The capillary bed offers the largest hemodynamic resistance to the cortical blood supply

Journal of Cerebral Blood Flow & Metabolism, Journal Year: 2016, Volume and Issue: 37(1), P. 52 - 68

Published: Oct. 10, 2016

The cortical angioarchitecture is a key factor in controlling cerebral blood flow and oxygen metabolism. Difficulties imaging the complex microanatomy of cortex have so far restricted insight about distribution microcirculation. A new methodology combining advanced microscopy data with large scale hemodynamic simulations enabled us to quantify effect on High-resolution images mouse primary somatosensory were input into comprehensive computational model perfusion supply ranging from pial vessels individual brain cells. Simulations flow, hematocrit tension show that wide variation states tortuous, randomly organized capillary bed responsible for relatively uniform tissue oxygenation. Computational analysis microcirculatory pressure drops further indicates bed, including capillaries adjacent feeding arterioles (d < 10 µm), are largest contributors hydraulic resistance.

Language: Английский

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Time to wake up: Studying neurovascular coupling and brain-wide circuit function in the un-anesthetized animal

NeuroImage, Journal Year: 2016, Volume and Issue: 153, P. 382 - 398

Published: Nov. 28, 2016

Functional magnetic resonance imaging (fMRI) has allowed the noninvasive study of task-based and resting-state brain dynamics in humans by inferring neural activity from blood-oxygenation-level dependent (BOLD) signal changes. An accurate interpretation hemodynamic changes that underlie fMRI signals depends on understanding quantitative relationship between cerebral blood flow, oxygenation volume. While there been extensive neurovascular coupling anesthetized animal models, anesthesia causes large disruptions metabolism, responsiveness cardiovascular function. Here, we review work showing circuit function awake are profoundly different those state. We argue time is right to bridge physiological mechanisms human neuroimaging signals, interpret them light underlying mechanisms. Lastly, discuss recent experimental innovations have enabled brain-wide un-anesthetized behaving models.

Language: Английский

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Dynamic Remodeling of Pericytes In Vivo Maintains Capillary Coverage in the Adult Mouse Brain

Cell Reports, Journal Year: 2018, Volume and Issue: 22(1), P. 8 - 16

Published: Jan. 1, 2018

Highlights•Brain capillary pericytes negotiate vascular territories with adjacent pericytes•Pericytes can extend or retract their processes on the timescale of days•Ablation a pericyte evokes robust extension from pericytes•Loss contact leads to local dilation until is regainedSummaryDirect and communication between endothelial cells critical for maintenance cerebrovascular stability blood-brain barrier function. Capillary have thin that reach hundreds micrometers along bed. The come in close proximity but do not overlap, yielding cellular chain discrete occupied by individual pericytes. Little known about whether this structurally dynamic adult brain. Using vivo two-photon imaging mouse cortex, we show while somata were immobile, tips underwent extensions and/or retractions over days. selective ablation single provoked exuberant neighboring uncovered regions endothelium. Uncovered had normal function dilated was regained. Pericyte structural plasticity may be health warrants detailed investigation.Graphical abstract

Language: Английский

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Functional ultrasound localization microscopy reveals brain-wide neurovascular activity on a microscopic scale

Nature Methods, Journal Year: 2022, Volume and Issue: 19(8), P. 1004 - 1012

Published: Aug. 1, 2022

The advent of neuroimaging has increased our understanding brain function. While most brain-wide functional imaging modalities exploit neurovascular coupling to map activity at millimeter resolutions, the recording responses microscopic scale in mammals remains privilege invasive electrophysiological or optical approaches, but is mostly restricted either cortical surface vicinity implanted sensors. Ultrasound localization microscopy (ULM) achieved transcranial cerebrovascular flow, up micrometre scales, by localizing intravenously injected microbubbles; however, long acquisition time required detect microbubbles within vessels so far ULM application mainly microvasculature structural imaging. Here we show how can be modified quantify hyperemia dynamically during activation reaching a 6.5-µm spatial and 1-s temporal resolution deep regions rat brain.

Language: Английский

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Astrocytic LRP1 enables mitochondria transfer to neurons and mitigates brain ischemic stroke by suppressing ARF1 lactylation

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(9), P. 2054 - 2068.e14

Published: June 20, 2024

Language: Английский

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Synaptic-like transmission between neural axons and arteriolar smooth muscle cells drives cerebral neurovascular coupling

Nature Neuroscience, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 2, 2024

Abstract Neurovascular coupling (NVC) is important for brain function and its dysfunction underlies many neuropathologies. Although cell-type specificity has been implicated in NVC, how active neural information conveyed to the targeted arterioles remains poorly understood. Here, using two-photon focal optogenetics mouse cerebral cortex, we demonstrate that single glutamatergic axons dilate their innervating via synaptic-like transmission between neural–arteriolar smooth muscle cell junctions (NsMJs). The presynaptic parental–daughter bouton makes dual innervations on postsynaptic dendrites arteriolar cells (aSMCs), which express types of neuromediator receptors, including a low level glutamate NMDA receptor subunit 1 ( Grin1 ). Disruption NsMJ by aSMC-specific knockout GluN1 diminished optogenetic whisker stimulation-caused functional hyperemia. Notably, absence aSMCs reduced atrophy following ischemia preventing Ca 2+ overload during constriction caused ischemia-induced spreading depolarization. Our findings reveal drives NVC open up new avenue studying stroke.

Language: Английский

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Receptor Ligand-Free Mesoporous Silica Nanoparticles: A Streamlined Strategy for Targeted Drug Delivery across the Blood–Brain Barrier

ACS Nano, Journal Year: 2024, Volume and Issue: 18(20), P. 12716 - 12736

Published: May 8, 2024

Mesoporous silica nanoparticles (MSNs) represent a promising avenue for targeted brain tumor therapy. However, the blood–brain barrier (BBB) often presents formidable obstacle to efficient drug delivery. This study introduces ligand-free PEGylated MSN variant (RMSN25-PEG-TA) with 25 nm size and slight positive charge, which exhibits superior BBB penetration. Utilizing two-photon imaging, RMSN25-PEG-TA particles remained in circulation over 24 h, indicating significant traversal beyond cerebrovascular realm. Importantly, DOX@RMSN25-PEG-TA, our loaded doxorubicin (DOX), harnessed enhanced permeability retention (EPR) effect achieve 6-fold increase accumulation compared free DOX. In vivo evaluations confirmed potent inhibition of orthotopic glioma growth by extending survival rates spontaneous models 28% offering an improved biosafety profile. Advanced LC-MS/MS investigations unveiled distinctive protein corona surrounding RMSN25-PEG-TA, suggesting proteins such as apolipoprotein E albumin could play pivotal roles enabling its Our results underscore potential MSNs treating tumors, supports development future drug–nanoparticle design paradigms.

Language: Английский

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Angiogenesis is uncoupled from osteogenesis during calvarial bone regeneration

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 4, 2024

Abstract Bone regeneration requires a well-orchestrated cellular and molecular response including robust vascularization recruitment of mesenchymal osteogenic cells. In femoral fractures, angiogenesis osteogenesis are closely coupled during the complex healing process. Here, we show with advanced longitudinal intravital multiphoton microscopy that early vascular sprouting is not directly to osteoprogenitor invasion calvarial bone regeneration. Early osteoprogenitors emerging from periosteum give rise bone-forming osteoblasts at injured edge. Microvessels growing inside lesions associated osteoprogenitors. Subsequently, cells collectively invade vascularized perfused lesion as multicellular layer, thereby advancing regenerative ossification. Vascular remodeling result in dynamic blood flow alterations accommodate bone. Single cell profiling bones demonstrates stromal heterogeneity comparable fractures increase types promoting Expression hypoxia-related genes slightly elevated reflecting ossification site. Endothelial Notch VEGF signaling alter growth repair without affecting progress. Our findings may have clinical implications for bioengineering approaches.

Language: Английский

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Pericytes as Inducers of Rapid, Matrix Metalloproteinase-9-Dependent Capillary Damage during Ischemia

Journal of Neuroscience, Journal Year: 2016, Volume and Issue: 37(1), P. 129 - 140

Published: Nov. 14, 2016

Blood-brain barrier disruption (BBB) and release of toxic blood molecules into the brain contributes to neuronal injury during stroke other cerebrovascular diseases. While pericytes are builders custodians BBB in normal brain, their impact on integrity ischemia remains unclear. We imaged pericyte-labeled transgenic mice with vivo two-photon microscopy examine relationship between plasma leakage photothrombotic occlusion cortical capillaries. Upon cessation capillary flow, we observed that occurred three times greater frequency regions where pericyte somata adjoined endothelium. Pericyte covered only 7% total length cortex, indicating a disproportionate amount from small fraction bed. Plasma was preceded by rapid activation matrix metalloproteinase (MMP) at somata, which visualized high resolution using fluorescent probe for metalloproteinase-2/9 activity, fluorescein isothiocyanate (FITC)-gelatin. Coinjection an MMP-9 inhibitor, but not MMP-2 reduced pericyte-associated FITC-gelatin fluorescence leakage. These results suggest contribute localized proteolytic degradation cerebral ischemia.Pericytes key component neurovascular unit essential function. However, acute ischemia, find involved creating heterogeneous The mechanism damage warrants further investigation, as it may yield new therapeutic targets neurological diseases involving flow impairment.

Language: Английский

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Neurovascular dysfunction in vascular dementia, Alzheimer’s and atherosclerosis

BMC Neuroscience, Journal Year: 2018, Volume and Issue: 19(1)

Published: Oct. 17, 2018

Efficient blood supply to the brain is of paramount importance its normal functioning and improper flow can result in potentially devastating neurological consequences. Cerebral response neural activity intrinsically regulated by a complex interplay between various cell types within relationship termed neurovascular coupling. The breakdown coupling evident across wide variety both psychiatric disorders including Alzheimer's disease. Atherosclerosis chronic syndrome affecting integrity function major vessels those that brain, it therefore hypothesised atherosclerosis impairs cerebral leading cerebrovascular dysfunction. This review will discuss mechanisms health disease how cause dysfunction may lead cognitive decline as well stroke. Understanding enable us develop potential therapies prevent treatment vascular diseases dementia,

Language: Английский

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