UC Irvine

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.