bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Arteriolar Vasomotion on Network Flow
Authors: Jacobsen Jens Brings
Published: June 2021

Background

Rhythmic, spontaneous change in microvascular diameter, vasomotion, is observed across numerous species and vascular beds. So far, a plausible physiological role for vasomotion remains to be established. It appears that vasomotion is more prevalent under conditions of insufficient perfusion, suggesting a protective role in hypoxia. Alternating reduction in diameter in some vessels could potentially cause increased perfusion in neighboring branches and ensure flushing of otherwise under‐perfused regions on a regular basis.

Methods

Flow simulations were performed in virtual vascular networks. First, each vessel adapted structurally to local pressure and flow, as well as to the local capillary perfusion requirement. Subsequently, the mature network was exposed to low perfusion pressure, with or without the presence of vasomotion in selected branches.

Results

In vasodilated networks forced diameter oscillations in one branch of a stem caused a 15% flow increase in the other branch from the same stem, independent of network perfusion pressure level. Allowing the network to develop a myogenic tone that matches the local network pressure, reduces the effect of forced diameter oscillation on flow in neighboring vessels; the higher the network perfusion pressure, the smaller is the effect of vasomotion. This is due to myogenic compensation in the non‐oscillating vessel. In all cases, however, total network flow was reduced by the presence of vasomotion.

Conclusion

Vasomotion can increase flow locally in neighboring network regions. This effect is strongest under the low tone conditions likely to be present during tissue hypoxia. On a whole‐network level, however, the presence of vasomotion reduces, rather than increases, the flow.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
ADAM17 Cleaves the Insulin Receptor α‐Subunit on Endothelial Cells and Induces Vascular Insulin Resistance in Type 2 Diabetes
Authors: de Araujo Silva Thaysa Ghiarone , Castorena‐Gonzalez Jorge , Restaino Robert M. , Foote Christopher A. , Morales‐Quinones Mariana , Wheeler Andrew A. , Rawlings Arthur L. , Staveley‐O'Carrol Kevin F. , Padilla Jaume , Martinez‐Lemus Luis A.
Published: June 2021

Microvascular insulin resistance is a hallmark of type 2 diabetes (T2D) and an underlying event in the pathophysiology of endothelial dysfunction and cardiovascular disease. However, the molecular mechanisms by which T2D causes vascular insulin resistance remain largely unknown. Hyperglycemia and the proinflammatory state associated with T2D are characterized, in part, by an increased activity of ADAM17, an enzyme that cleaves the ectodomain of various transmembrane proteins. Here, we hypothesized that increased expression and activation of ADAM17 sheds the insulin receptor α‐subunit (IRα) from endothelial cells causing vascular insulin resistance in T2D. We tested this hypothesis in isolated resistance arteries from T2D and non‐T2D subjects undergoing bariatric surgery and in cultured human umbilical vein endothelial cells (HUVECs). Resistance arteries from T2D subjects exhibited increased ADAM17 expression, reduced presence of endothelial IRα as well as the endogenous ADAM17 inhibitor, TIMP3, and impaired insulin‐induced vasodilation, relative to arteries from non‐T2D subjects (P<0.05). Exposure of HUVECs to high glucose (30mM, 24h) increased the expression and activity of ADAM17 (P<0.05), led to increased shedding of IRα detected in the cell culture media supernatant (P<0.05) and decreased IRα on cell surfaces as observed using super‐resolution microscopy. Moreover, pharmacological inhibition of ADAM17 led to reduced shedding of IRα and improved insulin signaling in cells exposed to high glucose or the ADAM17 activator, PMA (P<0.05). Collectively, these findings suggest that T2D, and in particular hyperglycemia, leads to ADAM17 shedding of IRα from the endothelial surface and reduced insulin‐dependent vasodilation, all of which supports ADAM17 activity as a new therapeutic target to ameliorate vascular insulin resistance in T2D.

Support or Funding Information

Research support: National Institutes of Health grants: R01 HL137769 (JP), R01 HL088105 (LM‐L).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The adenosine kinase inhibitor ABT‐702 improves coronary vasodilator and left ventricle diastolic dysfunction in obese ZSF1 rats
Authors: Davila Alec , Tian Yanna , Czikora Istvan , Bagi Zsolt
Published: June 2021

Coronary microvascular dysfunction contributes to the development of heart failure with preserved ejection fraction (HFpEF) for which no effective therapies are currently available. We tested the hypothesis that pharmacological inhibition of adenosine kinase (ADK), the major adenosine metabolizing enzyme, augments coronary artery vasodilation and improves left ventricle (LV) diastolic function in HFpEF. We employed the obese ZSF1 rat model of HFpEF. We assessed agonist‐induced coronary artery dilation and performed echocardiographic assessment of LV diastolic function before and after treatment with selective ADK inhibitor, ABT‐702 (1.5 mg/kg, i.p. for 8‐week). We found that obese ZSF1 rats exhibited impaired acetylcholine (ACh)‐induced coronary artery dilation and LV diastolic dysfunction, as indicated by reduced E/A ratio and increased deceleration time of mitral flow velocity. Treatment with ABT‐702 augmented ACh‐induced coronary vasodilation in obese ZSF1 rats, which was not affected by inhibition of NO synthase, with N(ω)‐nitro‐L‐arginine methyl ester (L‐NAME). ABT‐702 treatment also improved LV diastolic function in obese ZSF‐1 rats, but had no effect on lean controls. Collectively, these data suggest that a pharmacological inhibition of ADK provides beneficial effects on both coronary vasodilator and LV diastolic function in HFpEF.

Support or Funding Information

American Heart Association 17GRNT33680171, NIH F31 HL142183‐01 and NIH R01AG054651

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of cigarette smoking on hypercapnia induced shear‐mediated dilation in the internal carotid artery
Authors: Suzuki Kazuya , Washio Takuro , Tsukamoto Shingo , Kato Kazunori , Iwamoto Erika , Ogoh Shigehiko
Published: June 2021

It has been well established that chronic cigarette smoking causes peripheral endothelial dysfunction which is strongly associated with coronary and peripheral vascular diseases. Thus, smoking is a risk factor for these diseases. On the other hand, some previous studies suggest that smoking is also a risk factor for cerebral vascular disease. However, its physiological mechanism remains unknown. Under these backgrounds, we hypothesized that smoking also attenuated cerebral endothelial function. To test this hypothesis, we measured shear‐mediated dilation in the internal carotid artery (ICA) as an index of cerebral endothelial function in smokers and non‐smokers. The subject were young, healthy, male non‐smokers (n=6, age 21.2±0.8 years, BMI 21.3±4.1) and smokers (n=5, 21.8±1.6 years, BMI 19.5±1.8). Each smoker consumed an average of 9 cigarettes per day (range 6–10). Shear‐mediated dilation in the ICA was measured by using Doppler ultrasound. Shear‐mediated dilation in the ICA was induced for 3 min during inspiration of high carbon dioxide concentration gas (target end‐tidal carbon dioxide; +10mmHg from individual baseline value) and it was calculated as the percent rise in peak diameter during hypercapnia stimulation from baseline value. As a result, there was no difference in both baseline diameter and blood velocity of the ICA between smokers and non‐smokers (diameter, 4.39 ± 0.54 mm vs 4.87 ± 0.65 mm, P = 0.22; blood velocity, 35.2 ± 8.1 cm/s vs 32.7 ± 6.3 cm/s, P = 0.57). Similarly, shear‐mediated dilation in the ICA was not affected by habitual smoking (smokers vs. non‐smokers; 4.53 ± 2.34 % vs 2.23 ± 3.36 %, P = 0.23), indicating that the effect of chronic smoking on cerebrovascular endothelial function may be minimal in this age group. The findings of the present study suggest that the influence of chronic smoking on endothelial function in the brain is different from that of the peripheral vasculature.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cerebrovascular Reactivity in Resistance Trained Young Men
Authors: Corkery Adam T. , Miller Kathleen B. , Howery Anna J. , Barnes Jill N.
Published: June 2021

Cerebrovascular reactivity is a measure of cerebrovascular function and is often used as an indicator of cerebrovascular health. There is evidence that habitual exercise can influence cerebrovascular reactivity; however, the effect of habitual exercise has only been examined in aerobic trained individuals or under the context of cardiorespiratory fitness. Therefore, the purpose of our study was to investigate the effect of chronic resistance training on cerebrovascular reactivity. We recruited 22 young men, including 11 untrained (UT; age = 27 ± 4 yr) and 11 resistance trained (RT; age = 24 ± 4 yr) individuals. Middle cerebral artery velocity (MCAv), beat‐to‐beat mean arterial blood pressure (MAP), and end‐tidal CO2 (ETCO2) were continuously monitored during a stepped hypercapnia protocol. In order to account for the influence of blood pressure on MCAv, cerebrovascular conductance index (CVCi) was calculated as MCAv/MAP × 100. MCAv, MAP, and CVCi reactivities were calculated as the linear relationship between each respective variable and ETCO2. There were no group differences in MCAv, MAP, CVCi, or ETCO2 during baseline or any level of the stepped hypercapnia (p > 0.05 for all). There was a trend for RT adults to have a higher MCAv reactivity, compared to UT adults (RT: 2.4 ± 0.4 cm/s/mmHg vs. UT: 1.7 ± 0.2 cm/s/mmHg; p = 0.06); however, there were no group differences in CVCi reactivity (RT: 1.5 ± 0.6 cm/s/mmHg2 vs. UT: 1.6 ± 0.2 cm/s/mmHg2; p = 0.41). Additionally, the MAP response to hypercapnia differed between the groups, as RT adults had a greater MAP reactivity compared with UT adults (RT: 0.98 ± 0.40 mmHg/mmHg vs. UT: 0.25 ± 0.08 mmHg/mmHg; p < 0.05). In conclusion, chronic resistance training likely influences cerebrovascular reactivity, as RT individuals had a larger MAP reactivity and a trend for greater MCAv reactivity, compared with UT individuals. Our results suggest that in young men, chronic resistance training may influence the hemodynamic response to a physiological stimulus, such as hypercapnia.

Support or Funding Information

Supported by National Institute of Health grant HL118154

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Similar dysfunctional Ca2+ regulation in coronary smooth muscle from explanted human hearts and Ossabaw miniature swine strongly supports the translational relevance of this large animal model
Authors: Badin Jill K. , Eggenberger Caleb , Rodenbeck Stacey Dineen , Alloosh Mouhamad , Hashmi Zubair A. , Wang I‐wen , Sturek Michael
Published: June 2021

Introduction

Establishing a suitable animal model for metabolic syndrome (MetS) and coronary artery disease (CAD) is a challenge, as there are numerous risk factors and uncontrollable variables in the human population. However, Ossabaw miniature swine have been used with great success to recapitulate MetS and CAD in. The goal of this study was to determine whether the Ossabaw miniature swine is a clinically relevant large animal model on the cellular level, specifically with regards to intracellular Ca2+ ([Ca2+]i) handling, which is crucial for coronary smooth muscle (CSM) function.

Methods

Explanted human hearts from 32 heart failure patients (22 male, 10 female; aged 53.4 ± 2.1 years) undergoing transplantation surgery at the Methodist Hospital in Indianapolis, IN were collected. Coronary arteries were excised and CSM cells were enzymatically dispersed and loaded with the fluorescent [Ca2+]i indicator fura‐2. [Ca2+]i levels were measured during depolarization‐induced Ca2+ influx and caffeine‐induced sarcoplasmic reticulum (SR) Ca2+ store release.

Results

In explanted human hearts exhibiting either ischemic or dilated non‐ischemic cardiomyopathy, a greater coronary artery neointima formation was inversely correlated to depolarization‐induced Ca2+ influx and SR Ca2+ release in CSM cells. Furthermore, a greater number of MetS risk factors, including some factors individually (body mass index, LDL/HDL cholesterol ratio) was also correlated to decreased Ca2+ entry and, in patients with ischemic cardiomyopathy, decreased SR Ca2+ store release. Increased age, however, was correlated to an increased SR Ca2+ store release. These data are all consistent with previous studies of Ossabaw swine CSM.

Conclusion

The similar CSM Ca2+ regulation in coronary arteries of humans and Ossabaw swine provides strong evidence for the phenomenal translational relevance of this large animal model, both on the whole‐animal level and the CSM [Ca2+]i signaling level.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Differential Renal and Lumbar Sympathetic Nerve Activation Following Myocardial Infarction in Rats
Authors: Yoshimoto Misa , Ikegame Shizuka , Hyodo Fumi , Shiwa Yuki , Miki Kenju
Published: June 2021

Sympathetic nerve activation is considered an important contributor to mortality following acute myocardial infarction (MI). However, few studies have directly monitored sympathetic nerve activity (SNA) in response to acute MI. Herein, we directly and continuously monitored renal SNA (RSNA) and lumbar SNA (LSNA) before and after MI induced by left anterior descending artery (LAD) ligation. Wistar rats were instrumented with a telemetry transmitter and bipolar electrodes for continuous measurement of mean arterial pressure (MAP), heart rate (HR), RSNA, and LSNA. At 7 days after initial surgery, MAP, HR, RSNA, and LSNA were monitored continuously for 28 days. After 4 days of baseline measurements, rats received either LAD ligation via left thoracotomy (MI group; n=13) or sham surgery (n=11) under inhalation anesthesia. Rats in the MI group were subdivided into those that survived for 24 days (MI‐survivor group) and those that died within 3 days (MI‐3d group) after LAD ligation. Transthoracic echocardiography was performed before and aftJSOn day 1 in the MI‐3d group, LSNA increased by 202% ± 28% and MAP decreased by 38±4 mmHg compared with baseline values, while there were no changes in RSNA and HR. On day 1 in the MI‐survivor group, LSNA showed a trend towards an increase compared with baseline values, while there were no changes in RSNA and HR. In the MI‐survivor group, RSNA increased gradually from day 9, and peaked at day 24 (27%±14%) compared with the sham group, while there were no significant changes in MAP, HR, or LSNA. These data suggest that the RSNA may play an important role in compensating for impaired cardiac performance caused by MI, and that the LSNA and RSNA respond differently and in a region‐specific manner to MI.

Support or Funding Information

JSPS Grant.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The association of family history of hypertension and overweight induced early impairment in markers of oxidative stress and in heart rate variability
Authors: Viana Ariane , da Silva Dias Danielle , Nascimento Mario Cesar , dos Santos Fernando , Consolim‐Colombo Fernanda Marciano , Irigoyen Maria Cláudia , De Angelis Kátia
Published: June 2021

Considering the high prevalence of hypertension worldwide and the changes in lifestyle, the understanding of the mechanisms involved in the genesis of hypertension are important to reach more precise interventions. Our objective was to evaluate cardiovascular, autonomic and oxidative stress parameters in individuals with family history of hypertension (FH) with or without overweight. We performed a cross‐sectional study and selected 65 healthy sedentary men (24.08 ± 5.84 years) distributed into 4 groups: negative FH eutrophic (FNE, n=18) or with overweight (FNO, n=19) and positive FH eutrophic (FHE, n=17) or with overweight (FHO, n=17). The heart rate variability (HRV) was analyzed at rest by spectral analysis. The oxidative stress markers were evaluated in plasma. A positive correlation between levels LDL and WC/HC ratio was demonstrated (r: 0.54 p = 0.003) in FHE and FHO groups. We observed an increase in diastolic blood pressure in the FHO and FNO groups in relation to the FNE and FHE groups (p = 0.010). When we evaluated the cardiac sympathetic modulation (LF‐PI), we observed a significant increase in the FNO and FHO groups when compared to the FNE group (p = 0.0001). Furthermore, the FHO (2.30 ± 0.8) and FHE groups (2.52 ± 1) presented higher cardiac sympato‐vagal balance (LF/HF) compared to FNO (1.85 ± 0.67) and FNE groups (2.01 ± 0.84) (p =0.04). We observed an increase in systemic hydrogen peroxide concentration in the FHO group when compared to the other groups (p=0.003). Moreover, there was an increase in NADPH oxidase in plasma in FNO and FHO groups in relation the FNE and FHE groups (p = 0.04). In addition, there was an increase in plasma nitrite levels in FHO group compared to FNO, FNE and FHE groups (p=0.01). In conclusion our findings demonstrated that despite young and apparently healthy, the group with overweight and FH showed early impairment in HRV and in markers of oxidative stress. In addition, this group presented all dysfunctions observed in the presence of these risk factors alone, which may be associated with increased cardiovascular risk and target organ damage in this population.

Support or Funding Information

UNINOVE, CNPq, CAPES, FAPESP.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mechanisms Underlying Obesity‐Related Hypertension: An Experimental Weight Gain Study in Humans
Authors: McEniery Carmel M , Middlemiss Jessica , Maki‐Petaja Kaisa , Wilkinson Ian
Published: June 2021

Background

The association between body size and blood pressure (BP) is well recognised. However, not all overweight individuals have elevated BP suggesting that important adaptive mechanisms are present in some. Cardiac output (CO, a key determinant of BP, is elevated in young overweight individuals, but is not associated with the level of BP. However, peripheral vascular resistance (PVR) is associated with the level of BP in these individuals, suggesting that the ability to modulate PVR in response to increased CO is important.

Objective

We hypothesized that weight gain increases CO in healthy humans and that the ability of the peripheral vasculature to adapt to this increase determines BP. Therefore, we undertook an exploratory study of experimental weight gain in healthy young adults.

Methods

Sixteen healthy non‐obese males were recruited (mean±SD age 29±6 years). All participants were overfed approximately 1000kcal/day, alongside their normal diet, for 6–8 weeks, until a weight gain of 5kg was achieved and held stable for at least 1 week. Detailed anthropometric characteristics, BP, CO and PVR were assessed at baseline and at completion of the overfeeding intervention.

Results

Overfeeding resulted in a significant increase in body weight (6.11±3.08kg, P<0.001), lean mass (3.61±3.40kg, P=0.001) and fat mass (2.64±2.89kg, P=0.002). The increases in systolic BP (2±9mmHg) and diastolic BP (2±6mmHg) were not significant (P<0.2 for both) and the increase in heart rate was of borderline significance (5±10bpm, P=0.055). As hypothesised, there was a significant increase in cardiac output (0.81±1.35L/min, P=0.031), which was accompanied by a decrease in PVR (129±205dynes.sec.cm5, P=0.024). Dichotomising individuals on the basis of a systolic BP response to weight gain of ≥5mmHg (BP responders) revealed small differences vs non‐responders in the change in CO (+1.34±0.99L/min vs +0.4±1.50L/min) and PVR (−111±142 dynes.sec.cm5 vs −143±251 dynes.sec.cm5), although neither comparison was statistically significant.

Conclusions

Modest weight gain in healthy, non‐obese men is associated with an increase in both lean and fat tissue mass. A compensatory reduction in PVR in response to elevated cardiac output is likely to explain the lack of change in BP. Examining ‘responders’ versus ‘non responders’ in terms of BP change in response to weight gain is likely to provide useful insights into obesity‐associated hypertension in a larger trial.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Amoxicillin‐responsive alterations in commensal gut microbiota are associated with lowering of blood pressure in young hypertensive rats
Authors: Galla Sarah L , Chakraborty Saroj , Cheng Xi , Yeo Ji‐Youn , Mell Blair , Joe Bina
Published: June 2021

Pediatric hypertension is recognized as an emerging global health concern. While new guidelines are developed for facilitating clinical management, the reasons for the prevalence of hypertension in children remain unknown. We hypothesized that, similar to the known link between gut microbiota and adult hypertensives, alterations in gut microbiota that occur very early in childhood are also associated with an increased prevalence of pediatric hypertension. To test this hypothesis, we administered amoxicillin, the most commonly prescribed antibiotic to pediatric patients, to clear gut microbiota of just‐weaned, genetically hypertensive Dahl Salt‐Sensitive (S) rats. Amoxicillin treated rats had decreased BP compared to controls. This lowering effect on blood pressure persisted even after the antibiotics were discontinued. Results will be presented on the specific alterations in gut microbiota in response to amoxicillin treatment. Albeit in an experimental model, our results demonstrate the significant role of gut microbiota in the early development of hypertension and indicate that clearing dysbiotic gut microbiota early in childhood may have long‐term benefits for hypertension‐prone individuals.

Support or Funding Information

Funding for this work to BJ from the NHLBI/NIH (HL143082) is gratefully acknowledged.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Varying frequency and pulse width duration during electrical stimulation of cervical sympathetic chain in Zucker Fat rats dramatically alters hemodynamics
Authors: Hsieh Yee‐Hsee , Zenebe Woineshet J , Lewis Stephen J
Published: June 2021

The influence of electrical stimulation of the cervical sympathetic chain (CSC) on hemodynamics has not been thoroughly investigated. Previous studies using healthy strains of rats focused on upper airway dynamics as well as ventilatory parameters. This current study examined the changes in mean blood pressure (MAP), diaphragmatic electromyogram (EMG), and upper airway pressure (UAP) elicited by electrical stimulation of the CSC in Zucker‐fat rats, a model of obesity‐hypertension,. Under urethane anesthesia, male Zucker‐Fat rats (16 weeks of age, n=4), were instrumented to continuously record MAP, diaphragmatic EMG), and UAP. Both CSC were dissected, isolated and stimulated at 0.5 mA, with varying frequency (2.5, 5, 7.5, 10 and 20 Hz) and pulse widths duration (0.1, 0.2, 0.5 and 2.0 ms). Both frequency and pulse‐width dependent depressor response was observed with bilateral CSC stimulation. Lower frequency stimulations produced a 5% decrease in MAP and 12% decrease in UAP whereas the highest frequency of 20 Hz (0.5 mA, 0.2 ms kept constant) produced a 20% decrease in MAP and 25% decrease in UAP relative to baseline (panel A). The smallest pulse width (0.1 ms) produced a 3% decrease in MAP and 5% decrease in UAP whereas 2 ms produced a 25% MAP drop and 10% drop in UAP relative to baseline measures (panel B). Diaphragmatic changes were negligible with CSC stimulation. We conclude that bilateral electrical stimulation of the CSC effectively lowers MAP and UAP in an obesity‐hypertension rat model. In addition, both frequency and pulse width parameters can vary the hemodynamic response dramatically. Future studies will investigate optimal stimulation parameters and whether stimulation can lower hypertension in conscious Zucker‐Fat rats.

Support or Funding Information

Supported by NIH1OT2OD023860‐01, Galvani Bioelectronics

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Necessity of the Hypothalamic Paraventricular Nucleus for the Cardiovascular Responses to Activation of Bradykinin‐Sensitive Pericardial Afferents
Authors: Martin Doug , Reihe Casey
Published: June 2021

Sympathetic drive is a major controller of cardiovascular function. While the arterial baroreceptors are known to regulate sympathetic drive to the cardiovascular system, other reflex mechanisms also play a role. The heart itself has an important sensory function via a variety of cardiac receptors that modulate cardiovascular responses by both neural and humoral reflexes. Bradykinin‐sensitive sympathetic afferent nerves from the heart can trigger marked increases in efferent sympathetic nerve activity to some cardiovascular target organs such as the kidney, arteries and veins. We reported previously that activation of the hypothalamic paraventricular nucleus (PVN) triggers an increase in arterial pressure, venous tone and cardiac output. This work tested the hypothesis that the PVN is necessary for the cardiovascular responses to activation of bradykinin‐sensitive pericardial afferents.

Sprague Dawley rats were anesthetized with a cocktail of alpha chloralose (80 mg/kg) and urethane (800 mg/kg). Catheters were placed in the femoral artery and vein to record arterial and venous blood pressures. The rats were placed in a stereotaxic frame and bilateral guide cannulae were implanted toward the PVN and cemented in place. A PE 10 catheter was placed in the pericardial space for the injection of bradykinin (BK; 1 μg/kg), an agent known to stimulate cardiac sympathetic afferents. The chest was closed and the rat allowed to breathe spontaneously. After recovery from these surgical interventions, the cardiovascular responses to pericardial injection of BK were recorded following PVN injection of vehicle or omega‐conotoxin (1 ng/nl; 200 nl), an N‐type calcium channel antagonist to impair neurotransmission in the PVN.

Pericardial injection of BK following PVN injection of vehicle was associated with increases in mean arterial pressure (19±2 mm Hg) and heart rate (7±2 bpm). PVN injection of conotoxin did not markedly affect baseline arterial pressure or heart rate. However, after injection of conotoxin into the PVN, the pressor responses to pericardial injection of bradykinin were markedly attenuated (MAP: − 17±5 mm Hg; HR: −10±4 bpm).

We interpret these data to indicate that neurotransmission in the PVN is required for the cardiovascular responses to activation of bradykinin‐sensitive pericardial afferents.

Support or Funding Information

Supported by NIH R01 HL136741‐02, the Sanford School of Medicine Medical Student Summer Research Program and the Basic Biomedical Sciences program of the Sanford School of Medicine.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Orexin A receptor 1(OX1R) activation increases expression of cytokines in PC12 cells
Authors: Alharbi Wafa Fhad , Bigalke Jeremy , Chen Qing‐Hui , Shan Zhiyang Jenny
Published: June 2021

Orexin A is a multifunctional neuropeptide that regulates arousal, wakefulness, appetite and cardiovascular function. Orexin A exists its function through binding with orexin receptor 1 (OX1R) or orexin receptor 2 (OX2R). However, the downstream signal transduction pathway that orexin system mediated is not well determined. In this study, we investigate the hypothesis that binding of orexin A and OX1R results in activation of extracellular signal‐regulated kinase 1 & 2 (ERK1/2) and subsequently increases in inflammatory cytokines. We test this hypothesis using the neuron‐like PC12 cell which artificially expressing human OX1R. Incubation of human orexin A (100 nM) resulted in a time dependent increase in phosphorylated ERK1/2 (P‐ERK1/2) as well as the mRNA levels of Junb, a subunit of transcription factor AP‐1; leukemia inhibitory factor (LIF), and C‐C motif chemokine ligand 2 (CCL2), in PC12‐OX1R cells. The maximum increase in Junb was observe in 3 hours, while the maximum increase in LIF (18.3‐fold) and CCL2 (12.8‐fold) was observed in 6 hours following orexin A treatment. There was no significant increases in P‐ERK1/2, Junb, CCL2 and LIF was observed in orexin A treated PC12‐OX2R cells or PC12 cells. Pre‐incubation of orexin A (100 nM) with PD98059, a blocker for ERK1/2 phosphorylation, dramatically attenuated the expression of Junb, LIF and CCL2 in PC12‐OX1R cells. Our results suggested that activation of orexin system activity may though activation or ERK1/2 in turn stimulate AP1‐cytokine signaling.

Support or Funding Information

[Grant support: NIH R15HL129213 (Shan), Michigan Technological University and Portage Health Foundation research Excellence Fund]

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Fibrocytes are Increased in the Medial Layer of the Aorta from Spontaneously Hypertensive Rats
Authors: McKenzie Jaine , Arishe Olufunke , Ogbi Safia , Quinones Patricia Martinez , Klee Nicole , Khodadadi Hesam , Komic Amel , Baban Babak , Webb Clinton
Published: June 2021

Background

Chronic hypertension causes a state of inflammation and leads to vascular remodeling. Vascular remodeling involves alterations in vascular smooth muscle cells, endothelium, and extracellular matrix. Collagen deposition is increased in conductance and resistance vessels of hypertensive animals.

Fibrocytes are bone marrow‐derived cells found in the circulation that migrate toward injured tissue. At the injured site, fibrocytes contribute to healing by serving as antigen presenting cells and secrete cytokines such as IL‐6 and IL‐8 to recruit T cells. Fibrocytes also lay down extracellular matrix such as collagen, and its activation is implicated in many fibrotic diseases including cardiac fibrosis. Studies have shown that patients with hypertensive heart disease have increased number of circulating fibrocytes and that hearts of hypertensive patients have increased collagen levels. The role of fibrocytes in vascular remodeling in hypertension have not been investigated.

Hypothesis

This study tests the hypothesis that fibrocytes are increased in hypertension and play a role in vascular remodeling.

Methods

Male spontaneously hypertensive rats (SHR) and Wistar rats 13–16 weeks old were used in this study. Flow cytometry was used to determine the percentage of fibrocytes (CD34+/CD45+/CollagenI+) in the peripheral blood, aorta, mesenteric resistance arteries (MRA), and pudendal arteries. Wire myograph was used to evaluate the differences in vascular function in response to phenylephrine (PE), norepinephrine (NE), acetylcholine (ACh), and sodium nitroprusside (SNP) between SHR and Wistar. Immunohistochemistry was used to detect fibrocytes (CD34+/CD45+/Collagen I+) within the vascular walls of aorta, mesenteric, and pudendal arteries. Statistical analysis performed using nonlinear regression, two‐tailed unpaired t‐test, and two‐way ANOVA.

Results

Flow cytometry did not show a difference between the percentage of fibrocytes in SHR compared to Wistar. Wire myography demonstrated differences between the two groups in aortic contraction to PE (p<0.0001) and NE (p<0.0001), aortic relaxation to ACh (p<0.0001) and SNP (p<0.0001), MRA relaxation to ACh (p<0.0001), and pudendal artery relaxation to SNP (p<0.0001). Immunohistochemistry showed increased number of fibrocytes in the media layer of the SHR aorta (Figure 1) compared to Wistar (Figure 2).

Conclusions

The number of fibrocytes are increased in the media layer in the aorta in SHR compared to Wistar. The increased number of fibrocytes may contribute to increased collagen deposition leading to decreased vascular compliance in hypertensive animals.

Support or Funding Information

NIH P01 HL‐134604

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Group versus Individual Exercise Differentially Affects Stress Hormone Release in Zebrafish (Danio rerio)
Authors: Jones Alexis , Garcia Emily
Published: June 2021

Zebrafish (Danio rerio) are a small, tropical freshwater fish native to Southeast Asia. They are advantageous to the study of behavior and physiology due to their high physiological and genomic homology to mammals, external fertilization, rapid development, ease of experimental manipulations, and cost‐ and space‐effectiveness. It is well known that exercise is beneficial, but it is becoming increasingly important to understand the psychological and physiological consequences (both positive and negative) to individuals who engage in exercise. The purpose of this experiment was to determine whether cortisol release was affected by group versus individual exercise in zebrafish. Adult, wild‐type male and female zebrafish housed in a community aquarium were exercised in a swim tunnel at a moderate intensity for 10–20 minutes either individually or in small groups (4–5). Control fish were placed in the swim tunnel but it was not turned on. Immediately following each exercise bout, fish were placed in small containers of water to collect cortisol secreted from their gills. Fish that were exercised in a group had lower cortisol levels compared to fish that exercised individually. Fish that were kept in a group, whether exercised or not, secreted less cortisol during the subsequent sampling period. Exercising alone seems to cause the greatest stress response in zebrafish; fish that were exercised individually secreted the greatest amount of cortisol compared to other groups.

Support or Funding Information

Research in this abstract was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number P20GM103447. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Binge but Not Moderate Drinking Impairs Microvascular Flow Induced Dilation Following High Pressure in Young Adults
Authors: Hwang Chueh‐Lung , Bian Jing‐Tan , Thur Laurel A , Peters Tara A , Piano Mariann R , Phillips Shane A
Published: June 2021

Binge drinking or heavy‐episodic drinking is an emerging cardiovascular risk factor and is prevalent among young adults. On the other hand, moderate drinking may also increase cardiovascular risk. We previously demonstrated that flow‐induced dilation (FID) is reduced in young adult binge drinkers compared to abstainers. However, little is known about alteration associated with alcohol use in the vascular response to environmental stress (e.g. high pressure) or vascular function in moderate drinkers. Therefore, we sought to examine FID following high pressure in binge drinkers, moderate drinkers, and abstainers. In addition, we used tetrahydrobiopterin (BH4) to investigate the possible underlying mechanism. We isolated arterioles from gluteal subcutaneous adipose biopsies from 33 young adults (binge drinkers: n=12, moderate drinkers: n=11, and abstainers: n=10; age: 24±1 yrs and body mass index: 23.6±0.4 kg/m2; mean±SE). Arterioles were cannulated and pressurized (60 cmH2O) in an organ perfusion chamber. Lumen diameters were measured before and during responses to flow (pressure gradients of Δ10‐Δ100 cmH2O) prior to and following 1‐hour high intraluminal pressure (150 cmH2O) in the presence or absence of BH4 (10−5 M). Prior to high pressure, we found that moderate drinkers had similar FID across all pressure gradients as abstainers (P>0.1). At Δ100 cmH2O pressure gradient, both moderate drinkers and abstainers had higher % vasodilation than binge drinkers (13% higher, P=0.0047 and 20% higher, P<0.0005 respectively). This impairment in binge drinkers was restored by BH4 (+12%, P=0.02 vs. absence of BH4 and P>0.06 vs. moderate drinkers and abstainers). Following high pressure, FID was reduced only in binge drinkers (3–17% lower, P=0.005 vs. prior to high pressure) while the vasodilatory response to flow was maintained in moderate drinkers and abstainers (P>0.4 vs. prior to high pressure). BH4 ameliorated the impaired FID following high pressure across all pressure gradients in binge drinkers (+4–26%, P<0.05 vs. absence of BH4). In conclusion, arterioles from young adults who abstain or who drink moderately show maintained FID following exposure to elevated vascular pressure. The impaired FID associated with binge drinking can be further reduced by high pressure and reversed by treatment with BH4, suggesting endothelial nitric oxide synthase uncoupling in endothelial dysfunction induced by high pressure in binge drinkers.

Support or Funding Information

NIH R01 HL095701 and R21 AA024535

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Greater α1‐ and α2‐Adrenergic Mediated Vasoconstriction in Contracting Skeletal Muscle of Type 2 Diabetic Humans
Authors: Bock Josh , Hughes William , Ueda Kenichi , Feider Andrew , Hanada Satoshi , Kruse Nicholas , Iwamoto Erika , Casey Darren
Published: June 2021

Type 2 diabetics (T2D) have diminished exercise capacity (VO2max), an independent risk factor for cardiovascular disease. Inadequate blood flow during exercise largely contributes to the reduced VO2max characteristic of T2D. Offsetting sympathetic‐mediated, α‐adrenergic vasoconstriction in contracting skeletal muscle (i.e., functional sympatholysis) is a key regulatory mechanism matching O2 supply (blood flow) with demand (metabolism). Thus, we studied if functional sympatholysis was impaired in 18 T2D (13M/5F) versus 15 control subjects (10M/5F) using intra‐arterial infusions of phenylephrine (PE, α1‐agonist) and dexmedetomidine (DEX, α2‐agonist) at rest, as well as during handgrip exercise. Handgrip exercise trials lasted for 6min at a workload of 20% maximum grip strength. Steady‐state (SS) blood flow was achieved during the first 3min with either PE or DEX infused during the latter 3min. Forearm blood flow (FBF, ml/min) was calculated using brachial artery diameter and blood velocity measured via Doppler ultrasound. Forearm vascular conductance (FVC, ml/min/100mmHg) was calculated using FBF and mean arterial pressure (MAP, measured intra‐arterially). Both FBF and FVC were calculated from data averaged over the final 30sec of rest and SS exercise (before and during infusions). Functional sympatholysis for both PE and DEX trials (resting and exercise) was quantified as: ((SS FVCwith drug – SS FVCpre‐drug)/SS FVCpre‐drug)x100%. T2D and control subjects were of similar age (60±9 vs. 60±9years, p=0.87) and body mass index (30.9±5.5 vs. 29.5±4.6kg/m2, p=0.42); however, VO2max was lower in T2D compared to controls (20.7±5.9 vs. 27.7±8.5ml/kg/min, respectively, p<0.01). No differences in resting FBF, FVC, α1‐ or α2‐mediated vasoconstriction were observed between T2D and controls (p>0.05 for all). In response to handgrip exercise, T2D had 20% lower FBF (166±71 vs. 199±66ml/min, p=0.09) and 24% lower FVC (142±59 vs. 177±52ml/min/100mmHg, p<0.05) compared to controls, respectively. Of particular interest, α1‐ (−16.6±5.9 vs. −10.9±4.3%, p<0.01) and α2‐mediated (−23.8±6.6 vs. 19.5±7.0%, p<0.05) vasoconstriction during handgrip exercise was greater in T2D compared to controls. These data suggest impaired functional sympatholysis may contribute to the diminished exercise capacity of T2D and therefore, could increase their risk of developing cardiovascular disease.

Support or Funding Information

American Diabetes Association 1‐16‐ICTS‐015

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Influence of Diisopropyl fluorophosphate, an irreversible cholinesterase inhibitor, on metabolic and inflammatory parameters, cardiac function, autonomic modulation, and angiotensin 1–7 receptor
Authors: Stoyell‐Conti Filipe Fernandes , Machi Jacqueline F , Schmidt Rodrigo , Puthentharayil Joseph , Benny Alin , Rola Darshan , Lee Matthew , Muthuraj Muthunivas , Speth Robert C , Morris Mariana
Published: June 2021

Nowadays, an estimate of 25–32% of approximately 700,000 Gulf War veterans affected by the Gulf War illness (GWI) still experience symptoms associated with their deployment. It is important to emphasize that GWI is an archetypal, medically unexplained, chronic condition. Musculoskeletal pain, cognitive dysfunction, unexplained fatigue, exercise intolerance, chronic diarrhea, rashes, sleep disorders, and respiratory problems are some of the symptoms observed in Gulf War veterans affected by GWI. Understanding the mechanisms involved in GWI is important to provide a better assistance/treatment to this population. In this study, we used mice to verify the influence of Diisopropyl fluorophosphate (DFP), an irreversible cholinesterase inhibitor used to mimic the effects of sarin gas used during the Gulf War, on metabolic and inflammatory parameters, cardiac function (ECHO), autonomic modulation (spectral analysis) and angiotensin 1–7 receptor (Radioligand Binding Assay) in liver. The animals exposed to DFP showed lower levels of glucose (−8%), triglycerides (−23%) and IL‐10 (−32%), lower parasympathetic modulation (−33%), which led to a higher sympathovagal balance. They showed a lower ejection fraction (−13%) and higher myocardial performance index (30%), characterizing a cardiac dysfunction. In addition, they showed higher Bmax for 125/127I‐Angiotensin 1–7 binding assay, which represents a higher number of receptors (28%). Our results show that exposure to DFP leads to alterations on metabolic and inflammatory parameters, cardiac function, autonomic modulation, and renin‐angiotensin‐aldosterone system, which helps us to understand, at least in part, the mechanisms involved in GWI. Further studies are needed to elucidate the whole mechanisms behind GWI.

Support or Funding Information

W81XWH‐13‐2‐0085 Morris (PI); Cardiovascular Neuroscience Research Fund 337667 Speth (PI)

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sensory Nerve‐Mediated and Nitric Oxide‐Dependent Vasodilation Is Reduced in Non‐Hispanic Blacks Compared to Non‐Hispanic Whites
Authors: Walker Demetria , Hollowed Casey , Miller James , Otis Jeffrey , Hayat Matthew , Quyyumi Arshed , Wong Brett
Published: June 2021

Reduced microvascular function is recognized in healthy non‐Hispanic Blacks compared to non‐Hispanic Whites, but it is unclear whether sensory nerve function is altered in non‐Hispanic Blacks. Local heating of the skin allows for the simultaneous assessment of both sensory nerve‐mediated and nitric oxide (NO)‐dependent vasodilation. The purpose of this study was to test the hypothesis that the magnitude of cutaneous sensory nerve‐mediated and microvascular endothelial‐dependent vasodilation is reduced in non‐Hispanic Blacks compared to non‐Hispanic Whites. Six healthy participants who self‐identified as non‐Hispanic Black (n=3) or non‐Hispanic White (n=3) were instrumented with two microdialysis fibers on the forearm: 1) lactated Ringer's (control) and 2) topical anesthetic (5% lidocaine) to inhibit sensory nerve function. A rapid local heating protocol was conducted at each microdialysis site where the temperature of the skin was heated from 33°C to 39°C at a rate of 1°C/sec. Skin blood flow was continuously monitored at each site with laser‐Doppler flow (LDF) probes. At the plateau of skin blood flow, 20 mM L‐NAME was perfused at each site to inhibit NO synthase in order to calculate %NO‐dependent vasodilation. Following L‐NAME infusion, maximal skin blood flow was reached by infusing each site with 54 mM sodium nitroprusside and heating the skin to 43°C. Cutaneous vascular conductance (CVC) was calculated (LDF/MAP) and standardized to maximal blood flow (%CVCmax). Data shown are mean ± SD. At control sites, the initial peak (33 ± 9 %CVCmax) and plateau (52 ± 9 %CVCmax) in non‐Hispanic Blacks were reduced compared to non‐Hispanic Whites (53 ± 8 % and 67 ± 10 %CVCmax; P < 0.05 for all conditions). At sites treated with anesthetic, the initial peak was unaltered in non‐Hispanic Blacks (26 ± 10 %CVCmax) but was significantly reduced in non‐Hispanic Whites (23 ± 13 %CVCmax). Anesthetic did not affect the plateau in either non‐Hispanic Blacks (56 ± 5 %CVCmax) or non‐Hispanic Whites (62 ± 4 %CVCmax). Calculated %NO‐dependent vasodilation was reduced in non‐Hispanic Blacks (51 ± 6 %NO) compared to non‐Hispanic Whites (67 ± 8 %NO). These data indicate that sensory nerve function, microvascular function, and NO‐dependent vasodilation are all decreased in non‐Hispanic Blacks in comparison to non‐Hispanic Whites.

Support or Funding Information

NIH R01HL141205

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.