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Author Notes:

Correspondence: Daniel A. Lawrence, dlawrenc@umich.edu; Li Zhang lizhang@som.umaryland.edu

Enming Joseph Su and Chunzhang Cao contributed equally to this work.

Daniel A. Lawrence and Li Zhang contributed equally to this work.

The authors wish to thank Professor Richard Mortensen for helpful discussions and a critical reading of the manuscript.

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

The authors have declared that that Eriksson, Lawrence, Su, Strickland, Yepes, and Fredriksson hold two patents related to this work, US 8,765,671 and US 8,147,828, entitled “Methods and compositions for modulation of blood neural barrier”.

Subjects:

Research Funding:

This work was supported by National Institutes of Health Grants HL-055374, NS-079639, HL-054710, (to D.A. Lawrence); HL-114379, HL-120388 and HL-054710 (to D. Strickland); NS-082607 and HL-054710 (to L. Zhang); and Grants from the Novo Nordisk Foundation, The Swedish Heart and Lung Foundation 2012-0077, The Swedish Cancer Foundation 2014/630, and The Swedish Research Council 2011-3861 (to U. Eriksson).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Clinical Neurology
  • Neurosciences
  • Pathology
  • Neurosciences & Neurology
  • Stroke
  • Blood-brain barrier
  • Platelet-derived growth factor-CC
  • Tissue plasminogen activator
  • Mac-1
  • alpha(M)beta(2)
  • CD11b/CD18
  • LRP1
  • TISSUE-PLASMINOGEN ACTIVATOR
  • BLOOD-BRAIN-BARRIER
  • DENSITY-LIPOPROTEIN RECEPTOR
  • FOCAL CEREBRAL-ISCHEMIA
  • CENTRAL-NERVOUS-SYSTEM
  • FACTOR-ALPHA RECEPTOR
  • INTRACEREBRAL HEMORRHAGE
  • SUBSTRATE-SPECIFICITY
  • IMATINIB TREATMENT
  • INNATE IMMUNITY

Microglial-mediated PDGF-CC activation increases cerebrovascular permeability during ischemic stroke

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Journal Title:

Acta Neuropathologica

Volume:

Volume 134, Number 4

Publisher:

, Pages 585-604

Type of Work:

Article | Final Publisher PDF

Abstract:

Treatment of acute ischemic stroke with the thrombolytic tissue plasminogen activator (tPA) can significantly improve neurological outcomes; however, thrombolytic therapy is associated with an increased risk of intra-cerebral hemorrhage (ICH). Previously, we demonstrated that during stroke tPA acting on the parenchymal side of the neurovascular unit (NVU) can increase blood–brain barrier (BBB) permeability and ICH through activation of latent platelet-derived growth factor-CC (PDGF-CC) and signaling by the PDGF receptor-α (PDGFRα). However, in vitro, activation of PDGF-CC by tPA is very inefficient and the mechanism of PDGF-CC activation in the NVU is not known. Here, we show that the integrin Mac-1, expressed on brain microglia/macrophages (denoted microglia throughout), acts together with the endocytic receptor LRP1 in the NVU to promote tPA-mediated activation of PDGF-CC. Mac-1-deficient mice (Mac-1 −/− ) are protected from tPA-induced BBB permeability but not from permeability induced by intracerebroventricular injection of active PDGF-CC. Immunofluorescence analysis demonstrates that Mac-1, LRP1, and the PDGFRα all localize to the NVU of arterioles, and following middle cerebral artery occlusion (MCAO) Mac-1 −/− mice show significantly less PDGFRα phosphorylation, BBB permeability, and infarct volume compared to wild-type mice. Bone-marrow transplantation studies indicate that resident CD11b + cells, but not bone-marrow-derived leukocytes, mediate the early activation of PDGF-CC by tPA after MCAO. Finally, using a model of thrombotic stroke with late thrombolysis, we show that wild-type mice have an increased incidence of spontaneous ICH following thrombolysis with tPA 5 h after MCAO, whereas Mac-1 −/− mice are resistant to the development of ICH even with late tPA treatment. Together, these results indicate that Mac-1 and LRP1 act as co-factors for the activation of PDGF-CC by tPA in the NVU, and suggest a novel mechanism for tightly regulating PDGFRα signaling in the NVU and controlling BBB permeability.

Copyright information:

© 2017, The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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