Vascular PPARδ Protects Against Stroke-Induced Brain Injury

OBJECTIVE: To investigate the effects of peroxisome proliferator-activated receptor (PPAR)δ in the cerebral vasculature following stroke-induced brain injury. METHODS AND RESULTS: Here, we report a novel finding that selective PPARδ genetic deletion in vascular smooth muscle cells (VSMCs) resulted in increased cerebrovascular permeability and brain infarction in mice after middle cerebral artery occlusion (MCAO). Mechanistically, we revealed for the first time that PPARδ expression is reduced, but matrix metalloproteinase (MMP)-9 activity is increased in cultured VSMCs after oxygen-glucose deprivation and also in the cerebral cortex of mice following MCAO. Moreover, gain- and loss of PPARδ function in VSMCs significantly reduces and increases oxygen-glucose deprivation-induced MMP-9 activity, respectively. We have further identified that MMP-9 is a direct target of PPARδ-mediated transrepression by chromatin immunoprecipitation and PPARδ transcriptional activity assays. Furthermore, inhibition of MMP-9 activity by lentiviral MMP-9 short hairpin RNA effectively improves cerebrovascular permeability and reduces brain infarction in VSMC-selective PPARδ conditional knockout mice after MCAO. CONCLUSIONS: Our data demonstrate that PPARδ in VSMCs can prevent ischemic brain injury by inhibition of MMP-9 activation and attenuation of postischemic inflammation. The pharmacological activation of PPARδ may provide a new therapeutic strategy to treat stroke-induced vascular and neuronal damage.