VEGFR1 and VEGFR2 in Alzheimer's Disease
VEGFR1 and VEGFR2 in Alzheimer's Disease
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DOI：
10.3233/jad-170745
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发表时间：
2018-01-01
影响因子：
4
通讯作者：
Love, Seth
中科院分区：
文献类型：
--
作者：
Harris, Rachel;Miners, James Scott;Love, Seth
血管内皮生长因子（VEGF）是一种强有力的血管生成因子。尽管阿尔茨海默病（AD）脑中VEGF上调，可能是对β淀粉样蛋白、血管收缩和组织缺氧的反应，但微血管密度并没有随之增加。VEGF结合并激活VEGF受体2（VEGFR 2），但也结合VEGF受体1（VEGFR 1），其以活性较低的膜结合和无活性的可溶性（sVEGFR 1）形式存在并抑制促血管生成信号传导。我们已经研究了VEGF受体表达的改变是否可能导致AD患者缺乏对VEGF的血管生成反应。我们评估了50名AD患者和36名年龄匹配的对照组大脑顶叶皮质中VEGFR 1和VEGFR 2的细胞分布和蛋白水平，并将研究结果与相同组织样本中VEGF和von Willebrand因子水平（微血管密度的标志物）的测量结果相关联。VEGFR 2表达于神经元、星形胶质细胞和内皮细胞。VEGFR 1主要在神经元表达，在AD中显著降低（p = 0.02）。对一部分大脑的蛋白质印迹分析显示AD患者VEGF 1：sVEGF 1减少（p = 0.046）。尽管AD患者脑灌注不足，但血管生成的缺乏不能用VEGFR 2或总VEGFR 1的表达改变来解释;事实上，VEGFR 1的下调可能代表了对灌注不足的促血管生成反应。然而，预期sVEGFR 1的相对增加具有抗血管生成作用，这可能是AD的一个因素。
Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. Despite upregulation of VEGF in the brain in Alzheimer's disease (AD), probably in response to amyloid-beta, vasoconstriction, and tissue hypoxia, there is no consequent increase in microvessel density. VEGF binds to and activates VEGF receptor 2 (VEGFR2), but also binds to VEGF receptor 1 (VEGFR1), which exists in less-active membrane-bound and inactive soluble (sVEGFR1) forms and inhibits pro-angiogenic signaling. We have investigated whether altered expression of VEGF receptors might account for the lack of angiogenic response to VEGF in AD. We assessed the cellular distribution and protein level of VEGFR1 and VEGFR2 in parietal cortex from 50 AD and 36 age-matched control brains, and related the findings to measurements of VEGF and von Willebrand factor level (a marker of microvessel density) in the same tissue samples. VEGFR2 was expressed by neurons, astrocytes and endothelial cells. VEGFR1 was expressed predominantly neuronally and was significantly reduced in AD (p = 0.02). Western blot analysis on a subset of brains showed reduction in VEGFR1: sVEGFR1 in AD (p = 0.046). The lack of angiogenesis despite cerebral hypoperfusion in AD is not explained by altered expression of VEGFR2 or total VEGFR1; indeed, the downregulation of VEGFR1 may represent a pro-angiogenic response to the hypoperfusion. However, the relative increase in sVEGFR1 would be expected to have an anti-angiogenic effect which may be a factor in AD.