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.
Mol Med Rep. 2021 Dec;24(6). doi: 10.3892/mmr.2021.12500. Epub 2021 Oct 19.
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.
脑血管痉挛（CVS）是蛛网膜下腔出血（SAH）的常见并发症，其畸形率较高，而血管平滑肌细胞（VSMCs）表型转换被认为参与了 CVS 的调节。然而，据作者所知，其潜在的分子机制仍有待阐明。过氧化物酶体增殖物激活受体β/δ（PPARβ/δ）已被证明参与了血管细胞增殖的调节，并维持了血管的自动调节功能。本研究探讨了 PPARβ/δ 对 SAH 后 CVS 的潜在影响。通过血管内穿孔在雄性成年 Sprague-Dawley 大鼠中建立 SAH 模型，并在 SAH 前通过脑室内注射腺病毒 PPARβ/δ（Ad-PPARβ/δ）。通过 Western blot 或免疫荧光染色测量表型标志物α-平滑肌肌动蛋白和胚胎平滑肌肌球蛋白重链的表达水平。在荧光显微镜下评估基底动脉直径和血管壁厚度。测量 SAH 分级、神经评分、脑水含量和脑水肿，以研究 PPARβ/δ 对血管平滑肌表型转化的作用机制。结果显示，SAH 大鼠中合成蛋白的表达水平上调，伴有 CVS。使用 Ad-PPARβ/δ 激活 PPARβ/δ 可显著上调收缩蛋白的升高，抑制合成蛋白的表达，并通过调节 SAH 后 72 小时 VSMCs 的表型转换来减轻 SAH 诱导的 CVS。此外，初步研究表明，PPARβ/δ 下调 ERK 活性，降低磷酸化（p）ETS 结构域包含蛋白 Elk-1 和 p-p90 核糖体 S6 激酶的表达，这在 VSMC 表型变化中起着重要作用。此外，结果显示，Ad-PPARβ/δ 可以通过改善基底动脉直径和减轻血管壁厚度来积极改善 CVS。此外，后续实验表明，Ad-PPARβ/δ 可显著降低脑水含量和脑水肿，改善神经功能预后。综上所述，本研究确定了 PPARβ/δ 作为 VSMCs 表型转换的有效调节剂，并减轻了 SAH 后的 CVS，从而为迟发性脑缺血的治疗策略提供了新的见解。
