scholarly journals Electro-Metabolic Sensing Through Capillary ATP-Sensitive K+ Channels and Adenosine to Control Cerebral Blood Flow

2021 ◽  
Author(s):  
Maria Sancho ◽  
Nicholas R. Klug ◽  
Amreen Mughal ◽  
Thomas J. Heppner ◽  
David Hill-Eubanks ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Vascular Function ◽  
Brain Activity ◽  
List Type ◽  
Capillary Endothelial Cells ◽  
Metabolic Sensing ◽  
Cellular Components

SUMMARYThe dense network of capillaries composed of capillary endothelial cells (cECs) and pericytes lies in close proximity to all neurons, ideally positioning it to sense neuro/glial-derived compounds that regulate regional and global cerebral perfusion. The membrane potential (VM) of vascular cells serves as the essential output in this scenario, linking brain activity to vascular function. The ATP-sensitive K+ channel (KATP) is a key regulator of vascular VM in other beds, but whether brain capillaries possess functional KATP channels remains unknown. Here, we demonstrate that brain capillary ECs and pericytes express KATP channels that robustly control VM. We further show that the endogenous mediator adenosine acts through A2A receptors and the Gs/cAMP/PKA pathway to activate capillary KATP channels. Moreover, KATP channel stimulation in vivo causes vasodilation and increases cerebral blood flow (CBF). These findings establish the presence of KATP channels in cECs and pericytes and suggest their significant influence on CBF.HIGHLIGHTSCapillary network cellular components—endothelial cells and pericytes—possess functional KATP channels.Activation of KATP channels causes profound hyperpolarization of capillary cell membranes.Capillary KATP channels are activated by exogenous adenosine via A2A receptors and cAMP-dependent protein kinase.KATP channel activation by adenosine or synthetic openers increases cerebral blood flow.

Abstract 14820: Sirt7 Deficiency in Blood Vessel Components Impairs Vascular Function by Inhibiting Cell Cycle- and Inflammatory-Related Protein Expression

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Yuichi Kimura ◽  
Yasuhiro Izumiya ◽  
Satoshi Araki ◽  
Satoru Yamamura ◽  
Yoshiro Onoue ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Blood Flow ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Vascular Diseases ◽  
Tube Formation ◽  
Hindlimb Ischemia ◽  
Proliferation Assay

Introduction: Aging is a well-established cardiovascular risk factor and associated with vascular dysfunction. Sirt7, one of the members of mammalian sirtuin family, is thought to be involved in age-related diseases. However, little is known about the relative contribution of Sirt7 in vascular dysfunction. Hypothesis: Sirt7 maintains vascular cell functions and its deficiency plays a critical role in vascular diseases. Methods: Sirt7 loss- and gain-of-function experiments were performed with human aortic smooth muscle cells (HAoSMCs) and human umbilical vein endothelial cells (HUVECs). In vivo, blood flow recovery was evaluated by hindlimb ischemia model in homozygous Sirt7 deficient (Sirt7-/-) and wild-type (WT) mice. Irradiated WT mice were intravenously received bone marrow (BM) cells from WT or Sirt7 -/- mouse to achieve BM transfer. Results: An RNAi-medicated Sirt7 knockdown resulted in a significant inhibition of HAoSMCs proliferation following serum or Platelet-derived growth factor BB (PDGF-BB) stimulation as determined by cell count, BrdU cell proliferation assay and MTS proliferation assay. Knockdown of endogenous Sirt7 also reduced cell migration as revealed by Boyden chamber migration assay. The Cyclin D1 and Cyclin dependent kinase 2 (CDK2) protein levels were significantly decreased in Sirt7 siRNA-treated HAoSMCs in response to serum or PDGF-BB stimulation. In endothelial cells, knockdown of Sirt7 attenuated tube formation, proliferation and migration. These changes were accompanied by reduced ERK activation and VCAM-1 mRNA and protein expression in Sirt7 siRNA-treated HUVECs. Conversely, overexpression of Sirt7 by adenovirus enhanced tube formation and cell proliferation. In vivo, blood flow recovery in response to hindlimb ischemia was significantly attenuated in Sirt7-/- mice compared with WT mice. There was no difference in blood flow recovery between WT mice transplanted with WT or Sirt7-/- BM cells suggesting that Sirt7 deficiency in vascular cells have a predominant effect on attenuated blood flow recovery in response to hindlimb ischemia. Conclusions: Sirt7 in blood vessel components have an important role in maintenance of vascular function. Sirt7 could be a promising therapeutic target for vascular diseases.

Dietary nitrate facilitates an acetazolamide-induced increase in cerebral blood flow during visual stimulation

2014 ◽  
Vol 116 (3) ◽  
pp. 267-273 ◽  
Author(s):  
Rasmus Aamand ◽  
Yi-Ching Lynn Ho ◽  
Thomas Dalsgaard ◽  
Andreas Roepstorff ◽  
Torben E. Lund
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Dietary Intake ◽  
Vascular Function ◽  
Visual Stimulation ◽  
No Production ◽  
Positive Interaction ◽  
Healthy Human ◽  
Cerebrovascular System

The carbonic anhydrase (CA) inhibitor acetazolamide (AZ) is used routinely to estimate cerebrovascular reserve capacity in patients, as it reliably increases cerebral blood flow (CBF). However, the mechanism by which AZ accomplishes this CBF increase is not entirely understood. We recently discovered that CA can produce nitric oxide (NO) from nitrite, and that AZ enhances this NO production in vitro. In fact, this interaction between AZ and CA accounted for a large part of AZ's vasodilatory action, which fits well with the known vasodilatory potency of NO. The present study aimed to assess whether AZ acts similarly in vivo in the human cerebrovascular system. Hence, we increased or minimized the dietary intake of nitrate in 20 healthy male participants, showed them a full-field flickering dartboard, and measured their CBF response to this visual stimulus with arterial spin labeling. Doing so, we found a significant positive interaction between the dietary intake of nitrate and the CBF modulation afforded by AZ during visual stimulation. In addition, but contrary to studies conducted in elderly participants, we report no effect of nitrate intake on resting CBF in healthy human participants. The present study provides in vivo support for an enhancing effect of AZ on the NO production from nitrite catalyzed by CA in the cerebrovascular system. Furthermore, our results, in combination with the results of other groups, indicate that nitrate may have significant importance to vascular function when the cerebrovascular system is challenged by age or disease.

scholarly journals Circulating tPA contributes to neurovascular coupling by a mechanism involving the endothelial NMDA receptors

2019 ◽  
Vol 40 (10) ◽  
pp. 2038-2054 ◽  
Author(s):  
Antoine Anfray ◽  
Antoine Drieu ◽  
Vincent Hingot ◽  
Yannick Hommet ◽  
Mervé Yetim ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Neurovascular Unit ◽  
Neurovascular Coupling ◽  
Laser Speckle ◽  
Tissue Type ◽  
Blood Flow Increase ◽  
The Brain

The increase of cerebral blood flow evoked by neuronal activity is essential to ensure enough energy supply to the brain. In the neurovascular unit, endothelial cells are ideally placed to regulate key neurovascular functions of the brain. Nevertheless, some outstanding questions remain about their exact role neurovascular coupling (NVC). Here, we postulated that the tissue-type plasminogen activator (tPA) present in the circulation might contribute to NVC by a mechanism dependent of its interaction with endothelial N-Methyl-D-Aspartate Receptor (NMDAR). To address this question, we used pharmacological and genetic approaches to interfere with vascular tPA-dependent NMDAR signaling, combined with laser speckle flowmetry, intravital microscopy and ultrafast functional ultrasound in vivo imaging. We found that the tPA present in the blood circulation is capable of potentiating the cerebral blood flow increase induced by the activation of the mouse somatosensorial cortex, and that this effect is mediated by a tPA-dependent activation of NMDAR expressed at the luminal part of endothelial cells of arteries. Although blood molecules, such as acetylcholine, bradykinin or ATP are known to regulate vascular tone and induce vessel dilation, our present data provide the first evidence that circulating tPA is capable of influencing neurovascular coupling (NVC).

Effect of caffeine on theophyliine on cerebral blood flow response to brain activation: In vitro and in vivo studies

2005 ◽  
Vol 25 (1_suppl) ◽  
pp. S198-S198
Author(s):  
Joseph R Meno ◽  
Thien-son K Nguyen ◽  
Elise M Jensen ◽  
G Alexander West ◽  
Leonid Groysman ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Brain Activation ◽  
In Vivo Studies ◽  
Blood Flow Response ◽  
Flow Response

Abstract WP498: Impaired Pericyte Constriction and Cerebral Blood Flow Autoregulationin Diabetes

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Yedan Liu ◽  
Shaoxun Wang ◽  
Ya Guo ◽  
Huawei Zhang ◽  
Richard Roman ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Ex Vivo ◽  
Mitochondrial Dynamics ◽  
Vascular Cognitive Impairment ◽  
Treated Group ◽  
Diabetic Rats ◽  
Cerebrovascular Function

Diabetes is the primary pathological factor attributed to Alzheimer’s disease and vascular cognitive impairment. Previous studies demonstrated that hyperglycemia promoted oxidative stress in the cerebral vasculature. Cerebrovascular pericytes contribute to maintaining blood-brain barrier (BBB) integrity and regulating cerebral blood flow (CBF). However, whether hyperglycemia diminishes the contractile capability of pericytes, impairs CBF autoregulation and increases BBB permeability are unclear. In the present study, we examined the role of pericytes in cerebrovascular function and cognition in diabetes using cell culture in vitro , isolated penetrating arterioles ex vivo and CBF autoregulation in vivo . Reactive oxygen species were elevated in high glucose (HG, 30 mM) treated vs. normal glucose (NG, 5.5 mM) treated pericytes. Further, mitochondrial superoxide production was increased in HG-treated vs. NG-treated group (13.24 ± 1.01 arbitrary unit (a.u.)/30min vs. 6.98 ± 0.36 a.u./30min). Mitochondrial respiration decreased in HG-treated vs. NG-treated pericytes (3718 ± 185.9 pmol/min/mg, n=10 vs. 4742 ± 284.5 pmol/min/mg, n=10) as measured by a Seahorse XFe24 analyzer. HG-treated pericytes displayed fragmented mitochondria in association with increased fission protein (DRP1) and decreased fusion protein (OPA1) expression. HG-treated pericytes displayed lower contractile capability than NG-treated cells (20.23 ± 7.15% vs. 29.46 ± 9.41%). The myogenic response was impaired in penetrating arterioles isolated from diabetic rats in comparison with non-diabetic rats. Autoregulation of CBF measured by a laser Doppler flowmeter was impaired in diabetic rats compared with non-diabetic rats. Diabetic rats exhibited greater BBB leakage than control rats. The cognitive function was examined using an eight-arm water maze. Diabetic rats took longer time to escape than the non-diabetic rats indicating learning and memory deficits. In conclusion, hyperglycemia induces pericyte dysfunction by altering mitochondrial dynamics and diminishing contractile capability, which promotes BBB leakage, decreases CBF autoregulation and contributes to diabetes-related dementia.

scholarly journals Effects of aging and exercise training on spinotrapezius muscle microvascular Po2 dynamics and vasomotor control

2011 ◽  
Vol 110 (3) ◽  
pp. 695-704 ◽  
Author(s):  
Danielle J. McCullough ◽  
Robert T. Davis ◽  
James M. Dominguez ◽  
John N. Stabley ◽  
Christian S. Bruells ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Exercise Training ◽  
Sodium Nitroprusside ◽  
Vascular Function ◽  
Treadmill Running ◽  
Aged Rats ◽  
Phosphorescence Quenching

With advancing age, there is a reduction in exercise tolerance, resulting, in part, from a perturbed ability to match O2 delivery to uptake within skeletal muscle. In the spinotrapezius muscle (which is not recruited during incline treadmill running) of aged rats, we tested the hypotheses that exercise training will 1) improve the matching of O2 delivery to O2 uptake, evidenced through improved microvascular Po2 (PmO2), at rest and throughout the contractions transient; and 2) enhance endothelium-dependent vasodilation in first-order arterioles. Young (Y, ∼6 mo) and aged (O, >24 mo) Fischer 344 rats were assigned to control sedentary (YSED; n = 16, and OSED; n = 15) or exercise-trained (YET; n = 14, and OET; n = 13) groups. Spinotrapezius blood flow (via radiolabeled microspheres) was measured at rest and during exercise. Phosphorescence quenching was used to quantify PmO2 in vivo at rest and across the rest-to-twitch contraction (1 Hz, 5 min) transition in the spinotrapezius muscle. In a follow-up study, vasomotor responses to endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) stimuli were investigated in vitro. Blood flow to the spinotrapezius did not increase above resting values during exercise in either young or aged groups. Exercise training increased the precontraction baseline PmO2 (OET 37.5 ± 3.9 vs. OSED 24.7 ± 3.6 Torr, P < 0.05); the end-contracting PmO2 and the time-delay before PmO2 fell in the aged group but did not affect these values in the young. Exercise training improved maximal vasodilation in aged rats to acetylcholine (OET 62 ± 16 vs. OSED 27 ± 16%) and to sodium nitroprusside in both young and aged rats. Endurance training of aged rats enhances the PmO2 in a nonrecruited skeletal muscle and is associated with improved vascular smooth muscle function. These data support the notion that improvements in vascular function with exercise training are not isolated to the recruited muscle.

scholarly journals In vitro and in vivo evaluation of hypothermia on pharmacokinetics and pharmacodynamics of nimodipine in rabbits

2017 ◽  
Vol 46 (1) ◽  
pp. 335-347 ◽  
Author(s):  
Yu-xing Fei ◽  
Tian-hong Zhang ◽  
Jing Zhao ◽  
He Ren ◽  
Ya-nan Du ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Protein Binding ◽  
Plasma Concentrations ◽  
Liver Microsomes ◽  
Intrinsic Clearance ◽  
Pharmacokinetics And Pharmacodynamics ◽  
In Vivo Evaluation

Objective To investigate the effect of hypothermia on the pharmacokinetics and pharmacodynamics of nimodipine in rabbits using in vivo and in vitro methods. Methods Five healthy New Zealand rabbits received a single dose of nimodipine (0.5 mg/kg) intravenously under normothermic and hypothermic conditions. Doppler ultrasound was used to monitor cerebral blood flow, vascular resistance, and heart rate. In vitro evaluations of protein binding, hepatocyte uptake and intrinsic clearance of liver microsomes at different temperatures were also conducted. Results Plasma concentrations of nimodipine were significantly higher in hypothermia than in normothermia. Nimodipine improved cerebral blood flow under both conditions, but had a longer effective duration during the hypothermic period. Low temperature decreased the intrinsic clearance of liver microsomes, with no change in protein binding or hepatocyte uptake of nimodipine. Conclusion Nimodipine is eliminated at a slower rate during hypothermia than during normothermia, mainly due to the decreased activity of cytochrome P450 enzymes. This results in elevated system exposure with little enhancement in pharmacological effect.

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