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 Retinal Neurovascular Coupling in Diabetes

2020 ◽  
Vol 9 (9) ◽  
pp. 2829 ◽  
Author(s):  
Gerhard Garhöfer ◽  
Jacqueline Chua ◽  
Bingyao Tan ◽  
Damon Wong ◽  
Doreen Schmidl ◽  
...  
Keyword(s):  
Blood Flow ◽  
Diabetic Retinopathy ◽  
Molecular Mechanisms ◽  
Visual Stimulation ◽  
Neurovascular Coupling ◽  
Neural Tissue ◽  
Current Evidence ◽  
Compelling Evidence ◽  
Functional Hyperemia ◽  
Patients With Diabetes

Neurovascular coupling, also termed functional hyperemia, is one of the physiological key mechanisms to adjust blood flow in a neural tissue in response to functional activity. In the retina, increased neural activity, such as that induced by visual stimulation, leads to the dilatation of retinal arterioles, which is accompanied by an immediate increase in retinal and optic nerve head blood flow. According to the current scientific view, functional hyperemia ensures the adequate supply of nutrients and metabolites in response to the increased metabolic demand of the neural tissue. Although the molecular mechanisms behind neurovascular coupling are not yet fully elucidated, there is compelling evidence that this regulation is impaired in a wide variety of neurodegenerative and vascular diseases. In particular, it has been shown that the breakdown of the functional hyperemic response is an early event in patients with diabetes. There is compelling evidence that alterations in neurovascular coupling precede visible signs of diabetic retinopathy. Based on these observations, it has been hypothesized that a breakdown of functional hyperemia may contribute to the retinal complications of diabetes such as diabetic retinopathy or macular edema. The present review summarizes the current evidence of impaired neurovascular coupling in patients with diabetes. In this context, the molecular mechanisms of functional hyperemia in health and disease will be covered. Finally, we will also discuss how neurovascular coupling may in future be used to monitor disease progression or risk stratification.

scholarly journals Glial cell regulation of neuronal activity and blood flow in the retina by release of gliotransmitters

2015 ◽  
Vol 370 (1672) ◽  
pp. 20140195 ◽  
Author(s):  
Eric A. Newman
Keyword(s):  
Blood Flow ◽  
Arachidonic Acid ◽  
Glial Cells ◽  
Neuronal Activity ◽  
Neurovascular Coupling ◽  
Müller Cells ◽  
Future Research ◽  
Prostaglandin E ◽  
Sk Channels ◽  
Muller Cells

Astrocytes in the brain release transmitters that actively modulate neuronal excitability and synaptic efficacy. Astrocytes also release vasoactive agents that contribute to neurovascular coupling. As reviewed in this article, Müller cells, the principal retinal glial cells, modulate neuronal activity and blood flow in the retina. Stimulated Müller cells release ATP which, following its conversion to adenosine by ectoenzymes, hyperpolarizes retinal ganglion cells by activation of A1 adenosine receptors. This results in the opening of G protein-coupled inwardly rectifying potassium (GIRK) channels and small conductance Ca 2+ -activated K + (SK) channels. Tonic release of ATP also contributes to the generation of tone in the retinal vasculature by activation of P2X receptors on vascular smooth muscle cells. Vascular tone is lost when glial cells are poisoned with the gliotoxin fluorocitrate. The glial release of vasoactive metabolites of arachidonic acid, including prostaglandin E 2 (PGE 2 ) and epoxyeicosatrienoic acids (EETs), contributes to neurovascular coupling in the retina. Neurovascular coupling is reduced when neuronal stimulation of glial cells is interrupted and when the synthesis of arachidonic acid metabolites is blocked. Neurovascular coupling is compromised in diabetic retinopathy owing to the loss of glial-mediated vasodilation. This loss can be reversed by inhibiting inducible nitric oxide synthase. It is likely that future research will reveal additional important functions of the release of transmitters from glial cells.

scholarly journals Diverse Functions of Pericytes in Cerebral Blood Flow Regulation and Ischemia

2015 ◽  
Vol 35 (6) ◽  
pp. 883-887 ◽  
Author(s):  
Francisco Fernandez-Klett ◽  
Josef Priller
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Cerebral Ischemia ◽  
Brain Damage ◽  
Neuronal Activity ◽  
Flow Regulation ◽  
Functional Hyperemia ◽  
Mural Cells ◽  
Ischemic Tissue ◽  
The Brain

Pericytes are mural cells with contractile properties. Here, we provide evidence that microvascular pericytes modulate cerebral blood flow in response to neuronal activity (‘functional hyperemia’). Besides their role in neurovascular coupling, pericytes are responsive to brain damage. Cerebral ischemia is associated with constrictions and death of capillary pericytes, followed by fibrotic reorganization of the ischemic tissue. The data suggest that precapillary arterioles and capillaries are major sites of hemodynamic regulation in the brain.

scholarly journals Mechanisms Mediating Functional Hyperemia in the Brain

2017 ◽  
Vol 24 (1) ◽  
pp. 73-83 ◽  
Author(s):  
Amy R. Nippert ◽  
Kyle R. Biesecker ◽  
Eric A. Newman
Keyword(s):  
Nitric Oxide ◽  
Arachidonic Acid ◽  
Final Section ◽  
Neurovascular Coupling ◽  
Functional Hyperemia ◽  
Generating Functional ◽  
Signaling Mechanisms ◽  
The Brain ◽  
Astrocyte Endfeet

Neuronal activity within the brain evokes local increases in blood flow, a response termed functional hyperemia. This response ensures that active neurons receive sufficient oxygen and nutrients to maintain tissue function and health. In this review, we discuss the functions of functional hyperemia, the types of vessels that generate the response, and the signaling mechanisms that mediate neurovascular coupling, the communication between neurons and blood vessels. Neurovascular coupling signaling is mediated primarily by the vasoactive metabolites of arachidonic acid (AA), by nitric oxide, and by K+. While much is known about these pathways, many contentious issues remain. We highlight two controversies, the role of glial cell Ca2+ signaling in mediating neurovascular coupling and the importance of capillaries in generating functional hyperemia. We propose signaling pathways that resolve these controversies. In this scheme, capillary dilations are generated by Ca2+ increases in astrocyte endfeet, leading to production of AA metabolites. In contrast, arteriole dilations are generated by Ca2+ increases in neurons, resulting in production of nitric oxide and AA metabolites. Arachidonic acid from neurons also diffuses into astrocyte endfeet where it is converted into additional vasoactive metabolites. While this scheme resolves several discrepancies in the field, many unresolved challenges remain and are discussed in the final section of the review.

scholarly journals Functional Hyperemia and Mechanisms of Neurovascular Coupling in the Retinal Vasculature

2013 ◽  
Vol 33 (11) ◽  
pp. 1685-1695 ◽  
Author(s):  
Eric A Newman
Keyword(s):  
Blood Flow ◽  
Glial Cells ◽  
Neurovascular Coupling ◽  
Retinal Blood Flow ◽  
Retinal Vasculature ◽  
Functional Hyperemia ◽  
Cellular Mechanisms ◽  
Neuronal Stimulation ◽  
Health And Disease ◽  
Coupling Mechanisms

The retinal vasculature supplies cells of the inner and middle layers of the retina with oxygen and nutrients. Photic stimulation dilates retinal arterioles producing blood flow increases, a response termed functional hyperemia. Despite recent advances, the neurovascular coupling mechanisms mediating the functional hyperemia response in the retina remain unclear. In this review, the retinal functional hyperemia response is described, and the cellular mechanisms that may mediate the response are assessed. These neurovascular coupling mechanisms include neuronal stimulation of glial cells, leading to the release of vasoactive arachidonic acid metabolites onto blood vessels, release of potassium from glial cells onto vessels, and production and release of nitric oxide (NO), lactate, and adenosine from neurons and glia. The modulation of neurovascular coupling by oxygen and NO are described, and changes in functional hyperemia that occur with aging and in diabetic retinopathy, glaucoma, and other pathologies, are reviewed. Finally, outstanding questions concerning retinal blood flow in health and disease are discussed.

Role of endothelium-pericyte signaling in capillary blood flow response to neuronal activity

2021 ◽  
pp. 0271678X2110079
Author(s):  
Wenri Zhang ◽  
Catherine M Davis ◽  
Douglas M Zeppenfeld ◽  
Kirsti Golgotiu ◽  
Marie X Wang ◽  
...  
Keyword(s):  
Blood Flow ◽  
Neuronal Activity ◽  
Functional Hyperemia ◽  
Neuronal Activation ◽  
Two Photon Microscopy ◽  
Tightly Coupled ◽  
Whisker Stimulation ◽  
Optical Microangiography ◽  
Hyperemic Response

Local blood flow in the brain is tightly coupled to metabolic demands, a phenomenon termed functional hyperemia. Both capillaries and arterioles contribute to the hyperemic response to neuronal activity via different mechanisms and timescales. The nature and specific signaling involved in the hyperemic response of capillaries versus arterioles, and their temporal relationship are not fully defined. We determined the time-dependent changes in capillary flux and diameter versus arteriolar velocity and flow following whisker stimulation using optical microangiography (OMAG) and two-photon microscopy. We further characterized depth-resolved responses of individual capillaries versus capillary networks. We hypothesized that capillaries respond first to neuronal activation, and that they exhibit a coordinated response mediated via endothelial-derived epoxyeicosatrienoates (EETs) acting on pericytes. To visualize peri-capillary pericytes, we used Tie2-GFP/NG2-DsRed mice, and to determine the role of endothelial-derived EETs, we compared cerebrovascular responses to whisker stimulation between wild-type mice and mice with lower endothelial EETs (Tie2-hsEH). We found that capillaries respond immediately to neuronal activation in an orchestrated network-level manner, a response attenuated in Tie2-hsEH and inhibited by blocking EETs action on pericytes. These results demonstrate that capillaries are first responders during functional hyperemia, and that they exhibit a network-level response mediated via endothelial-derived EETs’ action on peri-capillary pericytes.

Hippocampal functional hyperemia mediated by NMDA receptor/NO signaling in rats during mild exercise

2012 ◽  
Vol 112 (1) ◽  
pp. 197-203 ◽  
Author(s):  
Takeshi Nishijima ◽  
Masahiro Okamoto ◽  
Takashi Matsui ◽  
Ichiro Kita ◽  
Hideaki Soya
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Nmda Receptor ◽  
Neuronal Activity ◽  
Treadmill Running ◽  
Functional Hyperemia ◽  
Neuronal Activation ◽  
Metabotropic Glutamate ◽  
Group I ◽  
No Signaling

Current studies have demonstrated that exercise increases regional cerebral blood flow (rCBF), an index of neuronal activity. However, neuronal regulation of the increased rCBF in the brain parenchyma is poorly understood. We developed a running model with rats for monitoring hippocampal cerebral blood flow (Hip-CBF) and found that mild treadmill running increases Hip-CBF in a tetrodotoxin-dependent manner, suggesting that functional hyperemia, an increase in rCBF in response to neuronal activation, occurs in the running rat's hippocampus (Nishijima T and Soya H. Neurosci Res 54: 186–191, 2006). To further support our hypothesis, it was important to discover the neurogenic pathways behind the increase in Hip-CBF that occurred during running. Here, we examine the possible role of N-methyl-d-aspartate (NMDA) receptor/nitric oxide (NO) signaling and group I metabotropic glutamate receptors in mediating the Hip-CBF increase. Hip-CBF during running was measured by laser-Doppler flowmetry. Intrahippocampal drug administration was performed by microdialysis. Mild treadmill running (10 m/min) increased Hip-CBF, which was remarkably attenuated by either NMDA receptor antagonists (1 mM MK-801) or NO synthase inhibitors (2 mM NG-nitro-l-arginine methyl ester). However, group I metabotropic glutamate receptor antagonists {1 mM 7-(hydroxyimino)cyclopropa[ b]chromen-1a-carboxylate ethyl ester + 1 mM 2-methyl-6-(phenylethynyl)pyridine hydrochloride} augmented the running-induced Hip-CBF increase. We also found that rCBF in the olfactory bulb was unchanged with running. These results strongly suggest that Hip-CBF during mild exercise is regulated locally under hippocampal neuronal activity, mediated mainly through NMDA receptor/NO signaling. Collectively, these results, together with our previous findings, support our hypothesis that mild exercise elicits neuronal activation, which then triggers functional hyperemia in the rat hippocampus.

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 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.

Sign in / Sign up

Export Citation Format

Share Document