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  1. Article ; Online: The Effect of Hyperoxemia on Neurological Outcomes of Adult Patients: A Systematic Review and Meta-Analysis.

    Hirunpattarasilp, Chanawee / Shiina, Hiroko / Na-Ek, Nat / Attwell, David

    Neurocritical care

    2022  Volume 36, Issue 3, Page(s) 1027–1043

    Abstract: Hyperoxemia commonly occurs in clinical practice and is often left untreated. Many studies have shown increased mortality in patients with hyperoxemia, but data on neurological outcome in these patients are conflicting, despite worsened neurological ... ...

    Abstract Hyperoxemia commonly occurs in clinical practice and is often left untreated. Many studies have shown increased mortality in patients with hyperoxemia, but data on neurological outcome in these patients are conflicting, despite worsened neurological outcome found in preclinical studies. To investigate the association between hyperoxemia and neurological outcome in adult patients, we performed a systematic review and meta-analysis of observational studies. We searched MEDLINE, Embase, Scopus, Web of Science, Cumulative Index to Nursing and Allied Health Literature, and ClinicalTrials.gov from inception to May 2020 for observational studies correlating arterial oxygen partial pressure (PaO
    MeSH term(s) Adult ; Blood Gas Analysis/methods ; Humans ; Ischemic Stroke ; Quality of Life ; Subarachnoid Hemorrhage/complications
    Language English
    Publishing date 2022-01-31
    Publishing country United States
    Document type Journal Article ; Meta-Analysis ; Review ; Systematic Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2381896-7
    ISSN 1556-0961 ; 1541-6933
    ISSN (online) 1556-0961
    ISSN 1541-6933
    DOI 10.1007/s12028-021-01423-w
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  2. Article ; Online: Noradrenaline released from locus coeruleus axons contracts cerebral capillary pericytes via

    Korte, Nils / James, Greg / You, Haoming / Hirunpattarasilp, Chanawee / Christie, Isabel / Sethi, Huma / Attwell, David

    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

    2023  Volume 43, Issue 7, Page(s) 1142–1152

    Abstract: Noradrenaline (NA) release from locus coeruleus axons generates vascular contractile tone in arteriolar smooth muscle and contractile capillary pericytes. This tone allows neuronal activity to evoke vasodilation that increases local cerebral blood flow ( ... ...

    Abstract Noradrenaline (NA) release from locus coeruleus axons generates vascular contractile tone in arteriolar smooth muscle and contractile capillary pericytes. This tone allows neuronal activity to evoke vasodilation that increases local cerebral blood flow (CBF). Much of the vascular resistance within the brain is located in capillaries and locus coeruleus axons have NA release sites closer to pericytes than to arterioles. In acute brain slices, NA contracted pericytes but did not raise the pericyte cytoplasmic Ca
    MeSH term(s) Pericytes/metabolism ; Locus Coeruleus/metabolism ; Capillaries/physiology ; Norepinephrine/pharmacology ; Norepinephrine/metabolism ; Receptors, Adrenergic, alpha-2/metabolism ; Axons/metabolism
    Chemical Substances Norepinephrine (X4W3ENH1CV) ; Receptors, Adrenergic, alpha-2
    Language English
    Publishing date 2023-01-23
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 604628-9
    ISSN 1559-7016 ; 0271-678X
    ISSN (online) 1559-7016
    ISSN 0271-678X
    DOI 10.1177/0271678X231152549
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  3. Article ; Online: Synapse development is regulated by microglial THIK-1 K

    Izquierdo, Pablo / Shiina, Hiroko / Hirunpattarasilp, Chanawee / Gillis, Grace / Attwell, David

    Proceedings of the National Academy of Sciences of the United States of America

    2021  Volume 118, Issue 42

    MeSH term(s) Animals ; Calcium/metabolism ; Female ; Male ; Mice ; Microglia/metabolism ; Potassium Channels, Tandem Pore Domain/antagonists & inhibitors ; Potassium Channels, Tandem Pore Domain/genetics ; Potassium Channels, Tandem Pore Domain/physiology ; Rats ; Rats, Sprague-Dawley ; Synapses/metabolism ; Synapses/physiology
    Chemical Substances Kcnk13 protein, mouse ; Potassium Channels, Tandem Pore Domain ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2021-10-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2106294118
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  4. Article ; Online: Hyperoxia evokes pericyte-mediated capillary constriction.

    Hirunpattarasilp, Chanawee / Barkaway, Anna / Davis, Harvey / Pfeiffer, Thomas / Sethi, Huma / Attwell, David

    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

    2022  Volume 42, Issue 11, Page(s) 2032–2047

    Abstract: Oxygen supplementation is regularly prescribed to patients to treat or prevent hypoxia. However, excess oxygenation can lead to reduced cerebral blood flow (CBF) in healthy subjects and worsen the neurological outcome of critically ill patients. Most ... ...

    Abstract Oxygen supplementation is regularly prescribed to patients to treat or prevent hypoxia. However, excess oxygenation can lead to reduced cerebral blood flow (CBF) in healthy subjects and worsen the neurological outcome of critically ill patients. Most studies on the vascular effects of hyperoxia focus on arteries but there is no research on the effects on cerebral capillary pericytes, which are major regulators of CBF. Here, we used bright-field imaging of cerebral capillaries and modeling of CBF to show that hyperoxia (95% superfused O<sub>2</sub>) led to an increase in intracellular calcium level in pericytes and a significant capillary constriction, sufficient to cause an estimated 25% decrease in CBF. Although hyperoxia is reported to cause vascular smooth muscle cell contraction via generation of reactive oxygen species (ROS), endothelin-1 and 20-HETE, we found that increased cytosolic and mitochondrial ROS levels and endothelin release were not involved in the pericyte-mediated capillary constriction. However, a 20-HETE synthesis blocker greatly reduced the hyperoxia-evoked capillary constriction. Our findings establish pericytes as regulators of CBF in hyperoxia and 20-HETE synthesis as an oxygen sensor in CBF regulation. The results also provide a mechanism by which clinically administered oxygen can lead to a worse neurological outcome.
    MeSH term(s) Calcium/metabolism ; Capillaries ; Cerebrovascular Circulation/physiology ; Constriction ; Constriction, Pathologic ; Endothelin-1/metabolism ; Humans ; Hyperoxia/metabolism ; Oxygen/metabolism ; Pericytes/metabolism ; Reactive Oxygen Species/metabolism
    Chemical Substances Endothelin-1 ; Reactive Oxygen Species ; Oxygen (S88TT14065) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2022-07-03
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 604628-9
    ISSN 1559-7016 ; 0271-678X
    ISSN (online) 1559-7016
    ISSN 0271-678X
    DOI 10.1177/0271678X221111598
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  5. Article ; Online: The role of pericytes in brain disorders: from the periphery to the brain.

    Hirunpattarasilp, Chanawee / Attwell, David / Freitas, Felipe

    Journal of neurochemistry

    2019  Volume 150, Issue 6, Page(s) 648–665

    Abstract: It is becoming increasingly apparent that disorders of the brain microvasculature contribute to many neurological disorders. In recent years it has become clear that a major player in these events is the capillary pericyte which, in the brain, is now ... ...

    Abstract It is becoming increasingly apparent that disorders of the brain microvasculature contribute to many neurological disorders. In recent years it has become clear that a major player in these events is the capillary pericyte which, in the brain, is now known to control the blood-brain barrier, regulate blood flow, influence immune cell entry and be crucial for angiogenesis. In this review we consider the under-explored possibility that peripheral diseases which affect the microvasculature, such as hypertension, kidney disease and diabetes, produce central nervous system (CNS) dysfunction by mechanisms affecting capillary pericytes within the CNS. We highlight how cellular messengers produced peripherally can act via signalling pathways within CNS pericytes to reshape blood vessels, restrict blood flow or compromise blood-brain barrier function, thus causing neuronal dysfunction. Increased understanding of how renin-angiotensin, Rho-kinase and PDGFRβ signalling affect CNS pericytes may suggest novel therapeutic approaches to reducing the CNS effects of peripheral disorders.
    MeSH term(s) Animals ; Brain/metabolism ; Brain/pathology ; Brain/physiopathology ; Brain Diseases/metabolism ; Brain Diseases/pathology ; Brain Diseases/physiopathology ; Mice ; Pericytes/metabolism ; Pericytes/pathology
    Language English
    Publishing date 2019-06-25
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 80158-6
    ISSN 1471-4159 ; 0022-3042 ; 1474-1644
    ISSN (online) 1471-4159
    ISSN 0022-3042 ; 1474-1644
    DOI 10.1111/jnc.14725
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  6. Article ; Online: SARS-CoV-2 triggers pericyte-mediated cerebral capillary constriction.

    Hirunpattarasilp, Chanawee / James, Greg / Kwanthongdee, Jaturon / Freitas, Felipe / Huo, Jiandong / Sethi, Huma / Kittler, Josef T / Owens, Raymond J / McCoy, Laura E / Attwell, David

    Brain : a journal of neurology

    2022  Volume 146, Issue 2, Page(s) 727–738

    Abstract: The SARS-CoV-2 receptor, ACE2, is found on pericytes, contractile cells enwrapping capillaries that regulate brain, heart and kidney blood flow. ACE2 converts vasoconstricting angiotensin II into vasodilating angiotensin-(1-7). In brain slices from ... ...

    Abstract The SARS-CoV-2 receptor, ACE2, is found on pericytes, contractile cells enwrapping capillaries that regulate brain, heart and kidney blood flow. ACE2 converts vasoconstricting angiotensin II into vasodilating angiotensin-(1-7). In brain slices from hamster, which has an ACE2 sequence similar to human ACE2, angiotensin II evoked a small pericyte-mediated capillary constriction via AT1 receptors, but evoked a large constriction when the SARS-CoV-2 receptor binding domain (RBD, original Wuhan variant) was present. A mutated non-binding RBD did not potentiate constriction. A similar RBD-potentiated capillary constriction occurred in human cortical slices, and was evoked in hamster brain slices by pseudotyped virions expressing SARS-CoV-2 spike protein. This constriction reflects an RBD-induced decrease in the conversion of angiotensin II to angiotensin-(1-7) mediated by removal of ACE2 from the cell surface membrane and was mimicked by blocking ACE2. The clinically used drug losartan inhibited the RBD-potentiated constriction. Thus, AT1 receptor blockers could be protective in COVID-19 by preventing pericyte-mediated blood flow reductions in the brain, and perhaps the heart and kidney.
    MeSH term(s) Humans ; SARS-CoV-2/metabolism ; COVID-19/metabolism ; Pericytes/metabolism ; Angiotensin II/pharmacology ; Angiotensin II/metabolism ; Angiotensin-Converting Enzyme 2/chemistry ; Angiotensin-Converting Enzyme 2/metabolism ; Capillaries ; Constriction ; Receptors, Virus/chemistry ; Receptors, Virus/metabolism ; Peptidyl-Dipeptidase A/genetics ; Peptidyl-Dipeptidase A/metabolism ; Protein Binding
    Chemical Substances spike protein, SARS-CoV-2 ; Angiotensin II (11128-99-7) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Receptors, Virus ; Peptidyl-Dipeptidase A (EC 3.4.15.1)
    Language English
    Publishing date 2022-07-22
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awac272
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  7. Article ; Online: SARS-CoV-2 binding to ACE2 triggers pericyte-mediated angiotensin-evoked cerebral capillary constriction

    Hirunpattarasilp, Chanawee / James, Gregory / Freitas, Felipe / Sethi, Huma / Kittler, Josef T. / Huo, Jiandong / Owens, Raymond J. / Attwell, David

    bioRxiv

    Abstract: The SARS-CoV-2 receptor, ACE2, is found on pericytes, contractile cells enwrapping capillaries that regulate brain, heart and kidney blood flow. ACE2 converts vasoconstricting angiotensin II into vasodilating angiotensin-(1-7). In brain slices from ... ...

    Abstract The SARS-CoV-2 receptor, ACE2, is found on pericytes, contractile cells enwrapping capillaries that regulate brain, heart and kidney blood flow. ACE2 converts vasoconstricting angiotensin II into vasodilating angiotensin-(1-7). In brain slices from hamster, which has an ACE2 sequence similar to human ACE2, angiotensin II alone evoked only a small capillary constriction, but evoked a large pericyte-mediated capillary constriction generated by AT1 receptors in the presence of the SARS-CoV-2 receptor binding domain (RBD). The effect of the RBD was mimicked by blocking ACE2. A mutated non-binding RBD did not potentiate constriction. A similar RBD-potentiated capillary constriction occurred in human cortical slices. This constriction reflects an RBD-induced decrease in the conversion of angiotensin II to angiotensin-(1-7). The clinically-used drug losartan inhibited the RBD-potentiated constriction. Thus AT1 receptor blockers could be protective in SARS-CoV-2 infection by reducing pericyte-mediated blood flow reductions in the brain, and perhaps the heart and kidney.
    Keywords covid19
    Language English
    Publishing date 2021-04-01
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2021.04.01.438122
    Database COVID19

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  8. Article ; Online: Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes.

    Nortley, Ross / Korte, Nils / Izquierdo, Pablo / Hirunpattarasilp, Chanawee / Mishra, Anusha / Jaunmuktane, Zane / Kyrargyri, Vasiliki / Pfeiffer, Thomas / Khennouf, Lila / Madry, Christian / Gong, Hui / Richard-Loendt, Angela / Huang, Wenhui / Saito, Takashi / Saido, Takaomi C / Brandner, Sebastian / Sethi, Huma / Attwell, David

    Science (New York, N.Y.)

    2019  Volume 365, Issue 6450

    Abstract: Cerebral blood flow is reduced early in the onset of Alzheimer's disease (AD). Because most of the vascular resistance within the brain is in capillaries, this could reflect dysfunction of contractile pericytes on capillary walls. We used live and ... ...

    Abstract Cerebral blood flow is reduced early in the onset of Alzheimer's disease (AD). Because most of the vascular resistance within the brain is in capillaries, this could reflect dysfunction of contractile pericytes on capillary walls. We used live and rapidly fixed biopsied human tissue to establish disease relevance, and rodent experiments to define mechanism. We found that in humans with cognitive decline, amyloid β (Aβ) constricts brain capillaries at pericyte locations. This was caused by Aβ generating reactive oxygen species, which evoked the release of endothelin-1 (ET) that activated pericyte ET
    MeSH term(s) Alzheimer Disease/metabolism ; Alzheimer Disease/physiopathology ; Amyloid beta-Peptides/chemistry ; Amyloid beta-Peptides/metabolism ; Animals ; Biopsy ; Capillaries/physiopathology ; Cerebral Cortex/blood supply ; Cerebral Cortex/pathology ; Cerebrovascular Circulation ; Constriction, Pathologic/physiopathology ; Endothelin-1/metabolism ; Humans ; Hypoxia/metabolism ; Hypoxia/physiopathology ; Mice ; Pericytes/metabolism ; Protein Multimerization ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Receptor, Endothelin A/metabolism ; Signal Transduction ; Vascular Resistance
    Chemical Substances Amyloid beta-Peptides ; Endothelin-1 ; Reactive Oxygen Species ; Receptor, Endothelin A
    Language English
    Publishing date 2019-06-20
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.aav9518
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