Antagonism of endothelin action normalizes altered levels of VEGF and its signaling in the brain of stroke-prone spontaneously hypertensive rat
Antagonism of endothelin action normalizes altered levels of VEGF and its signaling in the brain of stroke-prone spontaneously hypertensive rat
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DOI：
10.1016/j.ejphar.2007.07.023
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发表时间：
2007-11-28
影响因子：
5
通讯作者：
Kato, Norihiro
中科院分区：
文献类型：
--
作者：
Jesmin, Subrina;Maeda, Seiji;Kato, Norihiro
易卒中的自发性高血压大鼠（Stroke-prone spontaneous hypertensive rats，SHRSP）常发生自发性卒中，部分原因是脑血管系统的异常。在这里，我们调查的档案关键血管生成因子和它们的基本信号分子在SHRSP的脑在高血压的年龄依赖性阶段。VEGF及其受体Flk-1的分布依赖于年龄和高血压的分期（即，SHRSP额叶皮质pAkt和eNOS的表达在高血压前期和恶性高血压阶段下调，而在典型高血压阶段上调，其下游组分pAkt和eNOS的表达与年龄匹配的遗传对照、正常血压WKY大鼠相比呈时间依赖性下调。另一方面，内皮素-1及其A型受体（内皮素ETA受体）的表达上调，这取决于年龄和高血压的阶段。相反，内皮素B型受体水平下调。在恶性高血压的发展过程中，局部脑血流量减少。因此，随后的实验设计，以调查是否内皮素-1受体拮抗剂，使用内皮素-A/-B双受体拮抗剂SB 209670，可以正常化这些因素在SHRSP脑的分子谱。有趣的是，与年龄匹配的WKY相比，SHRSP中内皮素-1受体的阻断恢复正常，脑内皮素-1、内皮素ETA受体和内皮素ETB受体; VEGF和Flk-1;内皮型一氧化氮合酶（eNOS）和pAkt的水平。内皮素受体阻滞剂可能对阻止VEGF及其血管生成信号通路的缺陷在高血压诱导的SHRSP大鼠额叶皮质血管重构发病机制中的进展具有重要意义。(c)2007 Elsevier B.V保留所有权利。
Stroke-prone spontaneously hypertensive rats (SHRSP) often suffer from spontaneous stroke, in part, due to abnormalities in the cerebrovasculature. Here, we investigate the profile of key angiogenic factors and their basic signaling molecules in the brain of SHRSP during the age-dependent stages of hypertension. The profile of VEGF and its receptor, Flk-1, was dependent on age and stage of hypertension (i.e., down regulated at pre-hypertensive and malignant hypertensive stages, but up regulated at typical hypertensive stage), while that of its downstream components, pAkt and eNOS, were down regulated in a time-dependent manner in the frontal cortex of SHRSP compared to age-matched genetic control, normotensive WKY rats. On the other hand, the expression of endothelin-1 and its type A receptor (endothelin ETA receptor) were up regulated, depending on age and stage of hypertension. In contrast, levels of endothelin type B receptor were down regulated. The regional cerebral blood flow decreased during the development of malignant hypertension. Thus, subsequent experiments were designed to investigate whether endothelin-1 receptor antagonism, using endothelin-A/-B dual receptor antagonist SB209670, could normalize the molecular profile of these factors in SHRSP brain. Interestingly, blockage of endothelin-1 receptor restored to normal, levels of cerebral endothelin-1, endothelin ETA receptor and endothelin ETB receptor; VEGF and Flk-l; endothelial nitric oxide synthase (eNOS) and pAkt, in SHRSP, compared to age-matched WKY. Endothelin receptor blocker might be important to prevent the progression in the defect in VEGF and its angiogenic signaling cascade in the pathogenesis of hypertension-induced vascular remodeling in frontal cortex of SHRSP rats. (c) 2007 Elsevier B.V All rights reserved.