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This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/L276    most recent 00414.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Spiekerkoetter, E. Articles by Rabinovitch, M. Search for Related Content PubMed PubMed Citation Articles by Spiekerkoetter, E. Articles by Rabinovitch, M.

Reactivation of HV68 induces neointimal lesions in pulmonary arteries of S100A4/Mts1-overexpressing mice in association with degradation of elastin

¹Department of Pediatrics, Stanford University School of Medicine, Stanford, California; ²Institut Jacques Monod, Paris, France; and ³Danish Cancer Institute, Copenhagen, Denmark

Submitted 8 October 2007 ; accepted in final form 11 December 2007

S100A4/Mts-overexpressing mice have thick elastic laminae and mild pulmonary arterial hypertension (PAH), and the occasional older mouse develops occlusive neointimal lesions and perivascular inflammation. We hypothesized that a vasculotropic virus could induce neointimal lesions in the S100A4/Mts1 mouse by facilitating breakdown of elastin and migration and proliferation of smooth muscle cells. To test this hypothesis, we infected S100A4/Mts1 mice with gammaherpesvirus 68 (HV68). We observed, 6 mo after HV68 [4 x 10³ plaque-forming units (PFU)], perivascular inflammation in 10/15 S100A4/Mts1 mice and occlusive neointimal formation in 3/10 mice, accompanied by striking degradation of elastin. We then compared the early response after high-dose HV68 (4 x 10⁶ PFU) in C57Bl/6 and S100A4/Mts1 mice. In S100A4/Mts1 mice only, significant PAH, muscularization of distal vessels, and elastase activity were observed 6 wk after HV68. These features resolved by 3 mo without neointimal formation. We therefore infected mice with the M1-HV68 strain that reactivates from latency with higher efficiency and observed neointimal lesions at 3 mo in 2/5 C57Bl/6 (5–9% of vessels) and in 5/5 S100A4/Mts1 mice (13–40% of vessels) accompanied by mild PAH, heightened lung elastase activity, and intravascular viral expression. This suggested that enhanced generation of elastin peptides in S100A4/Mts1 mice may promote increased viral entry in the vessel wall. Using S100A4/Mts1 PA organ culture, we showed, in response to elastase activity, heightened production of elastin peptides associated with invasion of inflammatory cells and intravascular viral antigen. We therefore propose that early viral access to the vessel wall may be a critical determinant of the extent of vascular pathology following reactivation.

pulmonary hypertension; herpes virus; pulmonary vascular occlusive disease