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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 5

vGPCR/LacZ+ ear cells transfer angioproliferative disease to Rag1–/– mice.

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                  vGPCR/LacZ+
                  ear cells transfer angi...
(A) Sorted vGPCR/LacZ+ cells (3 × 104) were injected s.c. into the middle region of the dorsum of the ear of Rag1-deficient mice. Angiogenic lesions were visible in the ears of the group treated with DOX (lower left panel) but not in the ears of untreated animals (upper panels). (B) Flow cytometric analysis of ears that received vGPCR/LacZ+ cells. CD31+LacZ+ cells were absent in mice treated with regular chow (upper dot plot) but present in mice treated with DOX (lower dot plot). (C) Representative β-gal histochemistry of whole-mount preparation shows the high coincidence of vGPCR/LacZ+ cell aggregates (blue) with areas with angiogenic activity (shown in A). Vessel sprouting was occasionally observed (arrows, insert in C). (D) After 120 days of DOX treatment, the number of CD31+LacZ+ cells was 7-fold higher than the number of cells injected. Values shown are the mean ± SD. Scale bar: 50 μm.

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

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