scholarly journals Fractalkine-induced microglial vasoregulation occurs within the retina and is altered early in diabetic retinopathy

2021 ◽  
Vol 118 (51) ◽  
pp. e2112561118
Author(s):  
Samuel A. Mills ◽  
Andrew I. Jobling ◽  
Michael A. Dixon ◽  
Bang V. Bui ◽  
Kirstan A. Vessey ◽  
...  
Keyword(s):  
Blood Flow ◽  
Diabetic Retinopathy ◽  
Vascular Function ◽  
Immune Cell ◽  
Neurovascular Unit ◽  
Retinal Blood Flow ◽  
Proper Function ◽  
Early Diabetes ◽  
Vascular Regulation ◽  
The Brain

Local blood flow control within the central nervous system (CNS) is critical to proper function and is dependent on coordination between neurons, glia, and blood vessels. Macroglia, such as astrocytes and Müller cells, contribute to this neurovascular unit within the brain and retina, respectively. This study explored the role of microglia, the innate immune cell of the CNS, in retinal vasoregulation, and highlights changes during early diabetes. Structurally, microglia were found to contact retinal capillaries and neuronal synapses. In the brain and retinal explants, the addition of fractalkine, the sole ligand for monocyte receptor Cx3cr1, resulted in capillary constriction at regions of microglial contact. This vascular regulation was dependent on microglial Cx3cr1 involvement, since genetic and pharmacological inhibition of Cx3cr1 abolished fractalkine-induced constriction. Analysis of the microglial transcriptome identified several vasoactive genes, including angiotensinogen, a constituent of the renin-angiotensin system (RAS). Subsequent functional analysis showed that RAS blockade via candesartan abolished microglial-induced capillary constriction. Microglial regulation was explored in a rat streptozotocin (STZ) model of diabetic retinopathy. Retinal blood flow was reduced after 4 wk due to reduced capillary diameter and this was coincident with increased microglial association. Functional assessment showed loss of microglial–capillary response in STZ-treated animals and transcriptome analysis showed evidence of RAS pathway dysregulation in microglia. While candesartan treatment reversed capillary constriction in STZ-treated animals, blood flow remained decreased likely due to dilation of larger vessels. This work shows microglia actively participate in the neurovascular unit, with aberrant microglial–vascular function possibly contributing to the early vascular compromise during diabetic retinopathy.

scholarly journals Fractalkine-induced microglial vasoregulation occurs within the retina and is altered early in diabetic retinopathy

2020 ◽  
Author(s):  
Samuel A. Mills ◽  
Andrew I. Jobling ◽  
Michael A. Dixon ◽  
Bang V. Bui ◽  
Kirstan A. Vessey ◽  
...  
Keyword(s):  
Blood Flow ◽  
Diabetic Retinopathy ◽  
Neurovascular Unit ◽  
Renin Angiotensin System ◽  
Retinal Blood Flow ◽  
Early Diabetes ◽  
Angiotensin System ◽  
Ras Pathway ◽  
Vascular Regulation ◽  
The Brain

AbstractLocal blood flow control within the CNS is critical to proper function and is dependent on coordination between neurons, glia and blood vessels. Macroglia such as astrocytes and Müller cells, contribute to this neurovascular unit within the brain and retina, respectively. This study explored the role of microglia, the innate immune cell of the CNS, in retinal vasoregulation and highlights changes during early diabetes. Structurally, microglia were found to contact retinal capillaries and neuronal synapses. In the brain and retinal explants, the addition of fractalkine, the sole ligand for monocyte receptor Cx3cr1, resulted in capillary constriction at regions of microglial contact. This vascular regulation was dependent on microglial involvement, since mice lacking Cx3cr1, exhibited no fractalkine-induced constriction. Analysis of the microglial transcriptome identified several vasoactive genes, including angiotensinogen, a constituent of the renin-angiotensin system (RAS). Subsequent functional analysis showed that RAS blockade via candesartan, abolished microglial-induced capillary constriction. Microglial regulation was explored in a rat streptozotocin (STZ) model of diabetic retinopathy. Retinal blood flow was reduced after 4 weeks due to reduced capillary diameter and this was coincident with increased microglial association. Functional assessment showed loss of microglial-capillary response in STZ-treated animals and transcriptome analysis showed evidence of RAS pathway dysregulation in microglia. While candesartan treatment reversed capillary constriction in STZ-treated animals, blood flow remained decreased likely due to dilation of larger vessels. This work shows microglia actively participate in the neurovascular unit, with aberrant microglial-vascular function possibly contributing to the early vascular compromise during diabetic retinopathy.Significance StatementThis work identifies a novel role for microglia, the innate immune cells of the CNS, in the local control of the retinal vasculature and identifies deficits early in diabetes. Microglia contact neurons and vasculature and express several vasoactive agents. Activation of microglial fractalkine-Cx3cr1 signalling leads to capillary constriction and blocking the renin-angiotensin system (RAS) with candesartan abolishes microglial-mediated vasoconstriction in the retina. In early diabetes, reduced retinal blood flow is coincident with capillary constriction, increased microglial-vessel association, loss of microglial-capillary regulation and altered microglial expression of the RAS pathway. While candesartan restores retinal capillary diameter early in diabetes, targeting of microglial-vascular regulation is required to prevent coincident dilation of large retinal vessels and reduced retinal blood flow.

Retinal Vascular Implications of Ocular Hypertension

2021 ◽  
Author(s):  
Fidan Jmor ◽  
John C. Chen
Keyword(s):  
Blood Flow ◽  
Diabetic Retinopathy ◽  
Intraocular Pressure ◽  
Vascular Anatomy ◽  
Flow Regulation ◽  
Retinal Blood Flow ◽  
Vein Occlusion ◽  
Ocular Perfusion ◽  
The Relationship ◽  
Central Retinal Vein

In this chapter, we review the basics of retinal vascular anatomy and discuss the physiologic process of retinal blood flow regulation. We then aim to explore the relationship between intraocular pressure and retinal circulation, taking into account factors that affect retinal hemodynamics. Specifically, we discuss the concepts of ocular perfusion pressure, baro-damage to the endothelium and transmural pressure in relation to the intraocular pressure. Finally, we demonstrate the inter-relationships of these factors and concepts in the pathogenesis of some retinal vascular conditions; more particularly, through examples of two common clinical pathologies of diabetic retinopathy and central retinal vein occlusion.

INCREASED RETINAL BLOOD FLOW VELOCITY IN PATIENTS WITH EARLY DIABETES MELLITUS

Retina ◽  
2012 ◽  
Vol 32 (1) ◽  
pp. 112-119 ◽  
Author(s):  
Zvia Burgansky-Eliash ◽  
Adiel Barak ◽  
Hila Barash ◽  
Darin A Nelson ◽  
Orly Pupko ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Blood Flow ◽  
Flow Velocity ◽  
Blood Flow Velocity ◽  
Retinal Blood Flow ◽  
Early Diabetes ◽  
Retinal Blood Flow Velocity

Effect of Panretinal Photocoagulation on Retinal Blood Flow in Proliferative Diabetic Retinopathy

Ophthalmology ◽  
1986 ◽  
Vol 93 (5) ◽  
pp. 590-595 ◽  
Author(s):  
Juan E. Grunwald ◽  
Charles E. Riva ◽  
Alexander J. Brucker ◽  
Stephen H. Sinclair ◽  
Benno L. Petrig
Keyword(s):  
Blood Flow ◽  
Diabetic Retinopathy ◽  
Proliferative Diabetic Retinopathy ◽  
Retinal Blood Flow ◽  
Panretinal Photocoagulation

Ketogenic Diet, Aging, and Neurodegeneration

2016 ◽  
Author(s):  
Kui Xu ◽  
Joseph C. LaManna ◽  
Michelle A. Puchowicz
Keyword(s):  
Oxidative Stress ◽  
Energy Source ◽  
Blood Flow ◽  
Ketogenic Diet ◽  
Ketone Bodies ◽  
Neurovascular Unit ◽  
Cerebral Metabolic Rate ◽  
Downstream Effects ◽  
Atp Supply ◽  
The Brain

The brain is normally completely dependent on glucose, but is capable of using ketones as an alternate energy source, as occurs with prolonged starvation or chronic feeding of a ketogenic diet. Research has shown that ketosis is neuroprotective against ischemic insults in rodents. This review focuses on investigating the mechanistic links to neuroprotection by ketosis in the aged. Recovery from stroke and other pathophysiological conditions in the aged is challenging. Cerebral metabolic rate for glucose, cerebral blood flow, and the defenses against oxidative stress are known to decline with age, suggesting dysfunction of the neurovascular unit. One mechanism of neuroprotection by ketosis involves succinate-induced stabilization of hypoxic inducible factor-1alpha (HIF1α‎) and its downstream effects on intermediary metabolism. The chapter hypothesizes that ketone bodies play a role in the restoration of energy balance (stabilization of ATP supply) and act as signaling molecules through the up-regulation of salvation pathways targeted by HIF1α‎.

Retinal Blood Flow Alterations During Progression of Diabetic Retinopathy

1983 ◽  
Vol 101 (2) ◽  
pp. 225-227 ◽  
Author(s):  
A. Yoshida ◽  
G. T. Feke ◽  
J. Morales-Stoppello ◽  
G. D. Collas ◽  
D. G. Goger ◽  
...  
Keyword(s):  
Blood Flow ◽  
Diabetic Retinopathy ◽  
Retinal Blood Flow

scholarly journals The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Ahmad F Alghanem ◽  
Javier Abello ◽  
Joshua M Maurer ◽  
Ashutosh Kumar ◽  
Chau My Ta ◽  
...  
Keyword(s):  
Blood Flow ◽  
Shear Flow ◽  
Vascular Function ◽  
Umbilical Vein ◽  
Anion Channel ◽  
Retinal Blood Flow ◽  
Cell Alignment ◽  
Signaling Complex ◽  
Flow Stimulation ◽  
Umbilical Vein Endothelial Cells

The endothelium responds to numerous chemical and mechanical factors in regulating vascular tone, blood pressure, and blood flow. The endothelial volume-regulated anion channel (VRAC) has been proposed to be mechanosensitive and thereby sense fluid flow and hydrostatic pressure to regulate vascular function. Here, we show that the leucine-rich repeat-containing protein 8a, LRRC8A (SWELL1), is required for VRAC in human umbilical vein endothelial cells (HUVECs). Endothelial LRRC8A regulates AKT-endothelial nitric oxide synthase (eNOS) signaling under basal, stretch, and shear-flow stimulation, forms a GRB2-Cav1-eNOS signaling complex, and is required for endothelial cell alignment to laminar shear flow. Endothelium-restricted Lrrc8a KO mice develop hypertension in response to chronic angiotensin-II infusion and exhibit impaired retinal blood flow with both diffuse and focal blood vessel narrowing in the setting of type 2 diabetes (T2D). These data demonstrate that LRRC8A regulates AKT-eNOS in endothelium and is required for maintaining vascular function, particularly in the setting of T2D.

scholarly journals Longitudinal stability of retinal blood flow regulation in response to flicker stimulation and systemic hyperoxia in mice assessed with laser speckle flowgraphy

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Junya Hanaguri ◽  
Harumasa Yokota ◽  
Masahisa Watanabe ◽  
Lih Kuo ◽  
Satoru Yamagami ◽  
...  
Keyword(s):  
Blood Flow ◽  
Vascular Function ◽  
Systemic Blood Pressure ◽  
Laser Speckle ◽  
Retinal Blood Flow ◽  
Laser Speckle Flowgraphy ◽  
Adult Mice ◽  
Ocular Perfusion ◽  
Vascular Area ◽  
Flicker Stimulation

AbstractThis study aimed to evaluate longitudinal changes in retinal blood flow in response to flicker stimulation and systemic hyperoxia in mice using a laser speckle flowgraphy (LSFG-Micro). The retinal blood flow in vascular area surrounding the optic nerve head was measured in 8-week-old male mice every 2 weeks until age 20-week. The coefficient of variation of retinal blood flow under resting condition was analyzed every 2 weeks to validate the consistency of the measurement. On day 1 of the experiment, retinal blood flow was assessed every 20 s for 6 min during and after 3 min flicker light (12 Hz) stimulation; on day 2, retinal blood flow was measured every minute for 20 min during and after 10 min systemic hyperoxia; and on day 3, electroretinography (ERG) was performed. Body weight, systemic blood pressure, and ocular perfusion pressure increased significantly with age, but the resting retinal blood flow and ERG parameters remained unchanged. Retinal blood flow significantly increased with flicker stimulation and decreased with systemic hyperoxia, independent of age. The LSFG-Micro provides consistent and reproducible retinal blood flow measurement in adult mice. Longitudinal assessments of retinal blood flow in response to flicker stimulation and systemic hyperoxia may be useful indexes for noninvasive monitoring of vascular function in retinas.

scholarly journals 2126 Optimizing a technique for visualizing retinal and choroidal blood flow noninvasively

2018 ◽  
Vol 2 (S1) ◽  
pp. 22-23
Author(s):  
Paras Vora ◽  
Nicholas Bell ◽  
Romulo Albuquerque ◽  
Jooyoung Cho ◽  
Gregory Botzet
Keyword(s):  
New York ◽  
Blood Flow ◽  
Diabetic Retinopathy ◽  
Digital Video ◽  
Human Subjects ◽  
Sampling Rate ◽  
Retinal Blood Flow ◽  
Current Standard ◽  
Choroidal Blood Flow ◽  
Video Cameras

OBJECTIVES/SPECIFIC AIMS: Diabetic retinopathy is an increasingly prevalent disease, difficult to screen for across the globe. We have developed and began optimizing an innovative technique to visualize and quantify retinal blood flow, to elucidate the role of the choroid in retinal pathologies such as diabetic retinopathy or choroidopathy. METHODS/STUDY POPULATION: Preliminary retinal was obtained from a surgical retina video library (Truvision, Goleta, CA, USA). Videos of different organs were recorded while vessels were occluded via a blood pressure cuff, using consumer-grade digital video cameras (NEX-5T, a7sii; Sony, New York, NY, USA). All other retinal videos were taken using a fundus camera (50×; Topcon, Oxland, NJ, USA) modified to support the above digital video cameras. All videos were processed using experimental software (MATLAB, Mathworks, Natick, MA, USA). RESULTS/ANTICIPATED RESULTS: Video imaging of the retina was optimized for lighting conditions and software requirements. Parameters were defined for the software imaging pipeline, such as frequency range of interest, sampling rate, and noise minimization. Software was developed to stabilize frames, accounting for eye saccades. Use of a biosensor enabled accurate measurement of pulse waveform, increasing signal-to-noise ratio. The optimal light requirements were determined such that adequate exposure of the retina is reproducible yet still comfortable for use in human subjects. DISCUSSION/SIGNIFICANCE OF IMPACT: This novel technique allows for an inexpensive, noninvasive, and reproducible ocular blood flow imaging platform. By optimizing this technique, we can proceed with our future plans for a pilot study to compare our imaging technique with the current standard, paving the way for future clinical studies.

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