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

Xu,Li; Wu,Jiang; Liu,Yuan; Chen,Gang; Ma,Chao; Zhang,Hongrong

doi:10.3892/mmr.2021.12500

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

Authors:
- Li Xu
- Jiang Wu
- Yuan Liu
- Gang Chen
- Chao Ma
- Hongrong Zhang
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Affiliations: Intensive Care Unit of Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215026, P.R. China, Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215026, P.R. China
Published online on: October 19, 2021 https://doi.org/10.3892/mmr.2021.12500
Article Number: 860
Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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 β/δ (PPARβ/δ) 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 PPARβ/δ on CVS following SAH. A model of SAH was established by endovascular perforation on male adult Sprague‑Dawley rats, and the adenovirus PPARβ/δ (Ad‑PPARβ/δ) was injected via intracerebroventricular administration prior to SAH. The expression levels of phenotypic markers α‑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 PPARβ/δ 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 PPARβ/δ using Ad‑PPARβ/δ 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 PPARβ/δ 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‑PPARβ/δ 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‑PPARβ/δ markedly reduced the brain water content and brain swelling and improved the neurological outcome. Taken together, the present study identified PPARβ/δ 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.

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