bluuebunny/crossref_metadata_2025 huggingface dataset:
Cerebral Vascular KIR2.x Channels are Distinctly Regulated by Membrane Lipids and Hemodynamic Forces.
Authors: Sancho Maria , Welsh Donald G.
Published: June 2021

This study examined membrane lipid (phosphatidylinositol‐bis‐phosphate (PIP2) and cholesterol) regulation of cerebral arterial KIR and whether these signaling molecules enable distinct channel pools to uniquely sense hemodynamic forces. Endothelial and smooth muscle cells were freshly isolated from rat cerebral arteries; patch‐clamp electrophysiology, Q‐PCR and immunohistochemistry delineated KIR channel activity and expression. Electrophysiology revealed a Ba2+‐sensitive KIR current in smooth muscle and endothelial cells, while Q‐PCR and immunohistochemistry confirmed KIR2.x mRNA and protein expression respectively. Each cellular pool of KIR channels was sensitive to particular membrane lipids and hemodynamic forces. Endothelial KIR responded dynamically to PIP2 manipulations, and laminar flow activated this channel pool in a PIP2 dependent manner. In contrast, smooth muscle KIR reacted to cholesterol perturbations, and pressure stimuli (e.g. hyposmotic challenge or negative pressure application) modulated this channel pool in a cholesterol dependent manner. The flow and pressure sensitivity of KIR channels was confirmed in intact cerebral arteries using vessel myography. In summary, while both vascular cell types express KIR2.x channels, each pool is distinctly regulated by membrane lipids and hemodynamic stimuli. This emerging picture of KIR regulation advances our mechanistic understanding of how hemodynamic forces interact to control arterial tone development.

Support or Funding Information

This research was supported by an operating grant from the Canadian Institute of Health Research. DG Welsh is Rorabeck Chair of Molecular Neuroscience and Vascular Biology at the University of Western Ontario.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effects of Heated versus Thermoneutral Bikram Yoga Interventions on Endothelial Function and Arterial Stiffness
Authors: Hunter Stacy D. , Laosiripisan Jitanan , Elmenshawy Ahmed , Tanaka Hirofumi
Published: June 2021

Bikram (hot) yoga is a style of hatha yoga practiced at 40.5° C with 40–60% relative humidity. We have previously documented improvements in endothelium‐dependent vasodilation but not arterial stiffness in healthy, middle‐aged adults with an 8‐week Bikram yoga intervention. Currently, it is unknown whether the effect of hot yoga on endothelial function might be attributed to the hatha yoga asanas or the high temperature/humidity. It is also unknown whether a longer intervention might produce significant alterations in arterial stiffness.

PURPOSE

The purpose of this investigation was to determine the effects of a 12‐week Bikram yoga intervention performed in standard heated conditions and in a thermoneutral environment on endothelium‐dependent vasodilation and arterial stiffness.

METHODS

Fifty‐two sedentary but apparently healthy adults aged 40–60 years were randomly assigned to one of three groups: Bikram yoga practiced at 40.5°C (n=19); Bikram yoga practiced at 23°C (n=14); or sedentary time‐control (n=19). The 12‐week yoga intervention consisted of 3 weekly 90‐minute Bikram yoga classes. The time control group was instructed to maintain current lifestyle patterns for the study duration. Body composition was determined via dual energy x‐ray absorptiometry (DXA). Endothelium‐dependent vasodilation was measured noninvasively using brachial artery flow‐mediated dilation (FMD) after 5 minutes of blood flow occlusion. Arterial stiffness was measured via brachial‐ankle pulse wave velocity (PWV).

RESULTS

Age, anthropometric variables, plasma lipid, glucose, and triglyceride concentrations, brachial artery FMD and brachial‐ankle PWV were not different among the three groups at baseline. Body fat percentage declined (p<0.01) and total‐ (p=0.051) and LDL‐cholesterol (p =0.09) concentrations tended to decline only in the hot (40.5°C) yoga group. Brachial artery FMD increased (P<0.05) in both yoga groups but brachial‐ankle PWV was not significantly altered in any group. There were no changes in any outcome variables in the time control group.

CONCLUSIONS

Bikram yoga practiced in hot/humid and thermoneutral conditions produced similar improvements in endothelium‐dependent vasodilation in healthy, middle‐aged adults. The addition of the heat led to reductions in body fat percentage. Bikram yoga does not appear to modulate arterial stiffness in middle‐aged adults.

Support or Funding Information

This study was funded by Pure Action, Inc. Austin, TX, USA

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Myoblasts enhance collateral capillary arteriogenesis during chronic ischemia
Authors: Hamzeinejad Vahid , Banuelos Leo , Cardinal Trevor Ryan
Published: June 2021

Peripheral arterial occlusive disease (PAOD) involves peripheral artery occlusion, which causes ischemia (i.e. insufficient blood flow) and is the leading cause of amputation. Natural bypass vessels known as collaterals can preserve downstream tissue viability by creating an alternative route for blood flow. Increased blood flow through preexisting collateral increases shear stress and triggers arteriogenesis, the outward remodeling of arterial vessels. The presence of collaterals improves prognosis in patients with ischemic disease, but many patients never develop identifiable collaterals to relieve peripheral ischemia. Animal models that lack preexisting collaterals are capable of forming collaterals from capillaries that undergo arteriogenesis to become arterialized capillary collaterals (ACC). A treatment to induce the formation of ACCs, particularly in diseased or aged tissues that lack the propensity to form new collateral vessels, could be highly effective in giving protection against ischemia. Exercise is a great therapy for PAOD, since following exercise, resident muscle stem cells known as satellite cells (SCs) activate and regulate local angiogenesis. SCs and their progeny myoblasts secrete factors known to be involved in arteriogenesis (many of these compounds involved in angiogenesis are also involved in arteriogenesis) and the recruitment of other cells involved in remodeling. Therefore, transplanting these putative arteriogenic cells is a potential therapy to recapitulate some of the beneficial effects of exercise therapy. In this study, the lateral feed artery in the spinotrapezius muscle of Balb/C mice was ligated to induce chronic ischemia; myoblasts were transplanted during surgery to enhance arteriogenesis of collateral capillaries. Implanted mice exhibited increased arteriogenesis, ACC diameter increased to 28.11 ± 0.85 μm vs 16.25 ± 0.62 μm in a no transplant control. As corollary, we evaluated the process for cell construct preparation and discovered that cells cultured on scaffold overnight (20.86 ± 1.6 μm) before transplant did not stimulate arteriogenesis as significantly as those who were cultured for 6‐hours only. Limited nutrient supply and gas exchange while incubating on scaffolds could induce stress on myoblast and cause limited reactivity/apoptosis post implant. In summary, myoblast transplantation increases ACC arteriogenesis; however, they need to be transplanted as early as possible post‐harvest from culture flask.

Support or Funding Information

Funding: CIRM ( California Institute for Regenerative Medicine)

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Selectively Impaired Vasodilation of Human White Matter Penetrating Cerebral Arterioles in Microvascular Brain Injury and Alzheimer's disease
Authors: Bagi Zsolt , Brander Dieter D. , Le Phuong D. , McNeal David D. , Gong Xi D. , Dou Huijuan , Fulton David , Beller Allison , Ngyuen Thuan D. , Larson Eric , Montine Thomas , Keene Dirk , Back Stephen D.
Published: June 2021

Microvascular brain injury (mVBI) is a common pathologic correlate of vascular contributions to cognitive impairment and dementia (VCID) that leads to white matter (WM) injury. VCID appears to arise from chronic recurrent WM ischemia. We hypothesized that in mVBI WM injury is specifically attributed to vasodilator dysfunction of WM penetrating arterioles. We analyzed 38 cases of mVBI with low and high Alzheimer's disease (AD) neuropathologic changes in prefrontal cortex WM from rapid autopsies in a population‐based cohort where VCID and AD frequently occur. Arteriolar vasodilator function was quantified by videomicroscopy. Acetylcholine‐mediated arteriolar dilation in mVBI with low AD pathology was significantly reduced in WM penetrators relative to pial arterioles. Astrogliosis‐defined WM injury was associated with impaired vasodilator function of WM penetrating arterioles. In mVBI with high AD pathology vasodilator function of WM penetrating arterioles was further diminished. Presence of moderate/frequent neuritic plaques and cerebral amyloid angiopathy were associated with impaired dilation in WM penetrating, but not in pial arterioles. In conclusion, we successfully assessed vasodilator function of human WM penetrating arterioles in postmortem rapid autopsy samples. We found that selectively impaired vasodilator function of WM penetrating arterioles in mVBI occurs in association with WM injury and AD neuropathologic change.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A Mathematical Model of Plasma Membrane Electrophysiology of a Brain Capillary Pericyte: Investigating Pericyte Contribution to the Electrical Properties of the Capillary Network
Authors: Mirza Asad M. , Moshkforoush Arash , Giles Wayne R. , Tsoukias Nikolaos
Published: June 2021

Introduction

Pericyte cells (PCs) are specialized cells found primarily on the abluminal surface of capillary blood vessels alongside endothelial cells (ECs). They play a role in angiogenesis, formation of the blood‐brain barrier, as well as in the regulation of blood flow. Due to their contractile nature, PCs can modulate capillary diameter and perfusion, however, little is known regarding their contribution to the electrical properties of the capillary network. Furthermore, recent studies show that capillaries can sense neural activity in the brain and transmit electrical signals to upstream feeding arterioles and arteries to match blood supply to local demand. Although passive electrotonic spread underlies signal propagation along the endothelium in larger vessels, evidence for amplification of transmitted signals and preferential upstream propagation have been presented in vessels as branching order increases. We use mathematical modeling to test under what conditions a PC can affect the electrical properties of the capillary network and whether it can act as a sink or an amplifier of conducted hyperpolarization.

Methods

A PC and an EC model incorporate the dynamic behavior of known plasma membrane currents, release and uptake of Ca2+ by intracellular stores and dynamic tracking of ionic (Ca2+, K+, Na+, and Cl−) concentrations in the cytosol (Fig. 1). The PC is electrically coupled to capillary ECs through gap junctions and a multicellular model of a capillary network is created. Electrical signal attenuation is examined following hyperpolarizing stimuli at capillary ends in the presence as well as absence of PCs at network bifurcations.

Results

Cell models predict physiological resting membrane potential and ionic concentrations. Model predictions were compared against experimental responses to agonist stimulation and K+ challenge for validation. Simulations show that a sufficient inwardly rectifying K+, Kir, channel current density may allow PCs to amplify conducted hyperpolarization. Increased coupling between a PC with the parent relative to the daughter capillaries at a bifurcation may allow preferential conduction of an electrical signal upstream the vascular network.

Conclusion

A detailed model of a brain capillary pericyte was developed and validated against experimental data. Model simulations suggest that with sufficient Kir density, pericytes can amplify conducted hyperpolarization and regulate the distance and direction of propagating vasodilation and thus blood flow distribution in the vascular network.

Support or Funding Information

This work was supported by the Ronald E. McNair Post‐Baccalaureate Achievement Program.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Excessive shear stress sensing on the arterial endothelium initiates cerebral aneurysm formation
Authors: Fukuda Miyuki , Fukuda Shunichi , Ando Joji , Yamamoto Kimiko , Ito Yuki , Inoue Takayuki , Tsukahara Tetsuya , Asahara Noriko , Hasegawa Koji , Shimazu Akira
Published: June 2021

Although rupture of cerebral aneurysms is a major cause of life‐threatening subarachnoid hemorrhage, there are no effective therapeutic drugs for the treatment of aneurysms, partly because the pathogenesis of the aneurysm remains unresolved. We hypothesize that shear stress‐related hemodynamics initiates cerebral aneurysm formation. To test this hypothesis, we examined here whether disruption or inhibition of the endothelial shear stress sensor, P2X4 purinoceptor, has any influence on expressions of known contributors to aneurysm formation or not.

P2X4 purinoceptor deficient (P2X4 KO) mice and Sprague‐Dawley rats were subjected to cerebral aneurysm‐generating surgery with ligation of unilateral common carotid artery and renal hypertension. P2X4 purinoceptor inhibitor, paroxetine (8 mg/kg/day) was administered to rats after the surgery. The incidence of aneurysm formation was examined with light microscopy, and expressions of contributors to aneurysm formation using a quantitative real‐time PCR analysis and immunohistochemical examinations.

The frequency of aneurysm induction in P2X4 KO mice was significantly lower than wild‐type mice (p=0.018). In addition, paroxetine significantly attenuated the incidence of induced aneurysms in rats after aneurysm‐generating surgery (p=0.031). Expression levels of inflammatory contributors to aneurysm formation, COX‐2, TNFα, MCP‐1, IL1β, and iNOS, were significantly increased in rats after aneurysm‐inducing surgery than control non‐operated animals by a quantitative real‐time PCR analysis. Paroxetine significantly reduced the expression levels of all the contributors.

These data suggest that shear sensing on the arterial endothelium initiates chronic inflammation in the arterial wall during cerebral aneurysm formation. Because paroxetine has been used for human as an antidepressant, clinical use of this P2X4 purinoceptor inhibitor is expected as a novel therapy for cerebral aneurysms.

Support or Funding Information

This work is supported by Japan Agency for Medical Research and development, AMED and JSPS KAKENHI Grant Number JP15K10323.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Oral Metoprolol Attenuates Dilation of Leptomeningeal Collateral Arteries after Middle Cerebral Artery Occlusion and Increases Infarct Volume in Sprague Dawley Rats
Authors: Henry David S. , McClenahan Samantha J. , Rusch Nancy J. , Rhee Sung W.
Published: June 2021

Background

Beta‐adrenergic receptor antagonists, or beta blockers (BBs), have long been a mainstay in the treatment of hypertension, heart failure, and angina. In 2014, the Eighth Joint National Committee removed BBs from the list of recommended first‐line hypertension therapies, citing an increased incidence of stroke among patients treated with BBs compared to other antihypertensive medications. However, in 2015, more than 72 million prescriptions of this drug class were filled in the United States. The mechanism behind worse stroke outcomes in BB‐treated patients is unknown. Leptomeningeal collateral arteries (LCAs) connect adjacent arterial trees of the cerebral circulation, and after ischemic stroke, provide an alternative pathway for blood flow to the affected cortical tissue. We hypothesize that beta‐adrenergic receptor‐mediated dilation of LCAs is an important part of this protective mechanism during ischemic stroke and that BBs attenuate this dilation, leading to worse stroke outcomes.

Methods and Results

LCAs dilated in a concentration‐dependent manner to topical application of the beta‐adrenergic receptor agonist isoproterenol in cranial window preparations in Sprague Dawley (SD) rats. Isolated, pressurized LCAs dilated in response to isoproterenol ex vivo, and this dilation was attenuated by the beta1‐selective blocker CGP20712 (30 nM). LCAs acutely dilated after middle cerebral artery occlusion (MCAO) in SD rats. The dilation of LCAs after MCAO was reduced in rats suffused with topical CGP20712 (100 nM) or gavaged with oral metoprolol (30 mg/kg), the most frequently prescribed BB. Similarly, blood flow through LCAs post‐MCAO was reduced in rats gavaged with metoprolol compared to control rats, as visualized by laser speckle contrast imaging. Finally, infarct volume, as measured by MRI one day post‐MCAO surgery, was larger in rats gavaged with metoprolol compared to control. Interestingly, the heart rate and systemic blood pressure measured by biotelemetry for 6 hours following MCAO surgery were not different in rats gavaged with metoprolol and water.

Conclusions

Our study suggests that BBs may promote worse stroke outcomes by disrupting beta‐adrenergic receptor‐mediated dilation of LCAs.

Support or Funding Information

Supported by NIH R01 HL097107, American Heart Association 17GRNT33670970, and Institutional Hornick and Fund‐to‐Cure‐Stroke grants

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cerebral Blood Flow Characteristics Responses Following Acute Aerobic Exercise in Individuals with and without Down Syndrome
Authors: Wee SANG OUK , Schroeder Elizabeth C. , Grigoriadis Georgios , Bunsawat Kanokwan , Rosenberg Alexander J. , Griffith Garett , Baynard Tracy , Fernhall Bo
Published: June 2021

Individuals with Down Syndrome (DS) commonly experience low to moderate levels of cognitive impairment and are at a high risk of developing dementia and Alzheimer's diseases (AD). Reduced cerebral blood flow (CBF) and altered CBF characteristics have been observed in the aging population without DS and has shown to have detrimental effects on cerebral microvasculature, which may increase the risk of developing dementia and AD. However, differences in CBF and its characteristics between individuals with and without DS and its response to exercise have not been studied.

Purpose

To examine the differences in CBF and its characteristics following a 20‐minute bout of moderate intensity walking in individuals with and without DS.

Methods

Thirty‐eight young (DS=19, Age=25 yrs) individuals with and without DS participated in this study. Changes in mean middle cerebral artery velocity (mMCAv), mMCAv characteristics (pulsatility index (PI), resistance index (RI)) and hemodynamic variables were measured before, immediately post and 30‐minute post exericse.

Results

Baseline hemodynamics, systolic blood pressure (BP), diastolic BP, mean arterial pressure (MAP), heart rate (HR) and mMCAv were not different between the DS and control group (p>0.05 for all). Neither group showed changes in mMCAv after moderate intensity treadmill walking exercise (p>0.05). However, the DS group exhibited significantly higher PI and RI at all time points when compared to controls (p<0.05 for both).

Conclusions

Our results demonstrate that CBF was not altered in individuals with DS at rest and following moderate intensity exercise and was not different from that of controls. However, higher PI and RI in DS group may be associated with reduced distal cerebral perfusion and microvascular damage in individuals with DS.

DS (N = 19)
Control (N = 19)

Baseline
Immediate post EX
30‐minute post EX
Baseline
Immediate post EX
30‐minute post EX

SBP (mmHg)
122±14
126±11*
121±13
120±10
130±12*
121±11

DBP (mmHg)
69±9
75±8*
70±9
72±6
81±8*
74±9

MAP (mmHg)
93±10
98±8*
94±9
94±7
103±7*
96±8

mMCAv (cm/s)
64.3±14.9
62.8±13.9
60.8±14.6
69.4±13.1
69.8±14.8
69.6±14.1

PI‡
0.97±0.14
1.04±0.19
1.02±0.14
0.87±0.12
0.89±0.15
0.86±0.14

RI‡
0.60±0.05
0.61±0.06
0.61±0.05
0.56±0.05
0.56±0.05
0.55±0.05

Significant group difference,

Significant time difference from the baseline.

Mean ± SD, Significance level, p < 0.05

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sodium Nitroglycerin Induces Cerebrovascular Vasodilation in Patients with Ischemic Heart Disease
Authors: Schulz Jenna M. , Al‐Khazraji Baraa K. , Vording Jennifer L. , Shoemaker J Kevin
Published: June 2021

Aging patients with ischemic heart disease (IHD) have impaired cerebrovascular vasodilation in response to hypercapnia, but whether this is due to endothelial dysfunction or impairment in the vascular smooth muscle remains unknown. Further, despite being a standard drug given to patients with cardiovascular disease, the role of an exogenous nitric oxide donor (sodium nitroglycerin – NTG, which acts independently of the endothelium) in the cerebrovasculature in these patients is not known. This study tested the hypothesis that age and IHD impair nitric oxide‐mediated dilation (sodium nitric oxide, 0.4 mg spray) of the nine larger cerebral arteries in the Circle of Willis (3 Tesla MRI), as well as mean flow velocity [transcranial Doppler ultrasound; right middle cerebral artery (MCA)] and calculated MCA cerebral blood flow. These measures were made in groups of IHD (n=10, 49–77 years), older controls (CTL; n=5, 51–78 years) and young healthy (YH; n=10, 20–26 years) individuals. Compared to baseline, right MCA velocity [V (cm/s)] decreased similarly in all three groups [ΔIHD: −5.8 ± 5.0 cm/s; ΔCTL: −5.8 ± 3.2 cm/s; ΔYH: −6.3 ± 4.4: all p<0.05 versus baseline; mean ± S.D.]. However, a main effect of drug indicated that NTG induced artery dilation in all six basal and the three extracranial arteries [average range of cross sectional area values for all vessels provided here: BL: 3.3 – 16.5 mm2; NTG: 3.9 – 17.9 mm2, p<0.05, mean], and this dilation was similar across all 3 groups [e.g. right MCA CSA – ΔIHD: 1.3 ± 1.4 mm2; ΔCTL: 0.7 ± 1.2 mm2; ΔYH: 1.3 ± 0.9 mm2, p>0.05 versus baseline; mean ± S.D.]. As a result, NTG exerted no change in MCA blood flow versus baseline. These results demonstrate that age and IHD have little impact on vascular smooth muscle responses to exogenous nitric oxide.

Support or Funding Information

Supported by Canadian Institute for Health Research (201503MOP‐342412‐MOV‐CEEA)

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Influence of altered physical activity on vascular function in older adults: A divergent impact on the conduit and microvascular systems
Authors: Broxterman Ryan M. , Trinity Joel D. , Gifford Jayson R. , Park Soung Hun , Shields Katherine L. , Drummond Micah J. , Richardson Russell S.
Published: June 2021

Aging is associated with a progressive decline in physiological and functional reserve capacity in humans. The rate of this decline is accelerated by periods of reduced activity. Prolonged reductions in physical activity (i.e. weeks) are commonly incurred with age‐related insults (i.e., hospitalization, injury, illness) in older adults. The effect of these periods of reduced activity on vascular function reserve remains to be determined. Any detrimental effects of this reduced activity on vascular function are clinically relevant, as this would pose an increased risk for adverse cardiovascular events. Furthermore, it remains to be determined if any detrimental effect on vascular function incurred during prolonged reduced activity is reversible with resumption of normal activity. Therefore, the purpose of the current study was to investigate the effects of prolonged reductions in physical activity, followed by a return to normal activity, on leg vascular function in older adults. Popliteal artery flow‐mediated dilation (FMD) and reactive hyperemia were measured at baseline, following 14 days of reduced activity (i.e. 70% reduction in steps per day), and 14 days after returning to normal activity in 5 healthy older subjects (2 men and 3 women, age: 70 ± 8 yrs, stature: 164 ± 13 cm; body mass, 69 ± 10 kg). The steps per day during the reduced activity period (3,212 ± 1,673 steps) were significantly lower than both baseline (11,007 ± 2,417 steps) and return to normal activity (10,068 ± 1,357 steps), while baseline and return to normal activity were not significantly different (p = 0.29). Popliteal artery FMD was significantly attenuated following reduced activity and returned to baseline after 2 weeks of normal activity (Figure 1A). There were no significant differences between conditions in popliteal artery shear rate (p = 0.43). The popliteal artery reactive hyperemia was not significantly different between conditions (p = 0.70, Figure 1B). Therefore, a prolonged, 14 day, alteration in physical activity in older adults directly influences leg conduit artery vascular function (i.e. FMD), while leg microvascular function (i.e. reactive hyperemia) remains unaltered. These results document the influence of alterations in physical activity on cardiovascular health in older adults, but also highlight a divergent impact on the conduit and microvascular systems

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Impaired ATP Release in Individuals with Type 2 Diabetes Assessed by the Intravascular Microdialysis Technique
Authors: Mortensen Stefan P. , Groen Martin B. , Knudsen Trine A. , Finsen Stine , Pedersen Bente K. , Hellsten Ylva
Published: June 2021

Background

ATP is a potent vasodilator in plasma and is released from erythrocytes upon deoxygenation. In vitro studies suggest that individuals with type 2 diabetes (T2D) have an impaired ATP release when exposed to low oxygen tension and a reduced capability to induce vasodilation. We sought to examine if patients with T2D have reduced plasma ATP levels during resting conditions, hypoxia and during increased metabolic demand compared to healthy individuals.

Methods

We measured femoral arterial and venous plasma ATP with the intravascular microdialysis technique during normoxia, hypoxia and one‐legged knee‐extensor exercise in 9 individuals with T2D and 8 healthy controls. Moreover, we infused ACh, SNP and ATP to test vascular function.

Results

Patients with T2D had an impaired increase in venous plasma [ATP] during exercise in parallel with a reduced leg blood flow and vascular conductance compared to the healthy controls. Arterial plasma [ATP] increased in both groups during exercise, but tended to be higher in the healthy controls (P=0.05–0.07). During systemic hypoxia, venous plasma [ATP] increased in both groups, but the increase was higher in the healthy controls. Leg vascular conductance was lower during ATP and ACh infusion in the patients with T2D compared to the healthy controls.

Conclusions

These findings demonstrate that patients with T2D have impaired ATP release during exercise and hypoxia compared to healthy humans. Moreover, T2D have a reduced vasodilatory response to infused ATP. These impairments in the ATP are likely to contribute to the reduced tissue perfusion in T2D.

Support or Funding Information

This study was funded by the Capital Region of Denmark.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Acute Estrogen Does Not Augment the β2 ‐ Adrenergic Receptor Mediated Vasodilation in Postmenopausal Women
Authors: Ranadive Sushant Mohan , Dillon Gabrielle A. , Joyner Michael
Published: June 2021

Introduction

Acute estrogen infusion augments β2 ‐adrenergic receptor responsiveness in premenopausal women. This suggests an influential role of estrogen in controlling the vasodilator responsiveness via β2 ‐adrenergic receptors in premenopausal women. Postmenopausal women present with a reduced β2 ‐adrenergic receptor responsiveness as compared to premenopausal women. This divergent finding in β2 ‐adrenergic receptor responsiveness could be due to loss of endogenous estrogen postmenopause.

Objective

Hence, the objective of the study was to compare the β2 ‐adrenergic vasodilator responses with and without estrogen in postmenopausal women. We hypothesized that the vasodilator effects during endothelial dependent, independent and during β2 ‐adrenergic agonist infusion would be significantly greater with acute, local estrogen administration.

Methods

Venous occlusion plethysmography was used to measure forearm blood flow (FBF) in 8 older (age = 59 ± 1 years) healthy, non‐obese (BMI = 23 ± 1 kg/m2) women. FBF was measured at baseline and during an intra‐arterial infusion of acetylecholine (ACH) at 1.0, 2.0, 4.0, and 8.0 μg/100 ml tissue/min, sodium nitroprusside (NTP) at 0.25, 0.5, 1.0 and 2.0 ug/100 ml tissue/min and terbutaline (β2 agonist) at 0.1, 0.5, 1.0, 2.0 μg/100 ml tissue/min before (with dextrose co‐infusion) and during acute, local intra‐arterial infusion of estrogen (20 ηg/mL at 1 mL/min). Forearm vascular conductance (FVC) was calculated as FBF divided by mean arterial pressure. Area under the curve (AUC) was calculated for the absolute FVC and percent baseline FVC of ACH, NTP and terbutaline.

Results

There were no significant differences in FVC with estrogen infusion as compared to control during ACH, NTP and all terbutaline doses except dose 2 of ACH (Table 1). The AUC are not significantly different during estrogen (p>0.05) as compared to control for ACH, NTP and terbutaline (figure 1).

Conclusions

These data suggest that acute administration of estrogen, which corresponds to the endogenous levels of estrogen seen in premenopausal women during mid‐cycle, does not augment the β2 ‐adrenergic vasodilator responses in postmenopausal women. Additionally, these data suggest that estrogen infusion does not increase the endothelial dependent and independent vasodilatory capacity in postmenopausal women.

Support or Funding Information

HL83947 (MJJ) and Mayo Clinic Women's Health Scholarship (K12 HD065987).

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Activation of Bradykinin‐Sensitive Pericardial Afferents Increases Systemic Venous Tone and Cardiac Output
Authors: Martin Doug , Reihe Casey
Published: June 2021

The venous system plays a critical role in blood pressure regulation by controlling venous return, cardiac filling, and cardiac output. Sympathetic drive is a major controller of venous function. However, outside of the arterial baroreflex, the mechanisms that regulate sympathetic drive to veins remain poorly defined in both physiological and disease conditions. The heart itself has an important sensory function via a variety of cardiac receptors that modulate cardiovascular function by 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. This work tested the hypothesis that the activation of bradykinin‐sensitive cardiac afferents increases venous tone and cardiac output.

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. A PE 10 catheter was placed in the pericardial space for the injection of bradykinin (BK), an agent known to stimulate cardiac sympathetic afferents. In some rats, a balloon tipped catheter was placed in the right atrium to allow transient arrest of cardiac pumping for the estimation of mean circulatory filling pressure (MCFP), an estimate of systemic venous tone. In other rats, an electromagnetic flow probe was placed on the aortic arch for the direct measurement of cardiac output.

In rats instrumented for the measurement of venous tone, pericardial injections of BK (0.4–20 μg/kg) were associated with dose‐related increases in mean arterial pressure (9±6 to 27±6 mm Hg) and MCFP (0.6±0.2 to 1.6±0.4 mm Hg). These responses were largely attenuated after ganglionic blockade. In rats instrumented for the measurement of cardiac output, pericardial injection of BK (10 μg/kg) increased mean arterial pressure (23±3 mm Hg) and cardiac output (16±2 ml/min).

We interpret these data to indicate that activation of bradykinin‐sensitive pericardial afferents increases venous tone sufficiently to increase cardiac filling and cardiac output.

Support or Funding Information

Supported by NIH R01 HL136741‐01 and the Basic Biomedical Sciences program of the Sanford School of Medicine, University of South Dakota.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effects of Acute Antioxidant Cocktail Combined with a High Sodium Meal on Arterial Stiffness and Wave Reflection
Authors: Smiljanec Katarina , Mbakwe Alexis U. , Lennon Shannon L.
Published: June 2021

Vascular dysfunction is a non‐traditional risk factor for cardiovascular disease (CVD). Further, increased arterial stiffness and wave reflection are considered independent predictors of CVD. High dietary sodium intake has been shown to impair vascular function through an increase in oxidative stress. Therefore, the objective of this study was to investigate the acute effects of an antioxidant cocktail combined with a high sodium meal on measures of arterial stiffness and wave reflection. Twenty‐six young healthy adults (11M, 15F; 22.8 ± 0.5 years; BMI 23.1 ± 0.4 kg/m2; systolic blood pressure 116 ± 2 mmHg, diastolic blood pressure 70 ± 1 mmHg) completed two trials separated by at least 48 hours. All subjects were fasted for 4 hours and women were tested during the early follicular phase of the menstrual cycle. Carotid‐femoral pulse wave velocity (PWV) and the synthesis of a central aortic pressure waveform (by radial artery applanation tonometry and generalized transfer function) were performed. Aortic augmentation index (AIx), an index of wave reflection, was calculated from the aortic pressure waveform. Participants ingested either two doses of an antioxidant cocktail (AO; each capsule contained 500 mg vitamin C, 300 IU vitamin E, and 300 mg alpha‐lipoic acid) or a placebo (PLA; cellulose). Dose one was consumed 30 min prior and dose two was consumed with the meal. The high sodium meal (1500 mg Na+) consisted of tomato soup with added table salt. Mean arterial pressure (MAP), AIx, and PWV were measured at baseline (BSL) and 30, 60, 90, and 120 minutes after meal consumption. Baseline measurements of AIx did not differ between the two visits (P > 0.05) but decreased over time in both trials (AO: BSL: 8.0 ± 1.4%, 60 min: 2.0 ± 1.3%; PLA: BSL: 6.2 ± 1.4%, 60min: −0.8 ± 1.9%; P‐time effect < 0.001). PWV was not different at baseline (AO: 5.3 ± 0.1 m/s, PLA: 5.2 ± 0.1 m/s; P > 0.05) nor did it change during the two trials (P > 0.05). Similarly, MAP was not different at baseline (P > 0.05) and it remained unchanged during the two trials (P > 0.05). In conclusion, acute consumption of a high sodium meal did not impair arterial stiffness or wave reflection in young, healthy adults.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of Salt Taste Threshold on Cardiovascular Response to Isotonic Exercise in Young Adults
Authors: Elias Simiat O. , Quadri Taofeek O. , Bamiro Saka A. , Umoren Grace A.
Published: June 2021

Increased salt intake among persons with high salt taste threshold may lead to exercise‐induced hypertension and eventually arterial hypertension. Salt sensitivity has been demonstrated among our populace. This study was designed to investigate the effect of salt taste threshold (STT) on cardiovascular response to exercise. The study protocol was carried out in accordance with the Declaration of Helsinki. Forty‐seven normotensive individuals participated in the study after giving informed consent. Baseline blood pressure, BP (mmHg) and heart rate, HR (beats/min) were determined in all subjects. Salt taste threshold (STT) was determined by making subjects taste increasing concentrations (15mmol/L–105 mmol/L) of NaCl prior to exercise and subjects were divided into Low salt tasters (LST, <60 mmol/L) and high salt tasters (HST, >60 mmol/L). Each participant completed 6 minutes of isotonic (Havard Step Test) exercise. Data were analyzed using Student t test with GraphPad Prism version 5. Significance was accepted at p<0.05. There were 39(83%) LST and 8(17%) were HST. Isotonic exercise led to significant increases in systolic (116±1 to 139±2 mmHg; p<0.0001) and diastolic (73±2 to 88±3 mmHg; p = 0.0007) BP; as well as HR (71.61±3.73 to 99.61±1.85; p<0.0001). However, the magnitude of the pressor response (%Δ) of high STTs to isotonic exercise was not different (p>0.05) from that of LSTs. Similarly, the %Δ in HR response of HST to isotonic exercise was not different (p=0.898) from that of LSTs. Plasma sodium (7.42 ±0.42 mmol/L) was higher in HSTs (p<0.0001) than that in Low salt tasters (6.48± 0.23 mmol/L). We conclude that salt sensitivity did not seem to affect response to isotonic exercise.

Support or Funding Information

Self‐funded

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
High resolution ultrasound imaging reveals cardiac and vascular dysfunction in the 3xTG mouse model of Alzheimer's disease.
Authors: Hoxha Brikena , Talley Nicholas , Anderson Miranda , Alkhouli Mustafa , Squire Michaela , Esfandiarei Mitra , Broderick Tom L.
Published: June 2021

Alzheimer's disease (AD) is a devastating neurodegenerative disease. Recent clinical studies have demonstrated that patients with AD exhibit compromised cardiac function. In this study, we investigated whether the 3x‐Tg mouse model of AD also presents with cardiovascular dysfunction. This model develops age‐related neuropathology including plaques and tangles, synaptic dysfunction, and amyloid‐beta deposits by six months. In vivo cardiovascular function, determined by echocardiography, was performed in seven‐month‐old male 3xTg mice (n=7) and age‐matched controls (n=8) under isoflurane‐induced anesthesia. While body weight was lower in AD mice compared to control mice, no differences in heart weight were observed between groups. There were no differences in aortic structure, expressed as aortic annulus, sinus of Valsalva, and sinotubular junction between groups. Ventricular dimensions, measured as interventricular septal end diastole and end systole, were also similar between groups. However, ejection fraction was lower in AD mice, whereas early (A) and late (E) atrial ventricular filling velocities, the E/A ratio, and mitral valve deceleration time were increased compared to control mice. In AD mice, pulse wave velocity was increased, which is indicative of increased stiffness and reduced elasticity of the aorta. We observed a significant increase in elastin fiber fragmentation within the media of the aorta, which was associated with overall decreased elastin content and fiber length. Aorta from AD mice also exhibited pronounced medial and adventitial wall thicknesses compared to control mice. Our results provide novel information on structural and functional properties of the heart and aorta in the 3x‐Tg mouse model of AD.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Central Nucleus of the Amygdala Mediates Sympathoinhibitory Responses to Activation of Paraventricular Nucleus of the Thalamus
Authors: Puigbonet Maria E. , Li Zhouhui , Ciriello John
Published: June 2021

The paraventricular nucleus of the thalamus (PVT) is known to relay sensory information from the brainstem, and information from limbic and cortical structures involved in visceral and homeostatic regulation, and affective behaviors. In turn, PVT relays this information to a number of forebrain structures, including the amygdala. However, whether PVT is involved in mediating cardiovascular information to other central sites is not clear. This study was done to investigate whether the cardiovascular responses elicited by PVT involved a pathway that included the central nucleus of the amygdala (ACe). In the first series of experiments, a systematic mapping of PVT was done to identify cardiovascular responsive sites using microinjection of glutamate (Glu; 10 nL, 0.25 M) in chloralose anesthetized Wistar rats. Glu injections into PVT elicited decreases in systemic mean arterial pressure (MAP, −20 ± 3 mmHg) and heart rate (HR; −15 ± 5 bpm). These depressor responses were mediated through sympathoinhibition as intravenous injections of the ganglionic blocker hexamethonium bromide prevented the responses. In the second series, iontophoretic injections of the anterograde tract tracer PHA‐L were made at PVT depressor sites in the Wistar rats. Dense PHA‐L fiber and presumptive terminal labeling was found within and around the region of the lateral ACe, while light to moderate labeling was observed within the medial ACe. Additionally, extensive labeling was observed throughout the extended amygdala, including the bed nucleus of the stria terminalis. In the final series, bilateral microinjection (100 nL) of either the synaptic blocker CoCl2, the non‐specific glutamate antagonist kynurenic acid or the specific NMDA receptor antagonists 2‐amino‐5‐phosphonovalerate or MK801 were made into ACe in the chloralose anesthetized Wistar rats. Injections of these compounds did not significantly alter the resting levels of arterial pressure (AP) or HR, but significantly attenuated (p<0.01) the MAP response (mean of all injected compounds; −7 ± 5 mmHg) to activation of PVT. On the other hand, these injections into ACe did not alter the HR response (mean of all injected compounds; −12 ± 3 bpm) to PVT stimulation. These data suggest that PVT may function as a relay of sensory information that affects AP responses associated with motivated and addictive behaviors, arousal and/or stress through a sympathoinhibitory neural circuit involving ACe.

Support or Funding Information

Supported in part by Heart and Stroke Foundation of Ontario.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Kidney‐Specific COP9 Signalosome (CSN) Deletion Mimics FHHt Effects on WNK/NCC Signaling
Authors: Cornelius Ryan J. , Yang Chao‐Ling , Ellison David H.
Published: June 2021

The Familial Hyperkalemic Hypertension (FHHt) cullin 3 (CUL3) mutant is unable to degrade WNK kinases normally, activating the thiazide‐sensitive NaCl cotransporter (NCC). Previous in vitro work showed that the CUL3 mutant has enhanced neddylation and does not bind to the COP9 signalosome (CSN), a deneddylase involved in regulating cullin‐RING ligases. We sought to determine whether this impaired binding was the cause of the increased WNK protein abundance in FHHt by inhibiting the CSN in vivo. The Pax8 mouse system was used to generate mice in which the catalytically active CSN subunit, JAB1, was deleted only along the nephron, after full development (KS‐Jab1−/−). JAB1 protein abundance was 62% lower in KS‐Jab1−/− kidney vs control. Western blot analysis demonstrated that loss of JAB1 caused enhanced neddylation of CUL3. Moreover, total CUL3 abundance was reduced by 37%, indicating decreased CUL3 stability, which is consistent with results reported by other groups for the FHHt CUL3 mutant. As expected, KLHL3 protein abundance was lower and total WNK1 and WNK4 protein abundance were higher. Phosphorylated WNK4 levels and the ratio of pNCC to total NCC were also higher, but, surprisingly, total NCC protein abundance was dramatically reduced. Consistent with the low total NCC, KS‐Jab1−/− mice did not develop an FHHt phenotype. Blood pressure was not significantly different between the two groups. KS‐Jab1−/− mice had lower plasma [K+] (3.20 ± 0.07 vs 3.55 ± 0.06 mM, P < 0.01), lower plasma bicarbonate ([TCO2]: 11.83 ± 0.87 vs 18.00 ± 0.57 mM, P < 0.001), and higher plasma [Cl−] (117.5 ± 1.7 vs 112.7 ± 1.3 mM; P < 0.05) compared to control mice. Urine output was approximately twice as high in KS‐Jab1−/− mice (9.4 ± 1.6 vs 4.7 ± 0.50 ml/day, P < 0.05), and there was Na+ and K+ wasting (Na+ clearance: 0.135 ± 0.013 vs 0.088 ± 0.006 ml/day/g, P < 0.01; K+ clearance: 4.90 ± 0.40 vs 3.68 ± 0.28 ml/day/g, P < 0.05). As we reported with CUL3 deletion, chronic JAB1 deletion also led to kidney tubule damage, as determined by H&E staining. In conclusion, KS‐Jab1−/− mice resemble many aspects of the FHHt CUL3 mutant, including changes in KLHL3 and WNK abundance, and increased phosphorylation of WNK and NCC; however, due to decreased levels of total NCC, the mice do not mimic all aspects of the FHHt phenotype.

Support or Funding Information

NIH R01 DK51496, NIH T32 DK067864, VA 1I01BX002228‐01A1, AHA 16POST3064003, NIH F32 DK112531

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.