• Peng Yang, Jiang Wu, Liyan Miao, Anatol Manaenko, Nathanael Matei, Yang Zhang, Liang Xu, William J Pearce, Richard E Hartman, Andre Obenaus, John H Zhang, Feng Xu, and Jiping Tang.
• 1Department of Emergency Surgery, the First Affiliated Hospital of Soochow University, Suzhou, China. 2Departments of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA. 3Department of Neurosurgery, the First Affiliated Hospital of Soochow University, Suzhou, China. 4Department of Pharmacy, the First Affiliated Hospital of Soochow University, Suzhou, China. 5Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University, Chongqing, China. 6Department of Neurosurgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China. 7Department of Psychology, Loma Linda University, Loma Linda, CA. 8Department of Pediatrics, Loma Linda University, Loma Linda, CA. 9Department of Anesthesiology, Loma Linda University, Loma Linda, CA. 10Department of Neurosurgery, Loma Linda University, Loma Linda, CA.
• Crit. Care Med. 2016 Jun 1; 44 (6): e390-402.

ObjectivePlatelet-derived growth factor-BB activates platelet-derived growth factor receptor-β and promotes vascular smooth muscle cell phenotypic transformation. Elevated levels of non-muscle myosin IIB (SMemb) are found in secretory smooth muscle cells along with inflammatory mediators, such as intercellular adhesion molecule-1, which can amplify neutrophil infiltration into the brain. In the present study, we investigated the role of platelet-derived growth factor-BB/platelet-derived growth factor receptor-β following intracerebral hemorrhage-induced brain injury in mice, with emphasis on its ability to promote vascular smooth muscle cell phenotypic transformation followed by increased intercellular adhesion molecule-1 expression and elevated neutrophil infiltration in the vicinity of the hematoma. We also determined the extent to which plasmin from the hematoma influences the platelet-derived growth factor-BB/platelet-derived growth factor receptor-β system subsequent to intracerebral hemorrhage.DesignControlled in vivo laboratory study.SettingAnimal research laboratory.SubjectsOne hundred and fifty six eight-week-old male CD1 mice.InterventionsBrain injury was induced by autologous arterial blood or plasmin injection into mouse brains. Small interfering RNA targeting platelet-derived growth factor receptor-β was administered 24 hours before intracerebral hemorrhage. A platelet-derived growth factor receptor antagonist, Gleevec, was administered following intracerebral hemorrhage. A mitogen-activated protein kinase-activated protein kinase 2 inhibitor (KKKALNRQLGVAA) was delivered with platelet-derived growth factor-BB in naïve animals. Platelet-derived growth factor-BB was injected with a plasmin inhibitor (ε-aminocaproic acid) in intracerebral hemorrhage mice. Plasmin-injected mice were given platelet-derived growth factor receptor-β small interfering RNA 24 hours before the operation. Neurological deficits, brain edema, western blots, and immunofluorescence were evaluated.Measurements And Main ResultsPlatelet-derived growth factor receptor-β small interfering RNA attenuated SMemb and intercellular adhesion molecule-1 expression and neutrophil infiltration at 24 hours post injury and reduced neurological deficits and brain edema at 24 and 72 hours following intracerebral hemorrhage. The platelet-derived growth factor receptor antagonist, Gleevec, reduced SMemb and intercellular adhesion molecule-1 expression. Platelet-derived growth factor receptor-β activation led to increased expression of intercellular adhesion molecule-1 and was reversed by KKKALNRQLGVAA in naïve mice. Plasmin inhibition suppressed platelet-derived growth factor receptor-β activation and neutrophil infiltration, whereas exogenous platelet-derived growth factor-BB increased platelet-derived growth factor receptor-β activation, regardless of plasmin inhibition. Platelet-derived growth factor receptor-β small interfering RNA decreased the expression of intercellular adhesion molecule-1 by plasmin injection.ConclusionThe platelet-derived growth factor-BB/platelet-derived growth factor receptor-β system contributes to neuroinflammation through vascular smooth muscle cell phenotypic transformation near the hematoma via the p38 mitogen-activated protein kinase/mitogen-activated protein kinase-activated protein kinase 2 pathway following intracerebral hemorrhage. Plasmin is hypothesized to be upstream of the proposed neuroinflammatory system. The therapeutic intervention targeting the platelet-derived growth factor-BB/platelet-derived growth factor receptor-β is a novel strategy to prevent plasmin-induced brain injury following intracerebral hemorrhage.

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