Reactivation of gammaHV68 induces neointimal lesions in pulmonary arteries of S100A4/Mts1-overexpressing mice in association with degradation of elastin.
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 (gammaHV68). We observed, 6 mo after gammaHV68 [4 x 10(3) 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 gammaHV68 (4 x 10(6) 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 gammaHV68. These features resolved by 3 mo without neointimal formation. We therefore infected mice with the M1-gammaHV68 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.
Spiekerkoetter
Edda
E
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305-5162, USA.
Alvira
Cristina Maria
CM
Kim
Yu-Mee
YM
Bruneau
Alexandra
A
Pricola
Katie Lynn
KL
Wang
Lingli
L
Ambartsumian
Noona
N
Rabinovitch
Marlene
M
D000818:Animals; D000956:Antigens, Viral / Q000378:metabolism; D001794:Blood Pressure; D004549:Elastin / Q000378:metabolism*; D018142:Gammaherpesvirinae / Q000502:physiology*; D006566:Herpesviridae Infections / Q000821:virology; D006976:Hypertension, Pulmonary / Q000503:physiopathology / Q000821:virology; D017380:Hypertrophy, Right Ventricular / Q000503:physiopathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011651:Pulmonary Artery / Q000473:pathology* / Q000821:virology*; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics*; D019562:Viral Load; D014775:Virus Activation; D053586:Virus Internalization
D000956:Antigens, Viral; D010455:Peptides; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D004549:Elastin