Platelet-Derived Growth Factor Receptor-β Regulates Vascular Smooth Muscle Cell Phenotypic Transformation and Neuroinflammation After Intracerebral Hemorrhage in Mice

Objective: Platelet-derived growth factor-BB activates platelet-derived growth factor receptor-beta 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-beta 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-beta 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-a 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 naive animals. Platelet-derived growth factor-BB was injected with a plasmin inhibitor (e-aminocaproic acid) in intracerebral hemorrhage mice. Plasmin-injected mice were given platelet-derived growth factor receptor-a 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-a 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-a activation led to increased expression of intercellular adhesion molecule-1 and was reversed by KKKALNRQLGVAA in naive mice. Plasmin inhibition suppressed platelet-derived growth factor receptor-beta activation and neutrophil infiltration, whereas exogenous platelet-derived growth factor-BB increased platelet-derived growth factor receptor-beta activation, regardless of plasmin inhibition. Platelet-derived growth factor receptor-beta 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-beta 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-beta is a novel strategy to prevent plasmin-induced brain injury following intracerebral hemorrhage.