NDLI: Protein S controls hypoxic/ischemic blood-brain barrier disruption through the TAM receptor Tyro3 and sphingosine 1-phosphate receptor

Content Provider	PubMed Central
Author	Zhu, Donghui Wang, Yaoming Singh, Itender Bell, Robert D. Deane, Rashid Zhong, Zhihui Sagare, Abhay Winkler, Ethan A. Zlokovic, Berislav V.
Abstract	The anticoagulant factor protein S (PS) has direct cellular activities. Lack of PS in mice causes lethal coagulopathy, ischemic/thrombotic injuries, vascular dysgenesis, and blood-brain barrier (BBB) disruption with intracerebral hemorrhages. Thus, we hypothesized that PS maintains and/or enhances the BBB integrity. Using a BBB model with human brain endothelial cells, we show PS inhibits time- and dose-dependently (half maximal effective concentration [EC50] = 27 ± 3 nM) oxygen/glucose deprivation-induced BBB breakdown, as demonstrated by measurements of the transmonolayer electrical resistance, permeability of endothelial monolayers to dextran (40 kDa), and rearrangement of F-actin toward the cortical cytoskeletal ring. Using Tyro-3, Axl, and Mer (TAM) receptor, tyrosine kinase silencing through RNA interference, specific N-terminus–blocking antibodies, Tyro3 phosphorylation, and Tyro3-, Axl- and Mer-deficient mouse brain endothelial cells, we show that Tyro3 mediates PS vasculoprotection. After Tyro3 ligation, PS activated sphingosine 1-phosphate receptor (S1P1), resulting in Rac1-dependent BBB protection. Using 2-photon in vivo imaging, we show that PS blocks postischemic BBB disruption in Tyro3 +/+, Axl −/−, and Mer −/− mice, but not in Tyro3 −/− mice or Tyro3 +/+ mice receiving low-dose W146, a S1P1-specific antagonist. Our findings indicate that PS protects the BBB integrity via Tyro3 and S1P1, suggesting potentially novel treatments for neurovascular dysfunction resulting from hypoxic/ischemic BBB damage.
Related Links	http://dx.doi.org/10.1182/blood-2010-01-262386
Ending Page	4972
Page Count	10
Starting Page	4963
File Format	PDF
ISSN	00064971
e-ISSN	15280020
Journal	Blood
Issue Number	23
Volume Number	115
Language	English
Publisher	American Society of Hematology
Publisher Date	2010-06-10
Access Restriction	Open
Rights Holder	American Society of Hematology
Subject Keyword	Immunology Cell Biology Biochemistry Hematology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Hematology Biochemistry Immunology

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