Background: Vascular remodelling is characterized by increased smooth muscle cell (SMC) proliferation and migration. Coincident with these events, SMC markers of differentiation are known to down-regulate in advanced stages of atherosclerosis, a process known as phenotypic modulation. However, it is not known when this first begins. Here we sought to determine if regions of the mouse aorta with varying susceptibilities for atherosclerosis display differential vascular remodelling and SMC gene expression at the earliest stages of disease.
Methods and results: LDLrKO mice were fed normal or high cholesterol diet for 0-98 days. In the latter, ORO and H&E staining of arch, thoracic and abdominal aortic sections revealed infrequent occurrences of lipid deposition at d28, but significant region-specific vascular remodelling. Immunostaining for PCNA revealed increased cellular proliferation in the intima and inner media at d28 in all three regions. qRT-PCR of SMC revealed increased expression of SM22alpha and SM-MHC in the arch by d28, which subsequently decreased by d98. By contrast, eNOS gene expression was consistently decreased in the arch over these times. A temporal increase in macrophage-specific CD68 expression was observed in the arch but not thoracic or abdominal regions.
Conclusion: Remodelling of the vascular myocyte compartment due to cellular proliferation is an early event in atherosclerosis and is associated with increases in SMC-specific gene expression. These events precede subsequent lesion formation and SMC phenotypic modulation.