Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer's phenotype
Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer's phenotype
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DOI：
10.1073/pnas.0608251104
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发表时间：
2007-01-16
影响因子：
11.1
通讯作者：
Zlokovic, Berislav V.
中科院分区：
文献类型：
--
作者：
Chow, Nienwen;Bell, Robert D.;Zlokovic, Berislav V.
脑血管病通过脑血流量（CBF）减少和失调导致阿尔茨海默病（AD）中的认知下降和痴呆。我们报告的血管平滑肌细胞（VSMC）在小软膜和脑内动脉，这是至关重要的CBF调节，表达在AD高水平的血清反应因子（SRF）和myocardin（MYOCD），两个相互作用的转录因子，编排一个VSMC分化的表型。与这一发现一致，AD VSMC过表达几种SRF-MYOCD调节的收缩蛋白，并表现出过度收缩表型。对照人脑VSMC中MYOCD过表达诱导AD样过度收缩表型，并减少小鼠离体主动脉内皮依赖性和非依赖性舒张。相反，沉默SRF使收缩蛋白含量正常化并逆转AD VSMC的过度收缩表型。在野生型小鼠和两种AD模型（荷兰/lowa/瑞典三重突变体人淀粉样β肽（A β）-前体蛋白（APP）表达小鼠和APPsw（+/-）小鼠）中，将MYOCD体内基因转移至小鼠软脑膜动脉增加了收缩蛋白含量，减少了脑激活产生的CBF反应。沉默Srf产生了相反的效果。在阿尔茨海默氏神经毒素A β作用下，SRF的表达没有改变。因此，小脑动脉中的SRF-MYOCD过表达似乎独立于介导动脉收缩过度和CIBF失调的A β a致病途径而启动，这与阿尔茨海默氏痴呆症相关。
Cerebral angiopathy contributes to cognitive decline and dementia in Alzheimer's disease (AD) through cerebral blood flow (CBF) reductions and dysregulation. We report vascular smooth muscle cells (VSMC) in small pial and intracerebral arteries, which are critical for CBF regulation, express in AD high levels of serum response factor (SRF) and myocardin (MYOCD), two interacting transcription factors that orchestrate a VSMC-differentiated phenotype. Consistent with this finding, AD VSMC overexpressed several SRF-MYOCD-regulated contractile proteins and exhibited a hypercontractile phenotype. MYOCD overexpression in control human cerebral VSMC induced an AD-like hypercontractile phenotype and diminished both endothelial-dependent and -independent relaxation in the mouse aorta ex vivo. In contrast, silencing SRF normalized contractile protein content and reversed a hypercontractile phenotype in AD VSMC. MYOCD in vivo gene transfer to mouse pial arteries increased contractile protein content and diminished CBF responses produced by brain activation in wildtype mice and in two AD models, the Dutch/lowa/Swedish triple mutant human amyloid beta-peptide (A beta)-precursor protein (APP)-expressing mice and APPsw(+/-) mice. Silencing Srf had the opposite effect. Expression of SRF did not change in VSMC subjected to Alzheimer's neurotoxin, A beta. Thus, SRF-MYOCD overexpression in small cerebral arteries appears to initiate independently of A beta a pathogenic pathway mediating arterial hypercontractility and CIBF dysregulation, which are associated with Alzheimer's dementia.