Cytomegalovirus Impairs Cytotrophoblast-Induced Lymphangiogenesis and Vascular Remodeling in an in Vivo Human Placentation Model
Cytomegalovirus Impairs Cytotrophoblast-Induced Lymphangiogenesis and Vascular Remodeling in an in Vivo Human Placentation Model
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DOI：
10.1016/j.ajpath.2012.08.003
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发表时间：
2012-11-01
影响因子：
6
通讯作者：
Pereira, Lenore
中科院分区：
文献类型：
--
作者：
Tabata, Takako;Petitt, Matthew;Pereira, Lenore
我们通过比较人胎盘绒毛中作为体外外植体的低传代亲内皮病毒株 VR1814 和减毒实验室病毒株 AD169 的感染以及移植到 SCID 小鼠（即患有严重联合免疫缺陷的小鼠）肾囊中的异种移植物来研究人巨细胞病毒发病机制。在这种体内人类胎盘模型中，人类细胞滋养层侵入肾实质，重塑常驻动脉，并诱导强烈的淋巴管生成反应。 VR1814 在葡萄树和细胞柱细胞滋养层中复制并减少体外锚定绒毛的形成。在异种移植物中，受感染的细胞滋养层侵入和重塑常驻动脉的能力严重减弱。浸润性淋巴管内皮细胞增殖、聚集，未能形成淋巴管。相比之下，AD169在外植体的细胞滋养细胞中生长不良，并且锚定绒毛在体外正常形成。同样，异种移植物中的病毒复制受到损害，细胞滋养层保留了侵袭能力，但一些部分重塑的血管包含淋巴内皮细胞并且可渗透血液。 VR1814感染的外植体中血管内皮生长因子（VEGF）-C和碱性成纤维细胞生长因子的表达均增加，而AD169感染的外植体中VEGF-A和可溶性VEGF受体3的表达增加。我们的研究结果表明，病毒复制和旁分泌因素可能会破坏血管重塑和细胞滋养层诱导的淋巴管生成，导致先天性人类巨细胞病毒感染并发的妊娠出血、缺氧和水肿。 （Am J Pathol 2012 年，181：1540 1559；http://dx.doi.org/10.1016/j.ajpath.2012.08.003）
We investigated human cytomegalovirus pathogenesis by comparing infection with the low-passage, endotheliotropic strain VR1814 and the attenuated laboratory strain AD169 in human placental villi as explants in vitro and xenografts transplanted into kidney capsules of SCID mice (ie, mice with severe combined immunodeficiency). In this in vivo human placentation model, human cytotrophoblasts invade the renal parenchyma, remodel resident arteries, and induce a robust lymphangiogenic response. VR1814 replicated in vinous and cell column cytotrophoblasts and reduced formation of anchoring villi in vitro. In xenografts, infected cytotrophoblasts had a severely diminished capacity to invade and remodel resident arteries. Infiltrating lymphatic endothelial cells proliferated, aggregated, and failed to form lymphatic vessels. In contrast, AD169 grew poorly in cytotrophoblasts in explants, and anchoring villi formed normally in vitro. Likewise, viral replication was impaired in xenografts, and cytotrophoblasts retained invasive capacity, but some partially remodeled blood vessels incorporated lymphatic endothelial cells and were permeable to blood. The expression of both vascular endothelial growth factor (VEGF)-C and basic fibroblast growth factor increased in VR1814-infected explants, whereas VEGF-A and soluble VEGF receptor-3 increased in those infected with AD169. Our results suggest that viral replication and paracrine factors could undermine vascular remodeling and cytotrophoblast-induced lymphangiogenesis, contributing to bleeding, hypoxia, and edema in pregnancies complicated by congenital human cytomegalovirus infection. (Am J Pathol 2012, 181:1540 1559; http://dx.doi.org/10.1016/j.ajpath.2012.08.003)