Lymphatic dysfunction in transgenic mice expressing KSHV k-cyclin under the control of the VEGFR-3 promoter
Lymphatic dysfunction in transgenic mice expressing KSHV k-cyclin under the control of the VEGFR-3 promoter
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DOI：
10.1182/blood-2004-08-3364
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发表时间：
2005-03-15
期刊：
影响因子：
20.3
通讯作者：
Blauvelt, A
中科院分区：
文献类型：
--
作者：
Sugaya, M;Watanabe, T;Blauvelt, A
卡波西肉瘤相关疱疹病毒（KSHV）感染KS肿瘤内的内皮细胞，这些细胞表达KSHV潜伏周期基因k-cyclin（kCYC）以及淋巴管内皮标志物血管内皮生长因子受体3（VEGFR-3）。为了进一步了解KSHV介导的发病机制，我们产生了在VEGFR-3启动子控制下表达kCYC的转基因小鼠。组织内kCYC mRNA和功能蛋白表达与VEGFR-3表达相关，并且在肺组织中最丰富地检测到。临床上，大多数转基因小鼠在6个月内死亡，继发于乳糜胸水的进行性积累。在皮肤中，通过磁共振成像检测到水肿，并且小鼠在创伤后表现出耳朵的持续红斑。组织学上，水肿皮肤显示红细胞外渗和红细胞在淋巴腔内积聚。此外，在转基因小鼠中，注射造影剂的淋巴引流明显受损。在许多组织中检测到了在体外表达kCYC的细胞中观察到的一个特征--核巨大，并且通过原位杂交选择性地发生在表达kCYC mRNA的淋巴管内皮细胞内。总之，小鼠VEGFR-3（+）细胞内的kCYC表达导致淋巴功能显著受损。kCYC可能有助于KS的某些临床和组织学特征的发展，包括KS肿瘤内的局部水肿和外渗红细胞的滞留。(c)2005年，美国血液学会。
Kaposi sarcoma-associated herpesvirus (KSHV) infects endothelial cells within KS tumors, and these cells express the KSHV latent-cycle gene k-cyclin (kCYC) as well as vascular endothelial growth factor receptor 3 (VEGFR-3), a marker for lymphatic endothelium. To further understand KSHV-mediated pathogenesis, we generated transgenic mice expressing kCYC under the control of the VEGFR-3 promoter. kCYC mRNA and functional protein expression within tissue correlated with VEGFR-3 expression and were most abundantly detected within lung tissue. Clinically, most transgenic mice died within 6 months of age secondary to progressive accumulation of chylous pleural fluid. In skin, edema was detected by magnetic resonance imaging and mice demonstrated persistent erythema of the ears following trauma. Histologically, erythematous skin showed extravasation of erythrocytes and accumulation of erythrocytes within lymphatic lumens. In addition, lymphatic drainage of injected contrast dyes was markedly impaired in transgenic mice. Karyomegaly, a feature observed in kCYC-expressing cells in vitro, was detected in many tissues, and selectively occurred within lymphatic endothelial cells expressing kCYC mRNA by in situ hybridization. In summary, kCYC expression within VEGFR-3(+) cells of mice causes marked impairment of lymphatic function. kCYC may contribute to the development of certain clinical and histologic features of KS, including localized edema and retention of extravasated erythrocytes within KS tumors. (c) 2005 by The American Society of Hematology.