bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deletion of the Acid-Sensing Ion Channel 1a Gene Leads to Age-Related Hypertension in Male but not Female Mice
Authors: Garcia Selina , Jernigan Nikki 
Published: May 2023

Acid-sensing ion channel 1a (ASIC1a) is a proton-gated cation channel that conducts both Na+ and Ca2+ in the cell. Studies have shown that ASIC1a is expressed in smooth muscle and endothelial cells of various vascular beds. Previously, we have shown that ASIC1a contributes to pulmonary hypertension and pulmonary arterial vasoconstrictor reactivity. Additionally, we recently discovered that inhibition of ASIC1a significantly reduced endothelial-dependent vasodilation in mesenteric arteries leading us to question whether ASIC1a contributes to the regulation of systemic mean arterial blood pressure (MABP). The incidences of cardiovascular disease are higher in males than females at a young age, however, this difference is largely diminished in post-menopausal females. Therefore, we aim to determine the age- and sex-related contribution of ASIC1a to cardiovascular homeostasis. We hypothesize that the genetic deletion of Asic1a will lead to age-related systemic hypertension in both male and female mice. MABP and heart rate (HR) were measured using radiotelemetry in conscious young (6-8 months) and aged (>15 months), male and female, Asic1a +/+ and Asic1a -/- mice. We found that Asic1a -/- male mice develop age-related systemic hypertension and increased HR compared to aged-matched Asic1a +/+ males. However, there were no differences in MABP in aged female mice and HR was significantly lower in Asic1a -/- mice compared to age-matched Asic1a +/+ mice (p=0.0008). To determine if Asic1a is contributing to age-induced systemic hypertension through a vascular or central regulation, norepinephrine and epinephrine levels were measured with an ELISA in young and aged Asic1a +/+ and Asic1a -/- mice. Although there was not a significant change in epinephrine between genotypes, norepinephrine was significantly increased in aged Asic1a -/- compared to young Asic1a -/- (p<0.0001) and aged-matched Asic1a +/+ (p<0.0001) mice indicating that the increased MABP is associated with elevated sympathetic nerve activity. Age increased norepinephrine levels in aged female mice, however, there was no statistical difference between genotypes. Together this data shows a sex-specific role for Asic1a to regulate age-induced systemic hypertension. Future studies will define the centrally-mediated mechanism by which Asic1a regulates MABP. Supported by National Heart, Lung, and Blood Institute Grants R01 HL-111084 to N.L. Jernigan and T32 HL-007736 to T.C. Resta This is the full abstract presented at the American Physiology Summit 2023 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.
Endothelial Piezo1 channel controls cerebral blood flow
Authors: Harraz Osama , Ippolito Michael , Senatore Amanda , Willemse Luc 
Published: May 2023

Cerebral blood flow is controlled to meet the ever-changing demands of active neurons. Brain capillaries are equipped with sensors of neurovascular coupling agents released from neurons/astrocytes onto the outer wall of a capillary. While capillaries can translate external signals into electrical and Ca2+ changes, control mechanisms from the lumen are less clear. The continuous flux of red blood cells and plasma through narrow-diameter capillaries imposes mechanical forces on the luminal (inner) capillary wall. We have recently discovered that the mechanosensitive Piezo1 channels operate as mechanosensors in CNS capillaries. Whether—and if so how—Piezo1-mediated mechanosensation regulates CBF is not known. Using genetically engineered mice in which endothelial Piezo1 is ablated (Piezo1EC-KO) or mutated (Piezo1EC-mut), we assessed channel activity and CBF. We provide evidence that Piezo1 plays an important role in CBF control and profoundly affects functional hyperemia during somatosensory stimulation. These observations are of profound significance for the control of brain blood flow in health and in disorders where hemodynamic forces are disrupted, such as hypertension. The American Heart Association (20CDA35310097), the National Institute of General Medical Sciences (P20GM135007), the Totman Medical Research Trust, the Larner College of Medicine, University of Vermont, and the Cardiovascular Research Institute of Vermont. This is the full abstract presented at the American Physiology Summit 2023 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.
Dorsal motor vagal neurons can suppress heart rate in mice
Authors: Kauffman Lily , Conley Nicholas , Campbell John 
Published: May 2023

The dorsal motor nucleus of the vagus (DMV) is a functionally heterogeneous vagal motor region which controls a variety of digestive and metabolic functions but also innervates the heart, where its role in controlling heart rate is less clear. We therefore chemogenetically activated DMV neurons in awake behaving mice while monitoring heart rate. To selectively activate DMV neurons, we injected an adeno-associated virus (AAV) which expresses the excitatory chemogenetic receptor, hM3Dq (8 injections, 40nl each), only after recombination by both Cre and Flp recombinases, into the DMV of Chat-Cre::Phox2b-Flp mice. Several months later, we injected the hM3Dq ligand clozapine N-oxide (CNO; 1mg/kg) via intraperitoneal injection (n=2 females, 3 males; mean age ± S.D., 32 ± 2 weeks) to activate hM3Dq+ DMV neurons while measuring heart rate via a non-invasive ECG system (ECGenie). We measured heart rate 20 minutes prior to CNO and 0, 20, 40 minutes and 1, 2, 6, 8, 24 hours later. CNO administration significantly but reversibly decreased heart rate (mean ± standard deviation, S.D.: 20min before CNO, 705 ± 15 bpm; 40min after CNO, 536 ± 86 bpm, p=0.0271; 24hr after CNO, 727 ± 25 bpm, p=0.7347; one-way ANOVA, all timepoints, F1.660, 6.638=10.31; Dunnet's post-hoc test, p=0.0107). In order to identify the specific neurons responsible, we repeated these studies in Calb2-Cre::Chat-Flp mice (n=2 females, 3 males; mean age ± S.D., 29 ± 2 weeks) to target Calb2+ DMV neurons, a recently identified DMV molecular subtype. However, in striking contrast to what we observed when activating DMV neurons generally, administering CNO to activate Calb2+ DMV neurons specifically did not significantly affect heart rate (mean ± S.D.: 20min before CNO, 691 ± 69 bpm; 40min after CNO, 718 ± 31 bpm, p=0.6787; 24hr after CNO, 710 ± 54 bpm, p=0.4701; one-way ANOVA, all timepoints, F2.911, 11.65=0.6277; Dunnet’s, p=0.6069). A higher dose of CNO (3.5mg/kg) also had no effect on heart rate in Calb2-Cre::Chat-Flp mice (data not shown). Together, our studies indicate that DMV neurons are capable of suppressing heart rate and that the underlying neurons likely do not express Calb2. Uncovering the DMV’s role in heart rate will expand our understanding of how this clinically relevant metric, associated with a host of cardiovascular disorders, is controlled. Ingrassia Family Echols Scholars Research Grant and Schwager Summer Research Scholarship to L.S.K.; ADA Pathway to Stop Diabetes Award 1-18-INI-14 and NIH grant HL153916 to J.N.C. This is the full abstract presented at the American Physiology Summit 2023 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.
Electrophysiological characteristics of leptin receptor-expressing neurons in the dorsomedial hypothalamus
Authors: Pryor Jack , Simonds Stephanie 
Published: May 2023

The adipocyte-derived hormone leptin acts at leptin receptor (LepR)-expressing neurons in the brain to regulate metabolic and cardiovascular functions. LepR neurons in the dorsomedial hypothalamus (DMH) are required for leptin-induced feeding suppression, regulate brown adipose tissue thermogenesis and locomotor activity. We have previously identified these neurons as necessary for the hypertensive effects of hyperleptinemia in obesity. These neurons are heterogenous, with LepRs differentially co-expressed with metabolism-regulating peptides and receptors including, glucagon-like peptide 1 (GLP-1), agouti-related peptide (AgRP) and proopiomelanocortin (POMC). Variations in LepR neuron gene expression profiles may indicate differences in leptin responsiveness, function specificity and electrophysiological characteristics. Work presented here used in vitro visualized whole-cell patch clamp electrophysiology to characterise the electrophysiological properties of leptin-excited, leptin-inhibited, and non-responsive LepR neurons in the DMH of transgenic LepR-YFP mice. Whole cell current clamp recordings were obtained from 34 DMH LepR neurons and of these, bath application of 100 nM leptin excited 38% (n=13). Of some leptin excited LepR neurons, the effect was indirect via elevated spontaneous excitatory postsynaptic potential (EPSP) frequency (n=2). Of other leptin excited LepR neurons, membrane depolarisation was direct via the activation of one or more non-selective cation conductances (n=11). In two cases, leptin-induced sub and suprathreshold 'pacemaker like' oscillations in membrane potential. Of leptin-excited neurons 23% (n=3) of neurons expressed transient outward rectification ( ITR), 54% (n=7) expressed low-threshold t-type calcium conductances ( IT), 8% expressed instantaneous or anomalous inward rectification ( IAN) (n=1) and 15% expressed hyperpolarization-activated non-selective cation conductances ( IH) (n=2). Bath application of 100 nM leptin inhibited 15% of LepR neurons tested (n=5). these inhibitory membrane effects were postsynaptic and via the activation of one or more potassium conductances. Of leptin inhibited neurons 60% expressed ITR, 60% (n=3) expressed IT, 40% (n=3) expressed IAN and 40% (n=2) expressed IH. In 47% of neurons tested, bath application of leptin did not have any clear inhibitory or excitatory membrane (n=16). Of these non-responsive neurons 50% (n=8) expressed ITR, 44% (n=7) expressed IT, 44% (n=7) expressed IAN and 25% (n=4) expressed IH. Work presented highlights the heterogeneity of DMH LepR neurons and further indicates the existence of function-specific subpopulations. This is the full abstract presented at the American Physiology Summit 2023 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.
Phase 3 Anticancer Agent, RRx-001, Ameliorates Hypoxia-Induced Pulmonary Hypertension
Authors: Cabrales Pedro , Reid Tony , Caroen Scott , Oronsky Bryan 
Published: May 2023

Background: The hallmark features of pulmonary artery hypertension (PAH), for which hypoxia triggers, are vascular remodeling, elevated pulmonary blood pressure, oxidative stress, and right ventricular hypertrophy. RRx-001 is a minimally toxic Phase 3 anticancer agent with anti-oxidative, anti-inflammatory, nitric oxide-donating, and anti-proliferative properties. This study aimed to investigate the effect of RRx-001 on intermittent hypoxia-induced PAH in rats. Methods: Male Wistar rats (180-220 g) were divided into four groups (n=6 per group): normoxic control, hypoxic with vehicle treatment (2 weeks breathing an atmosphere containing 10% oxygen), hypoxic treated with oral endothelin-1 receptor inhibitor, bosentan, 50 mg/kg per day for 2 weeks during hypoxia and one intravenous dose of 5mg/kg RRx-001 given the day before the start of the hypoxia. After sacrifice, hearts and lungs were removed and harvested for analysis. Results: Both RRx-001 and bosentan treated animals, separately and to a similar degree, significantly attenuated hypoxia-induced increases in right ventricular systolic pressure and right ventricular hypertrophy compared to control animals. RRx-001 and bosentan, separately and to a similar degree, also significantly decreased pulmonary artery media thickness. RRx-001 treatment reduced vasocostriction of pulmonary arterioles and the wall thickness/external diameter ratio of the pulmonary arteries compared to vehicle treated animals. Conclusions: RRx-001 reduces right ventricular systolic pressure and pulmonary vascular remodeling in a rat model of PAH, potentially making it a new therapeutic option for this disease. The combination of bosentan and RRx-001 will be attempted as a next step. Commercial and private foundation grants This is the full abstract presented at the American Physiology Summit 2023 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.
Stretch-induced mechanical stimulation effects on vascular smooth muscle contractility in aged resistance arteries
Authors: Mohajeri Amin , Padgham Samuel , Woodman Christopher , Trache Andreea 
Published: May 2023

Age–related impairments of skeletal muscle resistance arteries are associated with alterations in vascular smooth muscle cell (VSMC) contractility. Aerobic exercise is an effective intervention for reversing the impacts of aging on vascular contractility. In addition, we have shown that arterial wall-stretch, induced by a short-duration increase in intraluminal pressure in cannulated soleus muscle feed arteries (SFA), attenuates age-related changes in VSM contractility. The mechanisms responsible for the beneficial effect of wall stretch on contractility are not fully understood. Purpose: VSMC respond to extracellular mechanical signals by dynamic remodeling of actin fibers and cell-matrix adhesions. In this study, we investigated the impact of in vitro cyclic stretch on attenuating the age–induced alterations in VSMCs contractility by evaluating changes in vinculin, as a marker for cell-matrix adhesions, and smooth muscle α-actin (SMα-actin) fiber formation. Methods: VSMC isolated from SFA of young (4 month) and old (24 month) male F344 rats were cultured on fibronectin–functionalized silicon membranes. Equibiaxial cyclic stretch (10%) at 0.25 Hz frequency was applied to both young and old cells for 2 or 5 min. Static condition (no stretch) was used as control. At the end of the study, cells were fixed in their stretched or static state with 2% paraformaldehyde and stained for SMα-actin and vinculin. Dual color confocal imaging was performed using Olympus Fluoview 3000 microscope, and SlideBook software was used to analyze the data. Results: Young and old VSMC respond differently to stretch-induced mechanical stimulation. Results showed an increase in actin stress fibers formation in old VSMC for both time points when compared to young cells or old cells at rest. Similarly, vinculin recruitment at cell-matrix adhesion was increased in old VSMC. No differences were found between young and old cells in the static condition for any of the proteins. Conclusion: Taken together, these data show that stretch-induced mechanical stimulation increases actin stress fiber and integrin-based adhesions contributing to improved aged VSM cells contractility. Sydney and J.L. Huffines Institute for Sports Medicine and Human Performance This is the full abstract presented at the American Physiology Summit 2023 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.
Gestational high altitude long term hypoxia and impact of oxidative stress on ryanodine receptor activity in pulmonary arterial myocytes of fetal sheep
Authors: Khalil Brandon , Abd-Allah Muhammad , Moral Elena , Romero Monica , Juarez Rucha , Zhang Lubo , Puglisi Jose , Wilson Sean 
Published: May 2023

High altitude exposure reduces the oxygen tension in ambient air. The resultant hypoxia induces oxidative stress and causes vasoconstriction of the blood vessels within the pulmonary vasculature that can result in pulmonary hypertension. Previously we found that high altitude gestation deregulated Ca2+ spark activity in fetal pulmonary arteries, which is due to local ryanodine receptor (RyR) activation. These Ca2+ sparks are thought to be coupled to vasodilatory pathways and are important to vasodilation at birth, Furthermore, RyR activity is affected by the redox-status of the protein. Thus, the elevated oxidative stress in pulmonary arteries due to high altitude exposure may underlie the dysregulation in Ca2+ spark activity. We hypothesized that high altitude mediated long term hypoxia alters the impact of oxidative stress on Ca2+ spark activity. This hypothesis was examined in pulmonary arterial (PA) myocytes from low altitude (335m) and high altitude acclimatized fetal sheep (~3,800m for <100 days). Intracellular Ca2+ sparks were recorded within the myocytes of smooth muscle cells using line-scan confocal imaging of the Ca2+ indicator Fluo-4. Oxidative stress was elevated with acute exposure to tert-butyl H2O2 (TbH2O2) or reduced with the antioxidant N-Acetyl-Cysteine (NAC). Ca2+ spark activity and spatial-temporal properties were analyzed with automated custom designed software (SparkLab). Increased oxidative stress with TbH2O2 failed to influence Ca2+ spark activity independent of altitude. Interestingly, NAC preferentially reduced Ca2+ spark activity in myocytes of normoxic pulmonary arteries. These data suggest that RyR activity and resultant Ca2+ sparks in high altitude fetal sheep are resistant to acute changes in cellular redox status. NIH R01HL155295 and R01HL149608, NSF Grant MRI-DBI 0923559 and the Loma Linda University School of Medicine This is the full abstract presented at the American Physiology Summit 2023 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.
Do cytochrome P450 2C9 pathways contribute to the cerebrovascular response to small muscle exercise?
Authors: Mixon Chris , Matney Jacob , Buelow Alexander , Skillett Sarah , Ashley John , Song Jiwon , Black Christopher , Pereira Hugo , Kellawan J 
Published: May 2023

Cytochrome P450 2C9 (CYP450) contributes to regulation of cerebral blood flow in animal models, however, the involvement of CYP450 in human cerebrovascular control is under researched. To this effect, small muscle exercise has been utilized as a model to evaluate cerebral flow in humans, but whether CYP450 contributes to that response is unknown. PURPOSE: To determine if CYP450 contributes to cerebrovascular response during small muscle exercise. METHODS: 16 healthy young adults (10 females tested only in the first 5 days of their menstrual cycle) participated in a familiarization visit followed by 2 experimental visits separated by ≥72hrs. Participants received either a microcrystalline cellulose placebo (PLA 250mg) or the CYP450 inhibitor fluconazole (FLZ 150mg) in a single-blind, randomized, crossover design. After ingestion, participants rested for 120 minutes prior to the experiment. After which, mean arterial pressure (MAP, mmHg, finger photoplethysmography) and middle cerebral artery velocity (MCAv, cm/s, Transcranial Doppler) were measured continuously for 5 minutes of supine rest followed by 5 minutes of dynamic hand grip exercise (contraction/relaxation cycle 1:2 seconds) at heart level at resistance 20% of their maximal voluntary contraction. Cerebrovascular conductance index was calculated as CVCi = MCAv/MAP (cm/s/mmHg). RESULTS: Data was averaged as 3 second intervals to match the contraction rate and presented as change (Δ) from rest to exercise, reported as mean ± SD. All values were not different between treatments at steady state exercise (MAP PLA Δ 10.9±5.5 vs. FLZ Δ 10.4±3.3 mmHg, p = 0.88, MCAv PLA Δ 0.9±7.7 vs. FLZ Δ 1.2±4.7 cm/s, p = 0.88, CVCi PLA Δ -0.07±0.06 vs. FLZ Δ -0.06±0.06, p = 0.34). Interestingly, at exercise onset (~ 18s or first 6 contraction cycles) MCAv response was blunted with FLZ (PLA Δ 5.2±4.8, FLZ Δ 2.9±3.9 cm/s, p = 0.03, d = 0.51). This attenuation was not due to a change in MAP (PLA Δ 1.2±3.0, FLZ Δ 2.2±4.8 mmHg, p = 0.2, d = -0.25). Thus, attenuation of the MCAv in FLZ was due to a reduction in CVCi response (PLA Δ 0.04±0.04, FLZ Δ 0.009±0.04 cm/s/mmHg, p = 0.003, d = 0.8). CONCLUSION: Our results indicate that CYP450 does not affect MCAv, CVCi, or MAP once steady state is achieved during small muscle exercise. However, CYP450 inhibition attenuates vascular response at exercise onset. Therefore, CYP450 contributes to the cerebrovascular response to small muscle mass exercise, however, compensatory vascular mechanisms can overcome CYP450 inhibition indicating CYP450 has a significant yet non-obligatory role in cerebrovascular regulation during exercise in humans. This is the full abstract presented at the American Physiology Summit 2023 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 biological sex on the acute flow-mediated dilation response to maximal exercise in healthy older adults
Authors: Lapierre Stephanie , Kim Jin-Su , Beckers Alexander , Riesco Eléonor , Soonhuae Chatchamarn , Sakarya Yasemin , Handberg Eileen , Leach Dana , Christou Demetra 
Published: May 2023

Flow-mediated dilation (FMD) is a noninvasive measure of endothelial function and is a predictor of future cardiovascular disease risk. Previous studies have shown that biological sex modulates the FMD response to acute submaximal exercise in healthy older adults. However, the FMD response to maximal exercise has not been investigated in older adults; thus, whether sex impacts this response remains unknown. Therefore, the purpose of this study was twofold: 1) to investigate the FMD response to maximal exercise in older adults and 2) to test the hypothesis that FMD following maximal exercise will change differently in healthy older men compared with women. We studied twenty sedentary adults (50% women, age: 66±1 vs. 66±1 yrs, men vs. women, mean±SE, P>0.9), free of major clinical disease, who were not on hormone replacement therapy. Women were all postmenopausal. Vascular function was assessed before and after maximal exercise, based on a modified Balke treadmill test. FMD was assessed in response to 5 min forearm occlusion at 250 mmHg using brachial artery ultrasonography. We found pre-occlusion brachial diameter was larger in older men compared with women before (5.04±0.18 vs. 4.27±0.09 mm, P=0.002) and after maximal exercise (4.75±0.16 vs. 3.98±0.12 mm, P=0.001), but there was no sex × time interaction (P=0.1). Peak shear rate was significantly lower in older men compared with women before exercise (1852±81 vs. 2265±129 sec-1, P=0.01) and did not change after maximal exercise in either group (P=0.2). FMD was not significantly different in older men compared with women (P=0.1) before exercise and significantly increased following maximal exercise in both older men (3.84±0.66 vs. 6.55±1.27 %, pre- vs. post-exercise, P=0.009) and women (2.32±0.61 vs. 5.65±1.07 %, P=0.002), but the response was not impacted by sex (P=0.6 for sex × time interaction). When FMD was allometrically scaled to assess the potential effect of pre-occlusion diameter, our findings remained unchanged. Time to peak dilation was delayed in older men and women similarly following maximal exercise (51±2 vs. 75±7 and 56±7 vs. 85±7 sec, pre- vs. post-exercise, P≤0.02; P=0.7 for sex × time interaction). In conclusion, this investigation demonstrated for the first time in older adults that: 1) FMD is enhanced following maximal exercise and 2) biological sex does not influence the FMD response to maximal exercise This work was supported by National Institute of Aging grant AG063143-01. This is the full abstract presented at the American Physiology Summit 2023 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.