Peroxisome proliferator-activated receptor β/δ regulates cerebral vasospasm after subarachnoid hemorrhage via modulating vascular smooth muscle cells phenotypic conversion
Peroxisome proliferator-activated receptor β/δ regulates cerebral vasospasm after subarachnoid hemorrhage via modulating vascular smooth muscle cells phenotypic conversion
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过氧化物酶体增殖物激活受体β/β通过调节血管平滑肌细胞表型转换调节蛛网膜下腔出血后脑血管痉挛
DOI：
10.3892/mmr.2021.12500
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发表时间：
2021-10
影响因子：
3.4
通讯作者：
张洪荣
中科院分区：
文献类型：
--
作者：
张洪荣
脑血管痉挛（CVS）是蛛网膜下腔出血（SAH）的常见并发症，畸形率高，脑血管平滑肌细胞（VSMCs）的表型转换被认为参与了CVS的调控。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（Peroxisome proliferator-activated receptor β/δ，PPARβ/δ）参与调节血管细胞增殖，维持血管的自身调节功能。本研究探讨了SAH后PPARβ/δ对CVS的潜在影响。通过对雄性成年Sprague-Dawley大鼠进行血管内穿孔建立SAH模型，并在SAH前通过脑室内注射腺病毒PPARβ/δ（Ad-PPARβ/δ）。采用免疫印迹法和免疫荧光染色法检测α-平滑肌肌动蛋白（α-smooth muscle actin）和肌球蛋白重链（myosin heavy chain）的表达水平。荧光显微镜下观察基底动脉内径及管壁厚度。通过SAH分级、神经功能评分、脑含水量和脑肿胀度的测定，探讨PPARβ/δ在血管平滑肌表型转化中的作用机制。结果表明，SAH大鼠脑内合成蛋白的表达水平上调，并伴有CVS。在SAH后72 h，Ad-PPARβ/δ激活VSMCs，通过调节VSMCs的表型转换，显著上调收缩蛋白的表达，抑制合成蛋白的表达，减轻SAH诱导的CVS。此外，初步研究表明，PPARβ/δ下调ERK活性，并降低磷酸化（p-）ETS结构域蛋白Elk-1和p-p90核糖体S6激酶的表达，这些蛋白在VSMC表型改变中起重要作用。Ad-PPARβ/δ可通过改善基底动脉内径、减轻血管壁厚度而改善CVS。后续实验表明，Ad-PPARβ/δ能显著降低脑含水量和脑肿胀，改善神经功能。总之，本研究确定了PPARβ/δ作为VSMCs表型转换和SAH后CVS衰减的有用调节剂，从而为迟发性脑缺血的治疗策略提供了新的见解。
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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影响因子：
2.8
作者：
Leon C. D. Smyth;Justin Rustenhoven;Emma L. Scotter;P. Schweder;R. Faull;T. Park;M. Dragunow
通讯作者：
Leon C. D. Smyth;Justin Rustenhoven;Emma L. Scotter;P. Schweder;R. Faull;T. Park;M. Dragunow
影响因子：
8.3
作者：
Wu J;Zhang Y;Yang P;Enkhjargal B;Manaenko A;Tang J;Pearce WJ;Hartman R;Obenaus A;Chen G;Zhang JH
通讯作者：
Zhang JH
影响因子：
9.3
作者：
Maddahi A;Povlsen GK;Edvinsson L
通讯作者：
Edvinsson L
影响因子：
5.3
作者：
Fan R;Enkhjargal B;Camara R;Yan F;Gong L;ShengtaoYao;Tang J;Chen Y;Zhang JH
通讯作者：
Zhang JH
PPAR beta/delta，一种新型调节剂，用于大鼠蛛网膜下腔出血后血管平滑肌细胞表型调节和血管重塑
影响因子：
4.6
作者：
Zhang H;Jiang L;Guo Z;Zhong J;Wu J;He J;Liu H;He Z;Wu H;Cheng C;Sun X
通讯作者：
Sun X