Simultaneous two-photon imaging of oxygen and blood flow in deep cerebral vessels

Lecoq, Jérôme; Parpaleix, Alexandre; Roussakis, Emmanuel; Ducros, Mathieu; Houssen, Yannick Goulam; Vinogradov, Sergei A.; Charpak, Serge

doi:10.1038/nm.2394

Cited by 229 publications

(281 citation statements)

References 29 publications

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“…S3). This result is consistent with findings that tissue PO 2 levels are low enough to support HIF stabilization at basal conditions in vivo (24,26). In anemic WT mice, HIF-1α and nNOS protein levels were increased two-to threefold at 6 and 24 h, relative to nonanemic controls (Fig.…”

Section: Nnos Contributes To Adaptive Cardiovascular Responses Duringsupporting

confidence: 91%

Priming of hypoxia-inducible factor by neuronal nitric oxide synthase is essential for adaptive responses to severe anemia

Tsui

Marsden²,

Mazer³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

103

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Cells sense and respond to changes in oxygen concentration through gene regulatory processes that are fundamental to survival. Surprisingly, little is known about how anemia affects hypoxia signaling. Because nitric oxide synthases (NOSs) figure prominently in the cellular responses to acute hypoxia, we defined the effects of NOS deficiency in acute anemia. In contrast to endothelial NOS or inducible NOS deficiency, neuronal NOS (nNOS) −/− mice demonstrated increased mortality during anemia. Unlike wild-type (WT) animals, anemia did not increase cardiac output (CO) or reduce systemic vascular resistance (SVR) in nNOS −/− mice. At the cellular level, anemia increased expression of HIF-1α protein and HIF-responsive mRNA levels (EPO, VEGF, GLUT1, PDK1) in the brain of WT, but not nNOS −/− mice, despite comparable reductions in tissue PO 2 . Paradoxically, nNOS −/− mice survived longer during hypoxia, retained the ability to regulate CO and SVR, and increased brain HIF-α protein levels and HIF-responsive mRNA transcripts. Real-time imaging of transgenic animals expressing a reporter HIF-α(ODD)-luciferase chimeric protein confirmed that nNOS was essential for anemia-mediated increases in HIF-α protein stability in vivo. S -nitrosylation effects the functional interaction between HIF and pVHL. We found that anemia led to nNOS-dependent S -nitrosylation of pVHL in vivo and, of interest, led to decreased expression of GSNO reductase. These findings identify nNOS effects on the HIF/pVHL signaling pathway as critically important in the physiological responses to anemia in vivo and provide essential mechanistic insight into the differences between anemia and hypoxia.

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Section: Nnos Contributes To Adaptive Cardiovascular Responses Duringsupporting

confidence: 91%

Priming of hypoxia-inducible factor by neuronal nitric oxide synthase is essential for adaptive responses to severe anemia

Tsui

Marsden²,

Mazer³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

103

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“…For example, the model can be applied to localized measurements of CBF as well as intra-and extravascular oxygen concentrations that are now becoming available using two-photon imaging methods. [46][47][48] From these measurements, the model can provide estimates of temporal CMRO 2 responses. Moreover, the model can also predict blood oxygen-level dependent (BOLD) fMRI responses.…”

Section: Discussionmentioning

confidence: 99%

Model of the Transient Neurovascular Response Based on Prompt Arterial Dilation

Kim

Khan

Thompson

et al. 2013

J Cereb Blood Flow Metab

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Brief neural stimulation results in a stereotypical pattern of vascular and metabolic response that is the basis for popular brainimaging methods such as functional magnetic resonance imagine. However, the mechanisms of transient oxygen transport and its coupling to cerebral blood flow (CBF) and oxygen metabolism (CMRO 2 ) are poorly understood. Recent experiments show that brief stimulation produces prompt arterial vasodilation rather than venous vasodilation. This work provides a neurovascular response model for brief stimulation based on transient arterial effects using one-dimensional convection-diffusion transport. Hemoglobin oxygen dissociation is included to enable predictions of absolute oxygen concentrations. Arterial CBF response is modeled using a lumped linear flow model, and CMRO 2 response is modeled using a gamma function. Using six parameters, the model successfully fit 161/166 measured extravascular oxygen time courses obtained for brief visual stimulation in cat cerebral cortex. Results show how CBF and CMRO 2 responses compete to produce the observed features of the hemodynamic response: initial dip, hyperoxic peak, undershoot, and ringing. Predicted CBF and CMRO 2 response amplitudes are consistent with experimental measurements. This model provides a powerful framework to quantitatively interpret oxygen transport in the brain; in particular, its intravascular oxygen concentration predictions provide a new model for fMRI responses. Flow & Metabolism (2013) 33, 1429-1439 doi:10.1038/jcbfm.2013; published online 12 June 2013 Journal of Cerebral BloodKeywords: cerebral blood flow; cerebral hemodynamics; mathematical modeling; neurovascular coupling; neurovascular unit INTRODUCTION Neural activity causes local changes in cerebral oxygen consumption (CMRO 2 ), blood flow (CBF), and deoxyhemoglobin concentration. 1,2 This combination of neurometabolic and neurovascular coupling enables the use of hemodynamic imaging methods to infer brain activity. Of particular interest is the response to brief periods (few seconds) of neural activity, the hemodynamic response function (HRF). The stereotypical HRF permits the use of powerful linear analysis methods.Despite the utility of the HRF for quantifying brain activity, the mechanisms of transient oxygen transport remain poorly understood. There are at least three controversial issues. First, the role of venous volume changes is not clear, particularly in response to brief neural stimulation. [3][4][5] Second, there is disagreement about the relative role of capillaries and arterioles in oxygen transport to tissue. [6][7][8] Third, experiments in oxygen mass balance have sometimes shown that metabolic consumption is insufficient to account for global oxygen loss from the vasculature. It was therefore suggested that tissues at or adjacent to the vascular wall may consume the missing oxygen. 9,10 Thus, questions remain about oxygen transport both in steady state and as a consequence of brief stimulation.Various computational models have attempted to explain t...

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“…Two‐photon oxygen probes were characterized by improved spatial confinement and reduced risk of photodamage,26 but usually require expensive femtosecond pump lasers and higher excitation power density (≈10 6 W cm −2 ) 29, 30. Lanthanide‐doped upconversion nanoparticles (UCNPs) can be excited by low‐cost CW NIR laser (typically 980 nm) with low excitation power density (≈10 2 W cm −2 ),31, 32, 33 thereby eliminating most autofluorescence from biosamples and minimizing photodamage 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38. These features render UCNPs good platform for designing NIR‐excitable oxygen probes 29, 39…”

Section: Introductionmentioning

confidence: 99%

A Phosphorescent Iridium(III) Complex‐Modified Nanoprobe for Hypoxia Bioimaging Via Time‐Resolved Luminescence Microscopy

Yang

et al. 2015

Advanced Science

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Oxygen plays a crucial role in many biological processes. Accurate monitoring of oxygen level is important for diagnosis and treatment of diseases. Autofluorescence is an unavoidable interference in luminescent bioimaging, so that an amount of research work has been devoted to reducing background autofluorescence. Herein, a phosphorescent iridium(III) complex‐modified nanoprobe is developed, which can monitor oxygen concentration and also reduce autofluorescence under both downconversion and upconversion channels. The nanoprobe is designed based on the mesoporous silica coated lanthanide‐doped upconversion nanoparticles, which contains oxygen‐sensitive iridium(III) complex in the outer silica shell. To image intracellular hypoxia without the interferences of autofluorescence, time‐resolved luminescent imaging technology and near‐infrared light excitation, both of which can reduce autofluorescence effectively, are adopted in this work. Moreover, gradient O2 concentration can be detected clearly through confocal microscopy luminescence intensity imaging, phosphorescence lifetime imaging microscopy, and time‐gated imaging, which is meaningful to oxygen sensing in tissues with nonuniform oxygen distribution.

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Simultaneous two-photon imaging of oxygen and blood flow in deep cerebral vessels

Cited by 229 publications

References 29 publications

Priming of hypoxia-inducible factor by neuronal nitric oxide synthase is essential for adaptive responses to severe anemia

Priming of hypoxia-inducible factor by neuronal nitric oxide synthase is essential for adaptive responses to severe anemia

Model of the Transient Neurovascular Response Based on Prompt Arterial Dilation

A Phosphorescent Iridium(III) Complex‐Modified Nanoprobe for Hypoxia Bioimaging Via Time‐Resolved Luminescence Microscopy

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