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

Abstract

Objective Platelet-derived growth factor-BB (PDGF-BB) activates platelet-derived growth factor receptor-β (PDGFR-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 (ICAM-1), which can amplify neutrophil infiltration into the brain. In the present study, we investigated the role of PDGF-BB/PDGFR-β following intracerebral hemorrhage (ICH)-induced brain injury in mice, with emphasis on its ability to promote vascular smooth muscle cell (VSMC) phenotypic transformation followed by increased ICAM-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 PDGF-BB/PDGFR-β system subsequent to ICH. Methods Brain injury was induced by autologous arterial blood (bICH) or plasmin injection into mouse brains. Small interfering RNA targeting PDGFR-β was administered 24 hours before ICH. A PDGFR antagonist, Gleevec, was administered following ICH. A mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2, MK2) inhibitor (KKKALNRQLGVAA) was delivered with PDGF-BB in naïve animals. PDGF-BB was injected with a plasmin inhibitor (ɛ-Aminocaproic acid, EACA) in ICH mice. Plasmin-injected mice were given PDGFR-β small interfering RNA 24 hours before the operation. Neurological deficits, brain edema, Western blots and immunofluorescence were evaluated. Results PDGFR-βsiRNA-attenuated SMemb and ICAM-1 expression and neutrophil infiltration at 24 hours post-injury, and reduced neurological deficits and brain edema at 24 and 72 hours following ICH. The PDGFR antagonist, Gleevec, reduced SMemb and ICAM-1 expression. PDGFR-β activation led to increased expression of ICAM-1 and was reversed by KKKALNRQLGVAA in naïve mice. Plasmin inhibition suppressed PDGFR-β activation and neutrophil infiltration, whereas exogenous PDGF-BB increased PDGFR-β activation, regardless of plasmin inhibition. PDGFR-β siRNA decreased the expression of ICAM-1 by plasmin injection. Interpretation The PDGF-BB/PDGFR-β system contributes to neuro-inflammation through VSMC phenotypic transformation near the hematoma via the p38 MAPK/MK2 pathway following ICH. Plasmin is hypothesized to be upstream of the proposed neuro-inflammatory system. The therapeutic intervention targeting the PDGF-BB/PDGFR-β is a novel strategy to prevent plasmin-induced brain injury following ICH.

The phenotype of vascular smooth muscle cells co-cultured with endothelial cells is modulated by PDGFR-β/IQGAP1 signaling in LPS-induced intravascular injury

“…These results prompted us to further explore the regulation of IQGAP1 in response in injury and to determine whether IQGAP1 was involved in SMC differentiation. Consistent with the findings of previous studies 21, 42, increased expression of IQGAP1 was observed in LPS-treated SMCs in both the single and co-culture systems. Expression of IQGAP1 was higher in single culture compared with co-culture SMCs.…”

PDGFR-β modulates vascular smooth muscle cell phenotype via IRF-9/SIRT-1/NF-κB pathway in subarachnoid hemorrhage rats

“…Inhibition of PDGFR-β by Gleevec and PDGFR-β siRNA effectively preserved the VSMC contractile phenotype and alleviated neuroinflammation in the basal ganglia following ICH. 21 Another study from our laboratory shows that ICH significantly increased passive diameters of cerebral blood vessels compared to sham animals and that PDGFR-β inhibitor imatinib eliminated these differences. In addition, ICH significantly depressed incremental compliance and treatment with imatinib eliminated this effect.…”

Activation of melanocortin receptor 4 with RO27-3225 attenuates neuroinflammation through AMPK/JNK/p38 MAPK pathway after intracerebral hemorrhage in mice

“…Western blot was performed as previously described [ 35 ]. Mice were transcardially perfused with ice-cold PBS under deep anesthesia, and the brains were removed and separated into two hemispheres at 24 h after ICH or sham surgeries.…”