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The human herpesvirus 8 chemokine receptor vGPCR triggers autonomous proliferation of endothelial cells
Marcos G. Grisotto, … , Stuart C. Sealfon, Sergio A. Lira
Marcos G. Grisotto, … , Stuart C. Sealfon, Sergio A. Lira
Published May 1, 2006
Citation Information: J Clin Invest. 2006;116(5):1264-1273. https://doi.org/10.1172/JCI26666.
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Research Article Oncology Article has an altmetric score of 3

The human herpesvirus 8 chemokine receptor vGPCR triggers autonomous proliferation of endothelial cells

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Abstract

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.

Authors

Marcos G. Grisotto, Alexandre Garin, Andrea P. Martin, Kristian K. Jensen, PokMan Chan, Stuart C. Sealfon, Sergio A. Lira

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Figure 4

vGPCR/LacZ+ cells originate from cells present in adult ears.

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                  vGPCR/LacZ+
                  cells originate from ce...
Ear cells from perfused untreated iORF74/LacZ mice were cultured in Matrigel in the presence or absence of 10 μg/ml DOX. β-gal histochemistry and Q-PCR were performed before culture (day 0) and after 4, 10, and 15 days in culture. (A) By day, 10 small clusters of blue cells and structures that resembled vessels (arrows) were observed. (B) Immunohistochemistry analysis of the clusters present at day 10 after culture showed the presence of CD31+ cells forming vessel-like structures. (C) Quantification of LacZ+ cells in cultures of ear cells revealed a significant increase in the number of vGPCR/LacZ+ cells over time. (D) Expression of vGPCR increased over time in cultured cells in the presence of DOX (detected by Q-PCR). Data were normalized to ubiquitin expression levels and are representative of 3 experiments. Values shown are the mean ± SD. Statistical significance was calculated comparing values with those of day 0. *P < 0.05. Scale bars: 20 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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