title: 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.affiliation: Immunobiology Center and Department of Neurology and Center for Translational Systems Biology, Mount Sinai School of Medicine, New York, New York 10029-6574, USA.
authors.forename: Marcos G
authors.initials: MG
authors.lastname: Grisotto
authors.forename: Alexandre
authors.initials: A
authors.lastname: Garin
authors.forename: Andrea P
authors.initials: AP
authors.lastname: Martin
authors.forename: Kristian K
authors.initials: KK
authors.lastname: Jensen
authors.forename: Pokman
authors.initials: P
authors.lastname: Chan
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Sealfon
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Lira
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004318:Doxycycline / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000821:virology*; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D007763:Lac Operon; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic; D019707:Receptors, Chemokine / Q000737:chemistry / Q000502:physiology*
chemical_list: C115448:G protein-coupled receptor, Human herpesvirus 8; D019707:Receptors, Chemokine; D004318:Doxycycline