Glomeruloid microvascular proliferation follows adenoviral vascular permeability factor/vascular endothelial growth factor-164 gene delivery
Glomeruloid microvascular proliferation follows adenoviral vascular permeability factor/vascular endothelial growth factor-164 gene delivery
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DOI：
10.1016/s0002-9440(10)64062-x
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发表时间：
2001-03-01
影响因子：
6
通讯作者：
Dvorak, HF
中科院分区：
文献类型：
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作者：
Sundberg, C;Nagy, JA;Dvorak, HF
肾小球样小体是多形性胶质母细胞瘤和其他一些肿瘤和血管畸形的定义性组织学特征。其发病机制知之甚少。我们将一种非复制型腺病毒载体注射到无胸腺小鼠的耳中，该载体被设计成表达血管通透性因子/血管内皮生长因子-164（VPF/VEGF（164））。该载体感染强烈表达VPF/VEGF（164）mRNA的局部细胞10至14天，之后表达逐渐下降。局部表达的VPF/VEGF（164）诱导微血管通透性早期增加，在24小时内导致水肿和血管外纤维蛋白沉积;此外，许多原有微血管扩大形成薄壁、周细胞贫乏的“母”血管。在第3天首次检测到肾小球样体前体，其为母血管内皮衬里中快速增殖细胞的局灶性积聚，紧邻表达VPF/VEGF的细胞（164）最初，肾小球样体由内皮细胞组成，但随后周细胞和巨噬细胞也参与其中。由于内皮细胞和周细胞增殖，肾小球样小体扩大，严重损害了母血管腔和血流。随后，随着VPF/VEGF（164）表达的下降，肾小球样小体通过凋亡和重组进入正常外观的微血管而在数周内退化。这些结果提供了诱导肾小球样小体的第一个动物模型，并表明VPF/VEGF（164）足以诱导肾小球样小体，并且是维持肾小球样小体所必需的。
Glomeruloid bodies are a defining histological feature of glioblastoma multiforme and some other tumors and vascular malformations. Little is known about their pathogenesis. We injected a nonreplicating adenoviral vector engineered to express vascular permeability factor/vascular endothelial growth factor-164 (VPF/VEGF(164)) into the ears of athymic mice. This vector infected local cells that strongly expressed VPF/VEGF(164) mRNA for 10 to 14 days, after which expression gradually declined. Locally expressed VPF/VEGF(164) induced an early increase in microvascular permeability, leading within 24 hours to edema and deposition of extravascular fibrin; in addition, many pre-existing microvessels enlarged to form thin-walled, pericyte-poor, "mother" vessels. Glomeruloid body precursors were first detected at 3 days as focal accumulations of rapidly proliferating cells in the endothelial lining of mother vessels, immediately adjacent to cells expressing VPF/VEGF(164) Initially, glomeruloid bodies were comprised of endothelial cells but subsequently pericytes and macrophages also participated. As they enlarged by endothelial cell and pericyte proliferation, glomeruloid bodies severely compromised mother vessel lumens and blood flow. Subsequently, as VPF/VEGF(164) expression declined, glomeruloid bodies devolved throughout a period of weeks by apoptosis and reorganization into normal-appearing microvessels. These results provide the first animal model for inducing glomeruloid bodies and indicate that VPF/VEGF(164) is sufficient for their induction and necessary for their maintenance.