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Pericyte hypoxia-inducible factor-1 (HIF-1) drives blood-brain barrier disruption and impacts acute ischemic stroke outcome

Tsao, Chih-Chieh; Baumann, Julia; Huang, Sheng-Fu; Kindler, Diana; Schroeter, Aileen; Kachappilly, Nicole; Gassmann, Max; Rudin, Markus; Ogunshola, Omolara O (2021). Pericyte hypoxia-inducible factor-1 (HIF-1) drives blood-brain barrier disruption and impacts acute ischemic stroke outcome. Angiogenesis, 24(4):823-842.

Abstract

Pericytes play essential roles in blood-brain barrier integrity and their dysfunction is implicated in neurological disorders such as stroke although the underlying mechanisms remain unknown. Hypoxia-inducible factor-1 (HIF-1), a master regulator of injury responses, has divergent roles in different cells especially during stress scenarios. On one hand HIF-1 is neuroprotective but on the other it induces vascular permeability. Since pericytes are critical for barrier stability, we asked if pericyte HIF-1 signaling impacts barrier integrity and injury severity in a mouse model of ischemic stroke. We show that pericyte HIF-1 loss of function (LoF) diminishes ischemic damage and barrier permeability at 3 days reperfusion. HIF-1 deficiency preserved barrier integrity by reducing pericyte death thereby maintaining vessel coverage and junctional protein organization, and suppressing vascular remodeling. Importantly, considerable improvements in sensorimotor function were observed in HIF-1 LoF mice indicating that better vascular functionality post stroke improves outcome. Thus, boosting vascular integrity by inhibiting pericytic HIF-1 activation and/or increasing pericyte survival may be a lucrative option to accelerate recovery after severe brain injury.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Zurich Center for Integrative Human Physiology (ZIHP)
05 Vetsuisse Faculty > Veterinärwissenschaftliches Institut > Institute of Veterinary Physiology
Dewey Decimal Classification:570 Life sciences; biology
Scopus Subject Areas:Life Sciences > Physiology
Life Sciences > Clinical Biochemistry
Life Sciences > Cancer Research
Uncontrolled Keywords:Clinical Biochemistry, Cancer Research, Physiology
Language:English
Date:1 November 2021
Deposited On:18 Jun 2021 07:35
Last Modified:25 Oct 2024 01:39
Publisher:Springer
ISSN:0969-6970
Additional Information:This is a post-peer-review, pre-copyedit version of an article published in Angiogenesis. The final authenticated version is available online at: https://doi.org/10.1007/s10456-021-09796-4
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1007/s10456-021-09796-4
PubMed ID:34046769
Project Information:
  • Funder: SNSF
  • Grant ID: 31003A_150062
  • Project Title: Cell-specific HIF-1 compromises blood-brain barrier integrity: consequences for stroke outcome
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  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)

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