Involvement of platelet-derived growth factor receptor β in fibrosis through extracellular matrix protein production after ischemic stroke
Involvement of platelet-derived growth factor receptor β in fibrosis through extracellular matrix protein production after ischemic stroke
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DOI：
10.1016/j.expneurol.2014.12.007
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发表时间：
2015-02-01
影响因子：
5.3
通讯作者：
Kitazono, Takanari
中科院分区：
文献类型：
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作者：
Makihara, Noriko;Arimura, Koichi;Kitazono, Takanari
纤维化伴随着中枢神经系统（CNS）损伤后的修复过程。周细胞被认为是CNS中纤维化形成细胞的起源。在这里，我们研究了血小板源性生长因子受体β（PDGFR β），一个众所周知的迁移，增殖和周细胞存活的不可或缺的分子，是否参与细胞外基质蛋白，纤连蛋白和I型胶原蛋白的产生，这是缺血性中风后纤维化的关键。免疫组织化学显示在小鼠中风模型中，在3-7天时，在脑梗塞区域的血管细胞中诱导PDGFR β表达。表达PDGFR β的细胞在第7天后从Pen-infarction区域向缺血核心延伸，同时在梗死区域表达纤连蛋白和I型胶原。相反，结蛋白和α-平滑肌肌动蛋白，周细胞的标志物，只在血管细胞中表达。在PDGFR β杂合子敲除小鼠中，与野生型同窝小鼠相比，缺血性卒中后纤维连接蛋白和I型胶原蛋白的表达在mRNA和蛋白水平上均减弱，梗死体积增大。在培养的脑周细胞中，PDGF-B、PDGFR β、纤连蛋白和I型胶原蛋白的表达通过血清耗竭（SD）显著增加，但不包括结蛋白。SD诱导的纤连蛋白和I型胶原的上调被PDGFR β抑制剂SU 11652抑制，而PDGF-B进一步增加SD诱导的上调。总之，PDGFR β的表达水平可能是缺血性卒中后纤维化的关键决定因素。此外，PDGFR β信号传导参与缺血性卒中后纤连蛋白和I型胶原的产生。(C)2014爱思唯尔公司All rights reserved.
Fibrosis is concomitant with repair processes following injuries in the central nervous system (CNS). Pericytes are considered as an origin of fibrosis-forming cells in the CNS. Here, we examined whether platelet-derived growth factor receptor beta(PDGFR beta), a well-known indispensable molecule for migration, proliferation, and survival of pericytes, was involved in the production of extracellular matrix proteins, fibronectin and collagen type I, which is crucial for fibrosis after ischemic stroke. Immunohistochemistry demonstrated induction of PDGFR beta expression in vascular cells of pen-infarct areas at 3-7 days in a mouse stroke model. The PDGFR beta-expressing cells extended from pen-infarct areas toward the ischemic core after day 7 while expressing fibronectin and collagen type I in the infarct areas. In contrast, desmin and alpha-smooth muscle actin, markers of pericytes, were only expressed in vascular cells. In PDGFR beta heterozygous knockout mice, the expression of fibronectin and collagen type I was attenuated at both mRNA and protein levels with an enlargement of the infarct volume after ischemic stroke compared with that in wild-type littermates. In cultured brain pericytes, the expression of PDGF-B, PDGFR beta, fibronectin, and collagen type I, but not desmin, was significantly increased by serum depletion (SD). The SD-induced upregulation of fibronectin and collagen type I was suppressed by SU11652, an inhibitor of PDGFR beta, while PDGF-B further increased the SD-induced upregulation. In conclusion, the expression level of PDGFR beta may be a crucial determinant of fibrosis after ischemic stroke. Moreover, PDGFR beta signaling participates in the production of fibronectin and collagen type I after ischemic stroke. (C) 2014 Elsevier Inc. All rights reserved.