Abstract
Objective: Platelet-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. Design: Controlled in vivo laboratory study. Setting: Animal research laboratory. Subjects: One hundred and fifty six eight-week-old male CD1 mice. Interventions: Brain 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 Results: Platelet-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. Conclusion: The 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.
Original language | English |
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Pages (from-to) | e390-e402 |
Journal | Critical Care Medicine |
Volume | 44 |
Issue number | 6 |
DOIs | |
State | Published - Jun 1 2016 |
ASJC Scopus Subject Areas
- Critical Care and Intensive Care Medicine
Keywords
- intracerebral hemorrhage
- neuroinflammation
- phenotypic transformation
- platelet-derived growth factor receptor β
- platelet-derived growth factor-BB
- vascular smooth muscle cell
- Intercellular Adhesion Molecule-1/metabolism
- Actins/metabolism
- Intracellular Signaling Peptides and Proteins/antagonists & inhibitors
- Male
- p38 Mitogen-Activated Protein Kinases/metabolism
- Brain Edema/drug therapy
- Signal Transduction
- Imatinib Mesylate/pharmacology
- Becaplermin
- Fibrinolytic Agents/pharmacology
- Muscle, Smooth, Vascular/cytology
- Cerebral Hemorrhage/complications
- Nonmuscle Myosin Type IIB/genetics
- Receptor, Platelet-Derived Growth Factor beta/genetics
- Fibrinolysin/antagonists & inhibitors
- Phenotype
- Animals
- Neutrophils/physiology
- Mice
- RNA, Small Interfering/pharmacology
- Proto-Oncogene Proteins c-sis/metabolism
- Protein Serine-Threonine Kinases/antagonists & inhibitors