We examined cerebral and temporal arteries, all of which contained VZV antigen, from 3 patients with VZV vasculopathy, as well as a control artery that was negative for VZV antigen. Findings on the VZV-infected arteries were compared to the uninfected normal cerebral artery () which was composed of a single layer of endothelial cells adjacent to the lumen (intima), an internal elastic lamina, a wall of smooth muscle cells (media), and an outer layer consisting of collagen and adventitial fibroblasts (adventitia). Importantly, the arteries represented early and late infection: the artery from subject 1 was obtained 4 weeks after zoster before neurologic symptoms and signs relevant to that artery developed, while the arteries from subjects 2 and 3 were obtained at autopsy after 45 and 48 weeks of protracted neurologic illness, respectively. The presence of most VZV antigen in the adventitia of the early case, combined with a heavy antigenic burden in the media and intima of the 2 late cases, supports the notion that VZV spreads transmurally from the adventitia to the intima, presumably after transaxonal spread to the artery via ganglionic afferent fibers.18,19
Although it remains unknown why virtually all cases of VZV vasculopathy involve cerebral arteries rather than systemic arteries, it is possible that the absence of an external elastic lamina in cerebral arteries, unlike systemic arteries,20
facilitates transmural spread of virus in cerebral arteries with continued virus production in a thickened intima.
Results of histologic and immunohistochemical analyses of cerebral and temporal arteries from subjects with VZV vasculopathy were similar. All arteries contained a hyperplastic intima with a duplicated or disrupted internal elastic lamina. The degree of neointimal thickening was greater in the late cases (subjects 2 and 3) than in the early case (subject 1), suggestive of vascular remodeling that continues for months after initial VZV infection. Although a thin endothelial layer was readily seen on the luminal surface of the 3 VZV-infected arteries, the thickened intima did not contain CD31-positive cells, thus making endothelial cells an unlikely source of the hyperplastic intima. Instead, the thickened intima contained cells expressing both α-SMA and SM-MHC, indicating a smooth muscle cell origin. Furthermore, far fewer cells expressing α-SMA and SM-MHC were seen in the media of the late cases (subjects 2 and 3) compared to the early case (subject 1) or in the normal cerebral artery. Together, these findings suggest that some neointimal cells originated from smooth muscle cells in the media after VZV infection. The thickened intima also contained abundant cells that expressed α-SMA but not SM-MHC (myofibroblasts). While dedifferentiated smooth muscle cells can retain α-SMA and lose SM-MHC expression, it is also possible that these myofibroblasts originated from resident or circulating progenitor cells or adventitial fibroblasts. Unfortunately, there are no specific markers to identify the origin of these neointimal myofibroblasts.
The VZV-infected arteries did not contain a distinct core of extracellular lipid in the thickened intima characteristic of atheromatous lesions21
or medial hypertrophy seen in hypertensive vascular disease.22
Although intimal hyperplasia and a fragmented internal elastic lamina may be seen in cerebral arteries of patients with HIV-associated vasculopathy, other diverse pathologic changes characteristic of HIV vasculopathy—perivascular space dilatation, rarefaction, pigment deposition with vessel wall mineralization, and perivascular inflammatory cell infiltrates23
—as well as aneurysmal formation and fibrosis24
were conspicuously absent.
Analysis of the morphology and composition of the thickened intima and media, and the location of viral antigen in the adventitia in early VZV vasculopathy, revealed clues to the possible mechanisms of VZV-induced vascular remodeling that leads to stroke. Previous studies of pulmonary and coronary vascular wall remodeling revealed that the adventitia is a key regulator in vascular wall structure and function.25–36
After vascular injury (i.e., balloon injury,25,26,28
), adventitial fibroblasts can differentiate into myofibroblasts that proliferate and migrate to the intima. In addition, these “activated” adventitial fibroblasts can 1) secrete factors that create a proinflammatory environment, further contributing to vascular wall remodeling,29,30,32–34
and 2) affect adjacent adventitial fibroblasts and medial smooth muscle cells such that they acquire a proliferative, migratory, and invasive phenotype.27,32,35
Alternatively, adventitial dendritic cells have been shown to become activated and contribute to a proinflammatory environment leading to vascular wall remodeling, as seen in giant cell arteritis.36,37
It is possible that VZV infection of adventitial cells might lead to cerebrovascular wall remodeling in a similar manner. Further studies are under way to analyze the inflammatory environment and dendritic cell activation in VZV-infected arteries.