Research Paper Volume 11, Issue 22 pp 10167—10182

Tissue plasminogen activator disrupts the blood-brain barrier through increasing the inflammatory response mediated by pericytes after cerebral ischemia

Eryan Yang 1, 2, 3, *, , Ying Cai 2, *, , Xiuhua Yao 2, , Ji Liu 3, , Qixue Wang 4, , Weili Jin 1, 4, , Qiaoli Wu 2, , Weijia Fan 2, , Lina Qiu 3, , Chunsheng Kang 4, , Jialing Wu 2, 3, ,

  • 1 Graduate School of Tianjin Medical University, Tianjin 300070, China
  • 2 Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin 300350, China
  • 3 Department of Neurology, Tianjin Huanhu Hospital, Tianjin 300350, China
  • 4 Key Laboratory of Neurotrauma, Variation, and Regeneration, Ministry of Education and Tianjin Municipal Government, Tianjin Neurological Institute, Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China
* Equal contribution

received: August 14, 2019 ; accepted: October 28, 2019 ; published: November 18, 2019 ;

https://doi.org/10.18632/aging.102431
How to Cite

Copyright © 2019 Yang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Pericytes, important elements of the blood-brain barrier (BBB), play critical roles in maintaining BBB integrity and modulating hemostasis, angiogenesis, inflammation and phagocytic function. We investigated whether pericytes are involved in the recombinant tissue plasminogen activator (rt-PA)-induced inflammatory response, which disrupts the BBB, and investigated the potential mechanisms. Middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation (OGD) were employed to mimic hypoxic-ischemic conditions. Rt-PA was intravenously injected into mice 1 h after 1 h MCAO, and Rt-PA was added to the culture medium after 4 h OGD. Rt-PA treatment aggravated the disruption of the BBB compared with hypoxia treatment, and etanercept (TNF-α inhibitor) combined with rt-PA alleviated the rt-PA-induced BBB disruption in vivo and in vitro. Rt-PA treatment increased the TNF-α and MCP-1 levels and decreased the TGF-β, p-Smad2/3 and PDGFR-β levels compared with hypoxia treatment in vivo and vitro. TGF-β combined with rt-PA decreased TNF-α and MCP-1 secretion and alleviated BBB disruption compared with rt-PA; these changes were abrogated by TPO427736 HCL (a TGF-β/p-Smad2/3 pathway inhibitor) cotreatment in vitro. Rt-PA did not decrease TGF-β and p-Smad2/3 expression in PDGFR-β-overexpressing pericytes after OGD. These findings identify PDGFR-β/TGF-β/p-Smad2/3 signaling in pericytes as a new therapeutic target for the treatment of rt-PA-induced BBB damage.

Abbreviations

rt-PA: recombinant tissue plasminogen activator; BBB: blood-brain barrier; NVU: neurovascular unit; MCAO: middle cerebral artery occlusion; I/R: ischemia/ reoxygenation; animal model pericytes: mouse brain vascular pericytes; PDGFR-β: platelet-derived growth factor receptor-β; TGF-β: transforming growth factor-β1; OGD/R: oxygen-glucose deprivation/reoxygenation; endothelial: mouse microvascular endothelial cell; TNF-α: tumor necrosis factor-a; MCP-1: monocyte chemotactic protein 1; TPO427788 HCL: an inhibitor of the TGF-β/p-Smad2/3 pathway; TJ: tight junction; FITC-dextran: fluorescein isothiocyanate-conjugated dextran; TEER: transendothelial electrical resistance; CBF: cerebral blood flow; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PBS: phosphate-buffered saline; TBST: Tris-buffered saline and Tween 20; e-PDGFR-β: PDGFR-β overexpression; pc-DNA: pc-DNA3.1.