scholarly journals Brain endothelial cell TRPA1 channels initiate neurovascular coupling

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Pratish Thakore ◽  
Michael G Alvarado ◽  
Sher Ali ◽  
Amreen Mughal ◽  
Paulo W Pires ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Neuronal Activity ◽  
Neurovascular Coupling ◽  
Functional Hyperemia ◽  
Metabolic Demand ◽  
Mural Cell ◽  
Capillary Endothelial Cells ◽  
Activity Sensors ◽  
Retrograde Signal

Cerebral blood flow is dynamically regulated by neurovascular coupling to meet the dynamic metabolic demands of the brain. We hypothesized that TRPA1 channels in capillary endothelial cells are stimulated by neuronal activity and instigate a propagating retrograde signal that dilates upstream parenchymal arterioles to initiate functional hyperemia. We find that activation of TRPA1 in capillary beds and post-arteriole transitional segments with mural cell coverage initiates retrograde signals that dilate upstream arterioles. These signals exhibit a unique mode of biphasic propagation. Slow, short-range intercellular Ca2+ signals in the capillary network are converted to rapid electrical signals in transitional segments that propagate to and dilate upstream arterioles. We further demonstrate that TRPA1 is necessary for functional hyperemia and neurovascular coupling within the somatosensory cortex of mice in vivo. These data establish endothelial cell TRPA1 channels as neuronal activity sensors that initiate microvascular vasodilatory responses to redirect blood to regions of metabolic demand.

scholarly journals Brain Endothelial Cell TRPA1 Channels Initiate Neurovascular Coupling

2020 ◽  
Author(s):  
Pratish Thakore ◽  
Michael G. Alvarado ◽  
Sher Ali ◽  
Amreen Mughal ◽  
Paulo W. Pires ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Neuronal Activity ◽  
Transient Receptor Potential ◽  
Neurovascular Coupling ◽  
Laser Scanning Microscopy ◽  
K Channel ◽  
Transitional Region ◽  
Capillary Endothelial Cells ◽  
The Brain

Blood flow regulation in the brain is dynamically regulated to meet the metabolic demands of active neuronal populations. Recent evidence has demonstrated that capillary endothelial cells are essential mediators of neurovascular coupling that sense neuronal activity and generate a retrograde, propagating, hyperpolarizing signal that dilates upstream arterioles. Here, we tested the hypothesis that transient receptor potential ankyrin 1 (TRPA1) channels in capillary endothelial cells are significant contributors to functional hyperemic responses that underlie neurovascular coupling in the brain. Using an integrative ex vivo and in vivo approach, we demonstrate the functional presence of TRPA1 channels in brain capillary endothelial cells, and show that activation of these channels within the capillary bed, including the post-arteriole transitional region covered by ensheathing mural cells, initiates a retrograde signal that dilates upstream parenchymal arterioles. Notably, this signaling exhibits a unique biphasic mode of propagation that begins within the capillary network as a short-range, Ca2+ signal dependent on endothelial pannexin-1 channel/purinergic P2X receptor communication pathway and then is converted to a rapid, inward-rectifying K+ channel-mediated electrical signal in the post-arteriole transitional region that propagates upstream to parenchymal arterioles. Two-photon laser-scanning microscopy further demonstrated that conductive vasodilation occurs in vivo, and that TRPA1 is necessary for functional hyperemia within the somatosensory cortex of mice. Together, these data establish a role for endothelial TRPA1 channels as sensors of neuronal activity and show that they respond accordingly by initiating a vasodilatory response that redirects blood to regions of metabolic demand.

Regulation of blood flow in diabetic retinopathy

2020 ◽  
Vol 37 ◽  
Author(s):  
Amy R. Nippert ◽  
Eric A. Newman
Keyword(s):  
Blood Flow ◽  
Diabetic Retinopathy ◽  
Neuronal Activity ◽  
Neurovascular Coupling ◽  
Functional Hyperemia ◽  
Retinal Neurons ◽  
Adequate Supply ◽  
Oxygen Levels ◽  
Signaling Mechanisms ◽  
Diabetic Brain

Abstract Blood flow in the retina increases in response to light-evoked neuronal activity, ensuring that retinal neurons receive an adequate supply of oxygen and nutrients as metabolic demands vary. This response, termed “functional hyperemia,” is disrupted in diabetic retinopathy. The reduction in functional hyperemia may result in retinal hypoxia and contribute to the development of retinopathy. This review will discuss the neurovascular coupling signaling mechanisms that generate the functional hyperemia response in the retina, the changes to neurovascular coupling that occur in diabetic retinopathy, possible treatments for restoring functional hyperemia and retinal oxygen levels, and changes to functional hyperemia that occur in the diabetic brain.

scholarly journals Purinergic glio-endothelial coupling during neuronal activity: role of P2Y1 receptors and eNOS in functional hyperemia in the mouse somatosensory cortex

2015 ◽  
Vol 309 (11) ◽  
pp. H1837-H1845 ◽  
Author(s):  
Peter Toth ◽  
Stefano Tarantini ◽  
Antonio Davila ◽  
M. Noa Valcarcel-Ares ◽  
Zsuzsanna Tucsek ◽  
...  
Keyword(s):  
Somatosensory Cortex ◽  
Neuronal Activity ◽  
Critical Role ◽  
Neurovascular Coupling ◽  
No Synthase ◽  
Functional Hyperemia ◽  
Inhibitory Effects ◽  
Pathological Conditions ◽  
Whisker Stimulation

Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of cognitive impairment associated with aging and pathological conditions associated with accelerated cerebromicrovascular aging (e.g., hypertension, obesity). Although previous studies demonstrate that endothelial dysfunction plays a critical role in neurovascular uncoupling in these conditions, the role of endothelial NO mediation in neurovascular coupling responses is not well understood. To establish the link between endothelial function and functional hyperemia, neurovascular coupling responses were studied in mutant mice overexpressing or deficient in endothelial NO synthase (eNOS), and the role of P2Y1 receptors in purinergic glioendothelial coupling was assessed. We found that genetic depletion of eNOS (eNOS−/−) and pharmacological inhibition of NO synthesis significantly decreased the CBF responses in the somatosensory cortex evoked by whisker stimulation and by administration of ATP. Overexpression of eNOS enhanced NO mediation of functional hyperemia. In control mice, the selective and potent P2Y1 receptor antagonist MRS2179 attenuated both whisker stimulation-induced and ATP-mediated CBF responses, whereas, in eNOS−/− mice, the inhibitory effects of MRS2179 were blunted. Collectively, our findings provide additional evidence for purinergic glio-endothelial coupling during neuronal activity, highlighting the role of ATP-mediated activation of eNOS via P2Y1 receptors in functional hyperemia.

scholarly journals Increased 20-HETE signaling suppresses neurovascular coupling after ischemic stroke in regions beyond the infarct

2021 ◽  
Author(s):  
Zhenzhou Li ◽  
Heather L McConnell ◽  
Teresa L Stackhouse ◽  
Martin M Pike ◽  
Wenri Zhang ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Neurovascular Coupling ◽  
Brain Regions ◽  
Artery Occlusion ◽  
Stroke Patients ◽  
Natural Inhibitor ◽  
Cerebral Artery Occlusion ◽  
Infarct Border ◽  
Capillary Dilation

Neurovascular coupling, the process by which neuronal activity elicits increases in the local blood supply, is impaired in stroke patients in brain regions outside the infarct. Such impairment may contribute to neurological deterioration over time, but its mechanism is unknown. Using the middle cerebral artery occlusion (MCAO) model of stroke, we show that neuronal activity-evoked capillary dilation is reduced by ~75% in the intact cortical tissue outside the infarct border. This decrease in capillary responsiveness was not explained by a decrease in local neuronal activity or a loss of vascular contractility. Inhibiting synthesis of the vasoconstrictive molecule 20-HETE, either by inhibiting its synthetic enzyme CYP450 ω-hydroxylases or by increasing nitric oxide (NO), which is a natural inhibitor of ω-hydroxylases, rescued activity-evoked capillary dilation. The capillary dilation unmasked by inhibiting 20-HETE was dependent on PGE2 activation of EP4 receptors, a vasodilatory pathway previously identified in healthy animals. Cortical 20-HETE levels were increased following MCAO, in agreement with data from stroke patients. Inhibition of ω-hydroxylases normalized 20-HETE levels in vivo and increased cerebral blood flow in the peri-infarct cortex. These data identify 20-HETE-dependent vasoconstriction as a mechanism underlying neurovascular coupling impairment after stroke. Our results suggest that the brain's energy supply may be significantly reduced after stroke in regions previously believed to be asymptomatic and that ω-hydroxylase inhibition may restore healthy neurovascular coupling post-stroke.

scholarly journals Differential contribution of excitatory and inhibitory neurons in shaping neurovascular coupling in different epileptic neural states

2020 ◽  
pp. 0271678X2093407
Author(s):  
Hyun-Kyoung Lim ◽  
Nayeon You ◽  
Sungjun Bae ◽  
Bok-Man Kang ◽  
Young-Min Shon ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Field Potential ◽  
Neurovascular Coupling ◽  
Vessel Diameter ◽  
Functional Brain Imaging ◽  
Activity Level ◽  
Inhibitory Neurons ◽  
Activity Levels ◽  
Ictal Activity

Understanding the neurovascular coupling (NVC) underlying hemodynamic changes in epilepsy is crucial to properly interpreting functional brain imaging signals associated with epileptic events. However, how excitatory and inhibitory neurons affect vascular responses in different epileptic states remains unknown. We conducted real-time in vivo measurements of cerebral blood flow (CBF), vessel diameter, and excitatory and inhibitory neuronal calcium signals during recurrent focal seizures. During preictal states, decreases in CBF and arteriole diameter were closely related to decreased γ-band local field potential (LFP) power, which was linked to relatively elevated excitatory and reduced inhibitory neuronal activity levels. Notably, this preictal condition was followed by a strengthened ictal event. In particular, the preictal inhibitory activity level was positively correlated with coherent oscillating activity specific to inhibitory neurons. In contrast, ictal states were characterized by elevated synchrony in excitatory neurons. Given these findings, we suggest that excitatory and inhibitory neurons differentially contribute to shaping the ictal and preictal neural states, respectively. Moreover, the preictal vascular activity, alongside with the γ-band, may reflect the relative levels of excitatory and inhibitory neuronal activity, and upcoming ictal activity. Our findings provide useful insights into how perfusion signals of different epileptic states are related in terms of NVC.

Intracellular diaphragmed fenestrae in cultured capillary endothelial cells

1988 ◽  
Vol 89 (3) ◽  
pp. 441-447 ◽  
Author(s):  
R. Montesano ◽  
L. Orci
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Three Dimensional ◽  
Collagen Matrix ◽  
Cell Cytoplasm ◽  
Experimental Conditions ◽  
Intracellular Location ◽  
Capillary Endothelial Cells

The endothelium of visceral capillaries is characterized by the occurrence of numerous fenestrae, which are usually bridged by a thin, single-layered diaphragm. Both in vivo and in vitro, diaphragmed fenestrae perforate the endothelial cell cytoplasm in the most attenuated regions of the cell. We report here that in capillary endothelial cells grown under experimental conditions promoting the development of intracellular lumina (for example, suspension within a three-dimensional collagen matrix), diaphragmed fenestrae can form in a unique, previously undescribed intracellular location - that is, within thin cytoplasmic septa separating contiguous luminal compartments.

scholarly journals Glioma-induced alterations in neuronal activity and neurovascular coupling during disease progression

2019 ◽  
Author(s):  
Mary Katherine Montgomery ◽  
Sharon H. Kim ◽  
Athanassios Dovas ◽  
Kripa Patel ◽  
Angeliki Mela ◽  
...  
Keyword(s):  
Disease Progression ◽  
Neuronal Activity ◽  
Tumor Development ◽  
Neurovascular Coupling ◽  
High Amplitude ◽  
Wide Field ◽  
List Type ◽  
Cortical Function ◽  
Glioma Progression

AbstractDiffusely infiltrating gliomas are known to cause alterations in cortical function, vascular disruption and seizures. These neurological complications present major clinical challenges, yet their underlying mechanisms and causal relationships to disease progression are poorly characterized. Here, we followed glioma progression in awake Thy1-GCaMP6f mice using in-vivo wide-field optical mapping to monitor alterations in both neuronal activity and functional hemodynamics. The bilateral synchrony of spontaneous neuronal activity in glioma-infiltrated cortex gradually decreased, while neurovascular coupling was also progressively disrupted compared to uninvolved cortex. Over time, mice developed diverse patterns of high amplitude discharges and eventually generalized seizures that begin at the infiltrative margin of the tumors. Interictal and seizure events exhibited positive neurovascular coupling in uninfiltrated cortex, however glioma-infiltrated regions exhibited inverted hemodynamic responses driving seizure-evoked hypoxia. These results reveal a landscape of complex physiological interactions occurring during glioma progression and present new opportunities for exploring new biomarkers and therapeutic targets.Highlights-Glioma disrupts neural synchrony between bilateral cortical regions.-WFOM reveals frequent interictal discharges and seizures during glioma progression.-Tumor development is accompanied by local changes in neurovascular coupling.-Altered neurovascular coupling drives hypoperfusion of the tumor during seizures.

scholarly journals Inversion of neurovascular coupling after subarachnoid hemorrhage in vivo

2017 ◽  
Vol 37 (11) ◽  
pp. 3625-3634 ◽  
Author(s):  
Matilde Balbi ◽  
Masayo Koide ◽  
George C Wellman ◽  
Nikolaus Plesnila
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Subarachnoid Hemorrhage ◽  
Neuronal Activity ◽  
Ex Vivo ◽  
Brain Slices ◽  
Neurovascular Coupling ◽  
Vessel Diameter ◽  
Cerebral Arterioles

Subarachnoid hemorrhage (SAH) induces acute changes in the cerebral microcirculation. Recent findings ex vivo suggest neurovascular coupling (NVC), the process that increases cerebral blood flow upon neuronal activity, is also impaired after SAH. The aim of the current study was to investigate whether this occurs also in vivo. C57BL/6 mice were subjected to either sham surgery or SAH by filament perforation. Twenty-four hours later NVC was tested by forepaw stimulation and CO2 reactivity by inhalation of 10% CO2. Vessel diameter was assessed in vivo by two-photon microscopy. NVC was also investigated ex vivo using brain slices. Cerebral arterioles of sham-operated mice dilated to 130% of baseline upon CO2 inhalation or forepaw stimulation and cerebral blood flow (CBF) increased. Following SAH, however, CO2 reactivity was completely lost and the majority of cerebral arterioles showed paradoxical constriction in vivo and ex vivo resulting in a reduced CBF response. As previous results showed intact NVC 3 h after SAH, the current findings indicate that impairment of NVC after cerebral hemorrhage occurs secondarily and is progressive. Since neuronal activity-induced vasoconstriction (inverse NVC) is likely to further aggravate SAH-induced cerebral ischemia and subsequent brain damage, inverse NVC may represent a novel therapeutic target after SAH.

scholarly journals Increased 20-HETE Signaling Suppresses Capillary Neurovascular Coupling After Ischemic Stroke in Regions Beyond the Infarct

2021 ◽  
Vol 15 ◽  
Author(s):  
Zhenzhou Li ◽  
Heather L. McConnell ◽  
Teresa L. Stackhouse ◽  
Martin M. Pike ◽  
Wenri Zhang ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Neurovascular Coupling ◽  
Brain Regions ◽  
Artery Occlusion ◽  
Stroke Patients ◽  
Natural Inhibitor ◽  
Cerebral Artery Occlusion ◽  
Infarct Border ◽  
Capillary Dilation

Neurovascular coupling, the process by which neuronal activity elicits increases in the local blood supply, is impaired in stroke patients in brain regions outside the infarct. Such impairment may contribute to neurological deterioration over time, but its mechanism is unknown. Using the middle cerebral artery occlusion (MCAO) model of stroke, we show that neuronal activity-evoked capillary dilation is reduced by ∼75% in the intact cortical tissue outside the infarct border. This decrease in capillary responsiveness was not explained by a decrease in local neuronal activity or a loss of vascular contractility. Inhibiting synthesis of the vasoconstrictive molecule 20-hydroxyeicosatetraenoic acid (20-HETE), either by inhibiting its synthetic enzyme CYP450 ω-hydroxylases or by increasing nitric oxide (NO), which is a natural inhibitor of ω-hydroxylases, rescued activity-evoked capillary dilation. The capillary dilation unmasked by inhibiting 20-HETE was dependent on PGE2 activation of endoperoxide 4 (EP4) receptors, a vasodilatory pathway previously identified in healthy animals. Cortical 20-HETE levels were increased following MCAO, in agreement with data from stroke patients. Inhibition of ω-hydroxylases normalized 20-HETE levels in vivo and increased cerebral blood flow in the peri-infarct cortex. These data identify 20-HETE-dependent vasoconstriction as a mechanism underlying capillary neurovascular coupling impairment after stroke. Our results suggest that the brain’s energy supply may be significantly reduced after stroke in regions previously believed to be asymptomatic and that ω-hydroxylase inhibition may restore healthy neurovascular coupling post-stroke.

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