Hajime Takase1, Sherry Hsiang-Yi Chou1, Gen Hamanaka1, Ryo Ohtomo1, Mohammad R Islam1, Jong Woo Lee1, Liangge Hsu1, Justin Mathew1, Estefania Reyes-Bricio1, Kazuhide Hayakawa1, Changhong Xing1, Ming Ming Ning1, Xiaoying Wang1, Ken Arai1, Eng H Lo1, Josephine Lok2. 1. From Neuroprotection Research Laboratories (H.T., S.H.-Y.C., G.H., R.O., M.R.I., J.M., E.R.-B., K.H., C.X., M.M.N., X.W., K.A., E.H.L., J.L.), Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown; Departments of Neurology (S.H.-Y.C., J.W.L.) and Radiology (L.H.), Brigham and Women's Hospital, Boston; Department of Pediatrics, Pediatric Critical Care Medicine (J.L.), Department of Radiology (E.H.L.), and Department of Neurology (M.M.N., E.H.L.), Massachusetts General Hospital, Boston; Department of Neurosurgery (H.T.), Yokohama City University, Yokohama, Japan; and Departments of Critical Care Medicine, Neurology, and Neurosurgery (S.H.-Y.C.), University of Pittsburgh, PA. 2. From Neuroprotection Research Laboratories (H.T., S.H.-Y.C., G.H., R.O., M.R.I., J.M., E.R.-B., K.H., C.X., M.M.N., X.W., K.A., E.H.L., J.L.), Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown; Departments of Neurology (S.H.-Y.C., J.W.L.) and Radiology (L.H.), Brigham and Women's Hospital, Boston; Department of Pediatrics, Pediatric Critical Care Medicine (J.L.), Department of Radiology (E.H.L.), and Department of Neurology (M.M.N., E.H.L.), Massachusetts General Hospital, Boston; Department of Neurosurgery (H.T.), Yokohama City University, Yokohama, Japan; and Departments of Critical Care Medicine, Neurology, and Neurosurgery (S.H.-Y.C.), University of Pittsburgh, PA. jlok1@mgh.harvard.edu.
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.
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.
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