The human herpesvirus 8 chemokine receptor vGPCR triggers autonomous proliferation of endothelial cells
The human herpesvirus 8 chemokine receptor vGPCR triggers autonomous proliferation of endothelial cells
复制标题
DOI：
10.1172/jci26666
复制
发表时间：
2006-05-01
影响因子：
15.9
通讯作者：
Lira, SA
中科院分区：
文献类型：
--
作者：
Grisotto, MG;Garin, A;Lira, SA
我们使用了一种新的条件转基因系统来研究病毒G蛋白偶联受体（vGPCR）诱导血管增殖的机制，vGPCR是由人疱疹病毒8 （HHV8，也称为卡波西肉瘤疱疹病毒）编码的组成活性趋化因子受体。使用该系统，我们能够控制vGPCR的时间表达，并通过使用替代标记物LacZ监测其原位表达。在多西环素（DOX）处理后，表达vGPCR和LacZ的细胞（vGPCR/LacZ（+）细胞）逐渐聚集在观察到血管增生的区域。从血管生成病变中筛选的vGPCR/LacZ（+）细胞表达内皮祖细胞特征的标志物，产生血管生成因子，并在体外增殖。用DOX长期治疗转基因小鼠可导致耳朵、尾巴、鼻子和爪子皮肤肿瘤的发展。vGPCR/LacZ（+）细胞在早期病变中很常见，但在这些肿瘤中很少出现。最后，将vGPCR/LacZ（+）细胞转移到经DOX处理的Rag1（-/-）小鼠体内，导致血管增生，并随着时间的推移，肿瘤同时含有vGPCR/LacZ（+）和vGPCR/LacZ（-）细胞。综上所述，这些结果表明vGPCR直接触发血管增殖，并提示该分子在卡波西肉瘤发病机制中的新作用。
We have used a novel conditional transgenic system to study the mechanisms of angioproliferation induced by viral G protein-coupled receptor (vGPCR), the constitutively active chemokine receptor encoded by human herpesvirus 8 (HHV8, also known as Kaposi sarcoma herpesvirus). Using this system, we were able to control temporal expression of vGPCR and to monitor its expression in situ via the use of the surrogate marker LacZ. Upon treatment with doxycycline (DOX), cells expressing vGPCR and LacZ (vGPCR/LacZ(+) cells) progressively accumulated in areas where angioproliferation was observed. Sorted vGPCR/LacZ(+) cells from angiogenic lesions expressed markers characteristic of endothelial progenitor cells, produced angiogenic factors, and proliferated in vitro. Prolonged treatment of transgenic mice with DOX led to development of tumors in the skin of ears, tail, nose, and paws. vGPCR/LacZ(+) cells were frequent in early lesions but scarce within these tumors. Finally, transfer of vGPCR/LacZ(+) cells into Rag1(-/-) mice treated with DOX led to angioproliferation and, with time, to development of tumors containing both vGPCR/LacZ(+) and vGPCR/LacZ(-) cells. Taken together, these results indicate that vGPCR triggers angioproliferation directly and suggest a novel role for this molecule in the pathogenesis of Kaposi sarcoma.