Mitochondrial function was assessed using high resolution respirometry in hypothalamus and adrenal tissues. Protein expression was assessed by immunoblot. Results: CUS decreased mitochondrial respiration within key stress centers, with stressed males exhibiting decreased respiration in the amygdala (20%, p=0.05), and stressed females exhibiting decreased respiration in the hypothalamus (20%, p=0.004) and adrenal glands (17%, p=0.06). CUS increased mitochondrial complex protein in male adrenal gland (47%, p=0.01) and mitochondrial mass in hypothalamus (p=0.007). Finally, cleaved Gasdermin D expression was increased nearly 2-fold in male hypothalamus (p=0.03). Conclusions: Our data show sex- and region-dependent decreases in HPA axis mitochondrial function concurrent with upregulated protein expression and pore formation. These observations point to sex-specific effects of CUS to induce mitochondrial dysfunction.

This work was supported by P20GM109091 (F.H.), R01HL130972-01A1, R01HL5949, BX000168-10A1, BX005320 (F.G.S.), R01DK132948 (C.W. & F.P.) R01 MH129798 (SKW); VA VISN7 RDA (F.H.), 1U54HL169191-01 & BX002604 (M.J.R.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the abstract.

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.
Carbon Dioxide as a Novel Blood Pressure Therapy for Neurogenic Orthostatic Hypotension
Authors: Baker Jacquie , Ranada Shaun , Incognito Anthony , Sheldon Robert , Wilson Richard , Phillips Aaron , Raj Satish
Published: May 2024

BACKGROUND: On standing, people with neurogenic orthostatic hypotension (nOH) experience plummeting blood pressure (>20/10mmHg), crippling symptoms, and syncope. Current blood pressure therapies lack effcacy and have serious side effects. In healthy people, increased inspired CO2 increases blood pressure. This raises the tantalizing possibility that increased inspired CO2 may effectively treat nOH patients. OBJECTIVE: We aimed to understand if increased inspired CO2 can increase standing blood pressure in nOH. METHODS: Seventeen patients with nOH (F=5; 71±8 years) completed three randomized sit-to-stand tests with inspired CO2 maintained 0mmHg (0CO2), +5mmHg (+5CO2) or +10mmHg (+10CO2) relative to baseline. Respiratory and hemodynamics (blood pressure, heart rate, stroke volume, cardiac output, systemic vascular resistance) were continuously measured. Data are reported as mean ± SD. The change (stand-sit) in respiratory and hemodynamics between 0mmHg, +5mmHg and +10mmHg were compared using a repeated measures ANOVA with a Bonferroni correction. RESULTS: Inspired CO2 caused a dose-dependent increase in standing blood pressure (0CO2:-43±25mmHg; +5CO2:-22±26mmHg; +10CO2:-4±30mmHg; p<0.001). Blood pressure changes were predominantly facilitated by increased stroke volume (0CO2:-10±10mL; +5CO2:-5±10mL; +10CO2:0.1±10mL;p<0.001) and cardiac output (0CO2:-0.2±0.6L/min; +5CO2:0.2±0.5L/min; +10CO2:0.7±0.5L/min; p<0.001) as neither the changes in heart rate (p=0.2) nor systemic vascular resistance (p=0.6) were different across CO2 conditions. Breathing CO2 decreased the percentage of time that standing systolic blood pressure dropped ≥20mmHg (0CO2:75±35%; +5CO2:48±38%; +10CO2:32±37%; p<0.001) and fewer patients met the blood pressure criteria for orthostatic hypotension (p=0.02). CONCLUSION: Our data indicates increased inspired CO2 can increase standing blood pressure in nOH patients by increasing stroke volume and cardiac output. CO2 may offer a novel pressor therapy for patients with nOH.

This work was supported by a University of Calgary Seed Funding (S.R.R). J.R.B is supported by a Canadian Institutes of Health Research (CIHR) Fellowship, a Libin Cardiovascular Institute Post-Doctoral Fellowship in Women’s Cardiovascular Health, the Natural Sciences and Engineering Research Council of Canada (NSERC) Brain CREATE Program, and a Canadian Cardiovascular Society Fellowship. S.I.R. is supported by the NSERC Brain CREATE Program, an Alberta Graduate Excellence Scholarship, and an Alberta Strategy for Patient Oriented SUPPORT Unit scholarship. A.V.I is supported by a CIHR Fellowship and an Achievers in Medical Science Postdoctoral Fellowship.

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 Cross-Correlation Between Spikes and Local Field Potentials at Different Running Speeds During Entorhinal Cortex Inactivation
Authors: Zhao Ben , Qin Yu , Lovett Sarah , Besosa Cristina , Kennedy Jack , Burke Sara , Maurer Andrew
Published: May 2024

Understanding neural spike dynamics and their interaction with local field potentials is crucial for deciphering neural connectivity. This study utilizes data generously shared by Zutshi et al. in 2022 (PMID: 34890566) to investigate spike characteristics and their cross-correlation with local field potentials. Our findings reveal significant shifts in the interspike interval (ISI) distributions during the medial entorhinal cortex (mEC) inactivation, with the instantaneous burst frequency exhibiting an overall decrease and preference for lower frequencies. These differences in the spike distributions were observed in individual cells, accompanied by changes in mean firing rates. Further exploration of the cross-correlation between spike multiunit activity (MUA) and the theta rhythm uncovers distinct coupling patterns. In the control cases, spikes closely align with theta peaks, whereas this alignment is disrupted during the mEC inactivation. Notably, we find that the strength of this cross-correlation is amplified at higher running speeds. This research enhances our understanding of neural dynamics, shedding light on the intricate relationship between spikes, local field potentials, and running speed, with potential implications for neural connectivity studies.

R01MH126236 1R01MH109548-01A1.

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.
Impact of lymphangiogenesis on renal phosphate handling following kidney injury
Authors: Phan Thien , Creed Heidi , Weiss Dawson , Vu Myles , van der Weiden Christiaan , Reyna Andrea , Rutkowski Joseph
Published: May 2024

Overconsumption of inorganic phosphate (Pi) causes tubular cell damage and kidney dysfunction, and hyperphosphatemia can lead to Ca2+ retention, vascular calcification, and cardiovascular disease. Conversely, kidney injury and chronic kidney disease (CKD) cause hyperphosphatemia and Pi retention. We hypothesized that the damage caused by chronic Pi consumption likely induces kidney lymphangiogenesis and that changes to renal lymphatic density may alter kidney mineral handling. We identified significant lymphangiogenesis and increased expression of the lymphatic growth factors VEGF-C/D in kidneys of mice fed a 2% Pi diet for 2 months and as early as three weeks of diet. We then utilized “KidVD” mice, a mouse model of kidney-specific inducible expression of VEGF-D, to expand renal lymphatic density and test Pi handling. Mineral handling was largely normal in male and female KidVD mice compared to littermates on Pi diet. In a Pi-driven CKD model mice were injured with 10 mg/kg cisplatin dose, allowed to recover for 2 weeks, then challenged with chow or 2% Pi diet for 3 weeks with VEGF-D induction. This resulted in Pi retention in all mice. Pi handling in both male and female KidVD mice were normal to controls. Female KidVD, however, demonstrated significantly increased Ca2+ excretion compared to controls. Circulating FGF23 levels were significantly elevated in male and female with VEGF-D overexpression. Gene expression of Fgfr1 was also significantly increased in male and female KidVD mice. Renal lymphangiogenesis thus appears to specifically impact Ca2+ retention through the FGF23-Fgfr1 axis.

National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01 DK119497).

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.
Elevated plasma aldosterone impairs functional hyperemia and cognitive function
Authors: Stine Nathan , Sancho Maria , Wellman George , Koide Masayo
Published: May 2024

Aldosterone, a steroid hormone, plays an important role in blood pressure homeostasis and the maintenance of plasma electrolyte levels by activating the mineralocorticoid receptor (MR) in renal distal tubule and collecting duct epithelial cells. Recent studies revealed that MRs are also expressed in other tissues, including cardiac myocytes, vascular smooth muscle cells, and vascular endothelial cells (EC), and that elevated plasma aldosterone, termed hyperaldosteronemia (HA), has deleterious effects on the cardiovascular system. HA is present in 10-30% of hypertensive patients and unrecognized and asymptomatic HA is estimated to occur in > 10% of individuals with normal blood pressure. Despite the high prevalence of HA, little is known about its impact on cerebral blood flow (CBF) regulation and brain health. This study focused on the physiological processes that support the on-demand delivery of blood to regions of heightened neuronal activity (functional hyperemia). Specifically, we examined the impact of HA on the recently discovered novel mechanism, termed capillary-to-arteriole signaling, through which capillaries and their strong inward rectifier K+ (Kir 2.1) channels play a significant role in functional hyperemia. Importantly, early deficits in functional hyperemia are a hallmark of small vessel diseases of the brain, which are significant contributors to cognitive impairment and dementia. Employing HA model mice, we examined the impact of HA on functional hyperemia, capillary-to-arteriole signaling, Kir2.1 channel activity in freshly isolated capillary ECs (cECs), and cognitive function. Functional hyperemia, measured as whisker stimulation-induced CBF increases using laser Doppler flowmetry, was impaired in HA animals compared to vehicle-treated animals. Retrograde capillary-to-arteriole signaling, evaluated as upstream arteriolar dilation in response to capillary stimulation with 10 mM K+ in Capillary-Parenchymal Arteriole (CaPA), preparations was significantly attenuated in HA mice. Furthermore, cEC Kir2.1 channel currents, recorded using the conventional whole-cell configuration of the patch-clamp technique, were significantly smaller in HA mice compared to vehicle-treated mice. Further, HA model animals obtained lower scores in the Novel Object Recognition test, indicating that cognitive function in the form of memory retention may be impacted by elevated plasma aldosterone. These data suggest that HA impairs functional hyperemia and cognitive function, and that HA may be a novel risk factor for vascular cognitive impairment.

This work was supported by The National Institute of Health (P20-GM-135007 to MK and R01-HL-142888 to GCW).

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.
Incorporating Concept Maps into Physiology Laboratory Protocols to Support Content Mastery
Authors: Steele Keeler , Wonderlin Bill , Wehrwein Erica
Published: May 2024

The journey of an undergraduate physiology student weaves a tapestry of knowledge. Despite even the best pedagogical practices, misconceptions or missed key concepts are inevitable - in some respects, these (hopefully small) gaps may even be preferable for continued learning. Many degree programs have a capstone course or project that is the culmination of this journey. At Michigan State University (MSU), the Capstone Laboratory Course in Physiology has taken these knowledge gaps in stride and applied the use of concept maps to stitch the final pieces together. Concept maps are diagrams of physiologic phenomena and mechanisms broken down into simplistic parts, usually an effector and resultant change or process. Resembling circuit diagrams, these concept maps take an engineering approach to physiology, demonstrating how each component plays a role in the system in parallel or in series with each other. We used a collection of maps curated by Dr. William Wonderlin of MSU College of Human Medicine on a browser-based application of his own creation called PhysNav.org. In the pre-lab preparatory materials, students are shown a concept map showing the primary mechanism associated with a given week’s lab procedures. Each week students are asked to hypothesize the outcome of the in class experiment (e.g., “Will ECG lead I, II, or III show the largest QRS deflection”) and explain mechanistically using a concept map why they made that prediction. Before doing the weekly in-class human physiology lab protocol, students are asked to draw the map on a white board and annotate the changes that are expected to occur during an experiment based on their written hypothesis. Each team of students must verbally explain the mechanism and annotations to the teaching staff to be checked off before proceeding with the experiment. This checkpoint is essential to discover any misconceptions. Once approved, teams take a photo of the map to use for studying and post-lab homework. Students rate concept maps 4.23/5 for usefulness in review of content (n=53). The course also has independent projects where students develop their own concept map. Student rate concept maps 4.1/5 as being helpful for explaining project mechanisms (n=53). Student feedback about these concept maps has been positive, with some developmental critiques that have been well-received. Many students note that without these maps, they would not be prompted to diagram a concept or develop this type of approach to a mechanism. In conclusion, we have successfully incorporated concept mapping to ensure that lab protocols focus on physiology mechanisms and not just cookbook procedures.

Michigan State University Department of Physiology.

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.
Increasing Confidence in the HPV Vaccine
Authors: Bordenave Madison
Published: May 2024

HPV causes approximately 26,600 new cancer cases every year in the United States. HPV vaccination initiatives have helped lower HPV infection rates. However, vaccination rates still remain incredibly low. Less than 40% of adolescents that qualify for vaccination have completed a full series. Community engagement through focus groups, interviews, pre and post online surveys of parents have been shown to improve attitudes toward vaccinations. This is a qualitative cross-sectional survey using both quantitative and non-numerical data collected through interviews in order to further understand the reasoning of HPV vaccine hesitant parents who decide to either opt out of vaccination or fail to complete the vaccine series. The study seeks to implement educational strategies such as the testing of a website that works to close the information gap, the amount of available knowledge regarding HPV vaccination compared to the level of knowledge parents actually have. These strategies are implemented with the goal of addressing the concerns of vaccine hesitant parents and assessing their level of hesitancy before and after providing the requisite information regarding HPV vaccination through the interview process. The goal of this study is to both educate and aid in parents decision making when deciding to vaccinate their children for HPV. There is limited community based research available on HPV vaccination hesitancy amongst parents. The approach of using educational materials along with a webpage is new in addressing vaccine hesitancy with regards to HPV. This research could help increase HPV vaccination rates in order to lower HPV related cancers in the future. We found that knowledge played a critical role in improving attitudes toward the HPV vaccine and that improving the knowledge quality of vaccine participants may improve vaccination rates.

This work was supported by the American Cancer Society.

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.
Role of cholinergic agonists & hyperthermia on regional skin barriers: exposure science implications
Authors: Bullens Kelsey , Empey Natalie , McGrath Ashley , Wilson Thad
Published: May 2024

Regional differences in skin barrier properties are common in mammals, as some exterior surfaces are fairly impermeable and others are leakier. Neural-induced changes in skin physiology and temperature have the potential to alter skin barrier properties, but the circumstances and mechanisms are unclear. We hypothesized that increasing methylcholine (MCh) or acetylcholine (ACh) concentration would decrease the transepithelial resistance (an index of the skin barrier) measured across mouse paw pad skin jacketed at neutral skin (32°C) or internal (37°C) temperature. Additionally, we hypothesized that paw pads would have lower transepithelial resistance compared to mouse tail skin, and subjecting samples to 40°C (local cutaneous heat stress) would lower transepithelial resistance compared to paw pad skin tested at 32°C. 30 C57BL/6 mouse rear paw pads (containing sweat glands) and 7 mouse tail skins (no sweat glands) were dissected and mounted into a vertical Ussing chamber filled with Kreb’s bicarbonate buffer, gassed with 95% O₂ & 5% CO₂, and encased in a temperature jacket. Transepithelial resistance utilized a current clamp and was measured with Ag-AgCl2 electrodes placed in both epidermal and hypodermal baths during hypodermal-side-only cholinergic dosing (5 min/dose). ACh (0, 0.0833, 0.1666, 0.2499, 0.4166, 0.58323, and 0.74989 M) significantly decreased transepithelial resistance in paw pads clamped at 37°C in a dose-dependent manner. Tail skin had significantly higher transepithelial resistance than paw pad skin. However, transepithelial resistance decreased significantly with MCh (same dosing as ACh) at both skin sites. Increasing jacket temperature to 40°C did not alter the magnitude of decrease in transepithelial resistance to MCh in paw pads compared to 32°C. Transepithelial resistance observations were similar when data were expressed as absolute or relative changes to baseline. Increased ion movement in murine skin (signifying a leakier epithelium) occurred with cholinergic stimulation but not with local hyperthermia, suggesting that neural influences can suffciently affect skin function to directly alter regional skin barriers.

P30ES026529 with additional support from TL1TR001997 and R25ES027684.

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 Management of Spinal and Epidural Anesthesia-related Hypotension in the United States during C-section Childbirth
Authors: Nadella Harshita
Published: May 2024

Currently, neuraxial analgesia is the most effective method of analgesia during childbirth. However, the leading side effect, hypotension, makes it crucial to understand the existing treatments for spinal anesthesia-induced hypotension. This study attempts to elucidate anesthesia-induced hypotension and existing therapies. Researchers performed a scoping review using PubMed and Rayyan to select articles. Inclusion criteria were peer-reviewed articles written in English within the last five years, and nulligravida/primigravida women under 35 years old who reside in the USA. Researchers revealed the different means of treatment to reduce the incidence of spinal anesthesia-induced hypotension in mothers during C-sections. Norepinephrine and epinephrine showed to be more effcacious in maintaining blood pressure while avoiding unfavorable sequelae for the mother following delivery. The study outcome of participants receiving fixed-rate infusions of either norepinephrine or phenylephrine favored the use of norepinephrine. These patients exhibit lower rates of bradycardia ( p=0.004), contributing to a lesser need for bolus rescue of atropine ( p=0.01). Using colloid solutions during C-section compared to crystalloid solutions also revealed a lower incidence of hypotension with a p-value of < 0.00001. Modalities such as wrapping and subsequent elevation of the lower extremities also displayed a significantly higher systolic and diastolic blood pressure and ephedrine dose than the control group. Pharmacological treatment modalities are more effective than non-pharmacological treatments at preventing maternal hypotension. Epinephrine was the most effective treatment for maintaining maternal blood pressure, heart rate, and cardiac output. Further studies should be done to determine the optimal epinephrine dosage.

There was no funding provided for this research.

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 spatial distribution of CFTR-rich Ionocytes cells in the postnatal mouse airway development
Authors: Villanueva Sandra , Apablaza Tabata , Hernández Sebastián , Flores Carlos A.
Published: May 2024

Ionocytes are a new type of rare airway epithelial cells expressing Ascl3 and Foxi1 transcription factors, as well as 50% of Cftr-transcripts in mouse airways. However, their role and precise location remain mostly unexplored. This research aimed to shed light on ionocyte ontogeny and distribution within the mouse airway epithelium. Mice were bred in the C57Bl6/J background and maintained in the Specific Pathogen Free mouse facility of Centro de Estudios Científicos (CECs) with access to food and water ad libitum. We used 1,7, 10, 14,21 and 28-days-old wild-type mice, 6 and 8-week-old, and 1 year wild-type and 14-days-old 6 and 8-week-old CftrΔF508/ΔF508 animals. The tracheas were sliced in frontal sections, and the ionocytes were identified by immunofluorescence against the FOXI1 transcription factor. All values were expressed as mean ± S.E.M. All animal procedures were approved by the institutional IACUC (CECS-2022-03). We found that FOXI1+cells had a triangular shape with a basolateral process. Unexpectedly, we observed that FOXI1+cells appear postnatally close to the submucosal glands (SMG), and its number increases drastically between 6 and 8-week-old wild type mice. The quantity of FOXI1+cells cells in the adult trachea decreased towards the distal part (proximal=11.2±1.2 vs distal=4.0±0.9 FOXI1+cells/mm basal lamina, n=7, P=<0,001, t-test), and we did not find significative differences between WT and CftrΔF508/ΔF508 adult mouse. FOXI1+cells were often observed in the epithelia around the collecting duct exit and in the collecting duct epithelium of the SMG. In conclusion, our study provides new insights into the localization and distribution of ionocytes in the mouse airway epithelium. Our results indicate that ionocytes may play a role in regulating mucus composition in upper airways. We suggest that age-dependent changes in cell quantity might reflect the need of increased CFTR function in adult stages. Further research is needed to fully understand the function of ionocytes in the airway and their potential role in respiratory diseases such as cystic fibrosis.

Proyecto Postdoctoral 3220672 Proyecto FONDECYT 1221257.

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.
Neutrophils orchestrate early cardiac remodeling after cardiac pressure overload
Authors: Chalise Upendra , Souza-Neto Fernando , van Berlo Jop
Published: May 2024

Cardiac pressure overload is a chronic condition where the left ventricle undergoes pathological hypertrophy and fibrosis ultimately causing heart failure. Increased myocardial stretch in left ventricular pressure overload initiates activation of an inflammatory and fibrotic response within resident cells leading to infiltration of immune cells. Neutrophils and monocytes are among the first responders during cardiac injury. While the role of monocytes and macrophages in pressure overload has been somewhat elucidated by multiple groups, including our lab, the role of neutrophils in chronic cardiac injury such as pressure overload is still unclear. We hypothesized that, like acute ischemic injury, neutrophils infiltrate to the heart early in pressure overload and initiate an inflammatory cascade which worsens cardiac dysfunction after TAC and that depletion of neutrophils in the first week of TAC would improve cardiac function. Our published single cell RNAseq dataset of immune cells (CD45+) cells from sham and TAC heart at day (D) 7 shows a distinct clustering of neutrophils with S100a9 (34-fold) , S100a8 (31-fold) , Retnlg (9-fold) , Il1b (5-fold) , and Slpi (5-fold) as top 5 differentially expressed genes (DEGs). Geneset enrichment analysis of top 58 DEGs (≥1.5-folds), shows significant association with pathways such as innate immune system, neutrophil degranulation, and signaling by interleukins by Reactome 2022 pathway. Using a murine model of transaortic constriction (TAC) to induce left ventricular pressure overload, we evaluated cardiac neutrophil counts by flow cytometry over the first week of TAC at D 2, 4 and 7. We observed that neutrophils (CD45+Ly6G+CD11b+) numbers consistently increase until D4, with a 7-fold increase at D2 to a 17-fold increase at D4 before returning to sham levels by D7. Using antibody (Anti Gr-1, 4 ug/g) mediated depletion of neutrophils, we observed that neutrophil depletion showed a protective effect in females compared to isotype controls with decreased cardiac hypertrophy and improved ejection fraction; while in male mice no change was observed between isotype and antibody treated groups. In conclusion, our data show that neutrophils peak early in pressure overload and orchestrate early cardiac remodeling with a potential for a sexually dimorphic role.

We acknowledge funding from National Institute of Health under the awards numbers HL155993 and HL160665.

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.