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Abstract
Objective To determine if CSF and plasma levels of soluble vascular endothelial (sVE)-cadherin are associated with functional outcome after subarachnoid hemorrhage (SAH) and to investigate sVE-cadherin effects on microglia.
Methods Serial CSF and plasma were collected from prospectively enrolled patients with nontraumatic SAH from a ruptured aneurysm in the anterior circulation and who required an external ventricular drain for clinical indications. Patients with normal-pressure hydrocephalus without SAH served as controls. For prospective assessment of long-term outcomes at 3 and 6 months after SAH, modified Rankin Scale scores (mRS) were obtained and dichotomized into good (mRS ≤ 2) vs poor (mRS > 2) outcome groups. For SAH severity, Hunt and Hess grade was assessed. Association of CSF sVE-cadherin levels with long-term outcomes, HH grade, and CSF tumor necrosis factor (TNF)-α levels were evaluated. sVE-cadherin effects on microglia were also studied.
Results sVE-cadherin levels in CSF, but not in plasma, were higher in patients with SAH and were associated with higher clinical severity and higher CSF TNF-α levels. Patients with SAH with higher CSF sVE-cadherin levels over time were more likely to develop worse functional outcome at 3 months after SAH. Incubation of cultured microglia with sVE-cadherin resulted in increased inducible nitric oxide synthase, interleukin-1β, reactive oxygen species, cell soma size, and metabolic activity, consistent with microglia activation. Microinjection of sVE-cadherin fragments into mouse brain results in an increased number of microglia surrounding the injection site, compared to injection of denatured vascular endothelial–cadherin fragments.
Conclusions These results support the existence of a novel pathway by which sVE-cadherin, released from injured endothelium after SAH, can shift microglia into a more proinflammatory phenotype and contribute to neuroinflammation and poor outcome in SAH.
Glossary
- ANOVA=
- analysis of variance;
- BBB=
- blood-brain barrier;
- EVD=
- external ventricular drain;
- HBMEC=
- human brain microvascular endothelial cells;
- HH=
- Hunt and Hess;
- IACUC=
- Institutional Animal Care and Use Committee;
- IL=
- interleukin;
- iNOS=
- inducible nitric oxide synthase;
- iNPH=
- idiopathic normal-pressure hydrocephalus;
- IP=
- immunoprecipitation;
- LDH=
- lactate dehydrogenase;
- mRS=
- modified Rankin Scale;
- PBS=
- phosphate-buffered saline;
- ROS=
- reactive oxygen species;
- SAH=
- subarachnoid hemorrhage;
- sVE=
- soluble vascular endothelial;
- TNF=
- tumor necrosis factor;
- VE=
- vascular endothelial
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
↵* Drs. Takase and Chou contributed equally to this work as co–first authors.
CME Course: NPub.org/cmelist
- Received May 3, 2019.
- Accepted in final form October 4, 2019.
- © 2020 American Academy of Neurology
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