Submitted on October 8, 2007
Accepted on December 11, 2007
Reactivation of 
HV68 Induces Neointimal Lesions in Pulmonary Arteries of S100A4/Mts1 Over-expressing Mice in Association with Degradation of Elastin
Edda Spiekerkoetter1, Cristina M. Alvira2, Yu-Mee Kim1, Alexandra Bruneau3, Katie L Pricola1, Lingli Wang1, Noona Ambartsumian4, and Marlene Rabinovitch5*
1 Pediatrics, Stanford University School of Medicine, Stanford, California, United States
2 Pediatrics, Stanford University, Stanford, California, United States
3 Institut Jacques Monod, Paris, France
4 Danish Cancer Society, Copenhagen, Denmark
5 Pediatrics, Stanford University, School of Medicine, Stanford, California, United States
* To whom correspondence should be addressed. E-mail: marlener{at}stanford.edu.
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 we infected S100A4/Mts1 mice with 
HV68. We observed, 6m after HV68 (4x103 PFU), perivascular inflammation in 10/15 S100A4/Mts1 mice and occlusive neointimal formation in 3/10 accompanied by striking degradation of elastin. We then compared the early response after high dose HV68 (4x106 PFU) in C57 Bl/6 and S100A4/Mts1 mice. In S100A4/Mts1 mice only, significant PAH, muscularization of distal vessels and elastase activity were observed 6w after HV68. These features resolved by 3m without neointimal formation. We therefore infected mice with the M1-HV68 strain that reactivates from latency with higher efficiency, and observed neointimal lesions at 3m 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 show, 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.
