Differential regulation of matrix metalloproteinases in varicella zoster virus-infected human brain vascular adventitial fibroblasts

Abstract

Upon reactivation, varicella zoster virus (VZV) spreads transaxonally, infects cerebral arteries and causes ischemic or hemorrhagic stroke, as well as aneurysms. The mechanism(s) of VZV-induced aneurysm formation is unknown. However, matrix metalloproteinases (MMPs), which digest extracellular structural proteins in the artery wall, play a role in cerebral and aortic artery aneurysm formation and rupture. Here, we examined the effect of VZV infection on expression of MMP-1, -2, -3, and -9 in primary human brain vascular adventitial fibroblasts (BRAFS). At 6 days post-infection, VZV- and mock-infected BRAFs were analyzed for mRNA levels of MMP-1, -2, -3 and -9 by RT-PCR and for corresponding total intra- and extracellular protein levels by multiplex ELISA. The activity of MMP-1 was also measured in a substrate cleavage assay. Compared to mock-infected BRAFs, MMP-1, MMP-3 and MMP-9 transcripts, cell lysate protein and conditioned supernatant protein were all increased in VZV-infected BRAFs, whereas MMP-2 transcripts, cell lysate protein and conditioned supernatant protein were decreased. MMP-1 from the conditioned supernatant of VZV-infected BRAFs showed increased cleavage activity on an MMP-1-specific substrate compared to mock-infected BRAFs. Differential regulation of MMPs in VZV-infected BRAFs may contribute to aneurysm formation in VZV vasculopathy.

Significant Associations of Neurological Complications of Herpes Zoster With Stroke in Rheumatoid Arthritis Patients

“…Accumulation of monocytes/macrophages in the vascular wall can cause atherogenesis . A recent study found that the VZV induced upregulation of matrix metalloproteinases 1, 3, and 9 in brain vascular adventitial fibroblasts, which is associated with disruption of the vessel wall integrity and aneurysm formation. Previous studies also found that matrix metalloproteinases produced by inflammatory cells in virus‐infected arteries may further potentiate pathological vascular remodeling .…”

Varicella zoster virus vasculopathy: The expanding clinical spectrum and pathogenesis

“…Although the mechanisms of vascular remodeling triggered by VZV are unknown, neutrophils may play a role since they produce reactive oxygen species in response to infection, which may mediate smooth muscle cell proliferation and migration (Hartney et al, 2011; Weber et al, 2004) and induce apoptosis and loss of vascular smooth muscle cells (Hsieh et al, 2001; Li et al, 2003). Neutrophils also secrete elastase and matrix metalloproteinases (MMPs; together with activated matrix metalloproteinases directly secreted by VZV infected vascular cells (Nagel et al, 2015b) – these enzymes can lead to extracellular matrix breakdown, weakening of the vessel wall and aneurysm formation (Ferry et al, 1997; Itoh and Nagase, 1995; Okada and Nakanishi, 1989). Finally, a thickened intima was associated with inflammation in vaso vasorum vessels in early VZV vasculopathy, consistent with the notion that inflammatory cells secrete soluble factors that contribute to pathological vascular wall remodeling (Frid et al, 2006; Stenmark et al, 2012).…”

Varicella Zoster Virus in the Nervous System

“…Consistent with studies of pathological remodeling in coronary and pulmonary arteries, the thickened intima was associated with inflammation in the underlying adventitia, supporting the notion that inflammatory cells secrete soluble factors that contribute to vascular remodeling. A recent study also revealed that VZV-infected brain vascular adventitial fibroblasts produce elevated levels of matrix metalloproteinases that degrade extracellular matrix and may contribute to migration of cells to the lumen and thrombosis as well as to aneurysm formation and hemorrhage 18 .…”