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

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 1

vGPCR/LacZ+ cells accumulate over time in lesional areas.

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vGPCR/LacZ+ cells accumulate over t...
(A) iORF74 mice were generated by coinjection of a DOX-dependent activator and responder vGPCR transgene (bracket indicates transgene cointegration). iORF74 mice and TRE-LacZ mice were crossed (X) to generate iORF74/LacZ mice. hLCR, locus control region; p, CMV minimal promoter; rβglobin A, rabbit β globin polyadenylation signal. (B and C) iORF74/LacZ mice develop highly vascularized lesions in the ears (B, arrows) and tumors in the tail (C), depending on the length of DOX treatment (30 days and 100 days respectively). (D) β-gal whole-mount histochemistry of ears from iORF74/LacZ mice untreated (0 d) or treated with DOX for 5, 10, and 15 days (n = 6 ears per time point). No blue cells were found in ears of control mice (not shown) or untreated iORF74 mice. After 5 days of DOX treatment, small clusters of blue cells were detected (arrows). The number and the size of clusters increased over time. Scale bar: 100 μm. (E) Visualization of the vascular tree and vGPCR/LacZ+ cells using biotinylated L. esculentum lectin and β-gal whole-mount histochemistry. After 10 days of DOX treatment, vGPCR/LacZ+ cells were present in small capillaries or venules (arrows) and surrounding hair follicles. Scale bar: 20 μm.