Vascular endothelial growth factor-dependent angiogenesis and dynamic vascular plasticity in the sensory circumventricular organs of adult mouse brain
Vascular endothelial growth factor-dependent angiogenesis and dynamic vascular plasticity in the sensory circumventricular organs of adult mouse brain
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DOI：
10.1007/s00441-014-2080-9
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发表时间：
2015-03-01
影响因子：
3.6
通讯作者：
Miyata, Seiji
中科院分区：
文献类型：
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作者：
Morita, Shoko;Furube, Eriko;Miyata, Seiji
室周感觉器官（Sensory circumventricular organ，CVOs）包括终板血管器（orgum vasculosum of the lamina terminalis，OVLT）、穹窿下器（subfornical organ，SFO）和最后区（area postrema，AP），缺乏典型的血脑屏障（blood-brain barrier，BBB），直接监测血液来源的信息，调节体液平衡、炎症、摄食和呕吐。到目前为止，除了血管内皮细胞的开窗外，几乎没有关于感觉CVOs的血管特征的记录。因此，我们研究是否连续血管生成发生在成年小鼠的感觉CVOs。血管生成诱导因子血管内皮生长因子-A（VEGF-A）和VEGF-A调节转录因子低氧诱导因子-1 α在OVLT和SFO的神经元和AP的神经元和星形胶质细胞中高度表达。周细胞调节因子血小板源性生长因子B在感觉CVOs的星形胶质细胞中表达较高。溴脱氧尿苷和Ki-67（一种与细胞增殖相关的核蛋白）的免疫组织化学显示内皮细胞活跃增殖。此外，caspase-3和基底膜标记物层粘连蛋白的免疫组织化学显示，分别存在内皮细胞凋亡和发芽。用VEGF受体相关酪氨酸激酶抑制剂AZD 2171治疗显著减少了内皮细胞的增殖和丝状伪足发芽，以及微血管的面积和直径。有丝分裂抑制剂胞嘧啶-b-D-阿拉伯呋喃糖苷减少了内皮细胞的增殖和血液来源的低分子量分子的血管通透性，而不改变血管面积和微血管直径。因此，我们的数据表明，持续的血管生成依赖于VEGF信号传导，并负责血管结构和渗透性的动态可塑性。
The sensory circumventricular organs (CVOs), which comprise the organum vasculosum of the lamina terminalis (OVLT), the subfornical organ (SFO) and the area postrema (AP), lack a typical blood-brain barrier (BBB) and monitor directly blood-derived information to regulate body fluid homeostasis, inflammation, feeding and vomiting. Until now, almost nothing has been documented about vascular features of the sensory CVOs except fenestration of vascular endothelial cells. We therefore examine whether continuous angiogenesis occurs in the sensory CVOs of adult mouse. The angiogenesis-inducing factor vascular endothelial growth factor-A (VEGF-A) and the VEGF-A-regulating transcription factor hypoxia-inducible factor-1 alpha were highly expressed in neurons of the OVLT and SFO and in both neurons and astrocytes of the AP. Expression of the pericyte-regulating factor platelet-derived growth factor B was high in astrocytes of the sensory CVOs. Immunohistochemistry of bromodeoxyuridine and Ki-67, a nuclear protein that is associated with cellular proliferation, revealed active proliferation of endothelial cells. Moreover, immunohistochemistry of caspase-3 and the basement membrane marker laminin showed the presence of apoptosis and sprouting of endothelial cells, respectively. Treatment with the VEGF receptor-associated tyrosine kinase inhibitor AZD2171 significantly reduced proliferation and filopodia sprouting of endothelial cells, as well as the area and diameter of microvessels. The mitotic inhibitor cytosine-b-D-arabinofuranoside reduced proliferation of endothelial cells and the vascular permeability of blood-derived low-molecular-weight molecules without changing vascular area and microvessel diameter. Thus, our data indicate that continuous angiogenesis is dependent on VEGF signaling and responsible for the dynamic plasticity of vascular structure and permeability.