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Glycocalyx is critical for blood‐brain barrier integrity by suppressing caveolin1‐dependent endothelial transcytosis following ischemic stroke

Brain pathology (Zurich, Switzerland), 2022-01, Vol.32 (1), p.e13006-n/a [Peer Reviewed Journal]

2021 The Authors. published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology ;2021 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology. ;2021. This article is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. ;ISSN: 1015-6305 ;EISSN: 1750-3639 ;DOI: 10.1111/bpa.13006 ;PMID: 34286899

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  • Title:
    Glycocalyx is critical for blood‐brain barrier integrity by suppressing caveolin1‐dependent endothelial transcytosis following ischemic stroke
  • Author: Zhu, Juan ; Li, Zheqi ; Ji, Zhong ; Wu, Yongming ; He, Yihua ; Liu, Kewei ; Chang, Yuan ; Peng, Yuqin ; Lin, Zhenzhou ; Wang, Shengnan ; Wang, Dongmei ; Huang, Kaibin ; Pan, Suyue
  • Subjects: Blood ; Blood-brain barrier ; Brain ; brain edema ; Caveolae ; Caveolin-1 ; caveolin1 ; Central nervous system ; Cerebral blood flow ; Cytoskeleton ; Degradation ; Destruction ; Drug delivery ; Edema ; Endocytosis ; Endothelial cells ; Extravasation ; glycocalyx ; Integrity ; Ischemia ; ischemia stroke ; Membrane permeability ; Molecular modelling ; Neurological complications ; Occlusion ; Permeability ; Stroke ; Syndecan ; Tight junctions ; transcytosis
  • Is Part Of: Brain pathology (Zurich, Switzerland), 2022-01, Vol.32 (1), p.e13006-n/a
  • Description: The breakdown of the blood‐brain barrier (BBB) is related to the occurrence and deterioration of neurological dysfunction in ischemic stroke, which leads to the extravasation of blood‐borne substances, resulting in vasogenic edema and increased mortality. However, a limited understanding of the molecular mechanisms that control the restrictive properties of the BBB hinders the manipulation of the BBB in disease and treatment. Here, we found that the glycocalyx (GCX) is a critical factor in the regulation of brain endothelial barrier integrity. First, endothelial GCX displayed a biphasic change pattern, of which the timescale matched well with the biphasic evolution of BBB permeability to tracers within the first week after t‐MCAO. Moreover, GCX destruction with hyaluronidase increased BBB permeability in healthy mice and aggravated BBB leakage in transient middle cerebral artery occlusion (t‐MCAO) mice. Surprisingly, ultrastructural observation showed that GCX destruction was accompanied by increased endothelial transcytosis at the ischemic BBB, while the tight junctions remained morphologically and functionally intact. Knockdown of caveolin1 (Cav1) suppressed endothelial transcytosis, leading to reduced BBB permeability, and brain edema. Lastly, a coimmunoprecipitation assay showed that GCX degradation enhanced the interaction between syndecan1 and Src by promoting the binding of phosphorylated syndecan1 to the Src SH2 domain, which led to rapid modulation of cytoskeletal proteins to promote caveolae‐mediated endocytosis. Overall, these findings demonstrate that the dynamic degradation and reconstruction of GCX may account for the biphasic changes in BBB permeability in ischemic stroke, and reveal an essential role of GCX in suppressing transcellular transport in brain endothelial cells to maintain BBB integrity. Targeting GCX may provide a novel strategy for managing BBB dysfunction and central nervous system drug delivery. Glycocalyx‐regulated transcellular transport across the BBB contributes significantly to the barrier function of the BBB in both normal and diseased conditions. GCX may be an essential target for manipulating BBB permeability to help with drug delivery to the brain or to protect against BBB injury under diseased conditions.
  • Publisher: Switzerland: John Wiley & Sons, Inc
  • Language: English
  • Identifier: ISSN: 1015-6305
    EISSN: 1750-3639
    DOI: 10.1111/bpa.13006
    PMID: 34286899
  • Source: Open Access: PubMed Central
    Journals@Ovid Open Access Journal Collection Rolling
    DOAJ Directory of Open Access Journals
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