Peroxisome proliferator-activated receptor β/δ regulates cerebral vasospasm after subarachnoid hemorrhage via modulating vascular smooth muscle cells phenotypic conversion

Cerebral vasospasm (CVS) is a common complication of subarachnoid hemorrhage (SAH) with high deformity rates and cerebral vascular smooth muscle cells (VSMCs) phenotypic switch is considered to be involved in the regulation of CVS. However, to the best of the authors' knowledge, its underlying molecular mechanism remains to be elucidated. Peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) has been demonstrated to be involved in the modulation of vascular cells proliferation and maintains the autoregulation function of blood vessels. The present study investigated the potential effect of PPAR beta/delta on CVS following SAH. A model of SAH was established by endovascular perforation on male adult Sprague-Dawley rats, and the adenovirus PPAR beta/delta (Ad-PPAR beta/delta) was injected via intracerebroventricular administration prior to SAH. The expression levels of phenotypic markers a-smooth muscle actin and embryonic smooth muscle myosin heavy chain were measured via western blotting or immunofluorescence staining. The basilar artery diameter and vessel wall thickness were evaluated under fluorescence microscopy. SAH grade, neurological scores, brain water content and brain swelling were measured to study the mechanisms of PPAR beta/delta on vascular smooth muscle phenotypic transformation. It was revealed that the expression levels of synthetic proteins were upregulated in rats with SAH and this was accompanied by CVS. Activation of PPAR beta/delta using Ad-PPAR beta/delta markedly upregulated the contractile proteins elevation, restrained the synthetic proteins expression and attenuated SAH-induced CVS by regulating the phenotypic switch in VSMCs at 72 h following SAH. Furthermore, the preliminary study demonstrated that PPAR beta/delta downregulated ERK activity and decreased the expression of phosphorylated (p-)ETS domain-containing protein Elk-1 and p-p90 ribosomal S6 kinase, which have been demonstrated to serve an important role in VSMC phenotypic change. Additionally, it was revealed that Ad-PPAR beta/delta could positively improve CVS by ameliorating the diameter of the basilar artery and mitigating the thickness of the vascular wall. Furthermore, subsequent experiments demonstrated that Ad-PPAR beta/delta markedly reduced the brain water content and brain swelling and improved the neurological outcome. Taken together, the present study identified PPARP as a useful regulator for the VSMCs phenotypic switch and attenuating CVS following SAH, thereby providing novel insights into the therapeutic strategies of delayed cerebral ischemia.

Automated summary

The study examined the potential impact of PPAR β/δ on CVS following SAH, revealing that PPAR β/δ can alleviate CVS by regulating the phenotypic switch of VSMCs after SAH. Activation of PPAR β/δ also improves the diameter of the basilar artery, reduces vascular wall thickness, decreases brain water content and brain swelling.