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

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 8

LacZ– cells in tumors of transplanted Rag mice derive from LacZ+ cells.

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LacZ– cells in tumors of transplant...
Sorted vGPCR/LacZ+ cells from the ears of DOX-treated iORF74/LacZ mice were transplanted into the tail skin of Rag1–/– mice. After transfer, mice were treated with DOX for 120 days. (A) An incipient tumor (nodule) in the area where vGPCR/LacZ+ cells were injected contained both LacZ+ and LacZ– cells (red circles). (B) The nodule is mainly composed of CD31+ cells (green). (C and D) Representative LacZ+ and LacZ– cells before (C) and after (D) laser capture microdissection. (E) Relative levels of vGPCR, neomycin, and LacZ DNA in total genomic DNA from microdissected samples (n = 5 per group). (F) Normalized values of DNA content of LacZ+ and LacZ– cells microdissected from the tail nodule in recipient mice (represented by the red circles in A). LacZ+ and LacZ– samples collected within the tumor have a similar DNA profile, suggesting that they derive from the same source (vGPCR/LacZ+ cells). Scale bars: 50 μm (A), 100 μm (B).