血管内ステント留置後の新生内膜形成におけるプロテオグリカンおよびTGF-βの動態の検討

Abstract

Recently several studies reported that proteoglycans modulate the function of cytokines. In particular, decorin and biglycan are known to bind to TGF-β and may participate in regulating extracellular matrix accumulation. In this study, we have analyzed the spatial and chronological distribution of these proteoglycans, cellular components and two cytokines, TGF-β and IL-1β in the stent-induced neointima formation to clarify their interactions in the process of neointima formation after vascular injury.We implanted Gianturco's Z type stents in cholesterol-loaded or normal rbbbit aortas and harvested the stent-implanted aortas for immunohistochemical and in situ hybridization analysis. In normal aorta, biglycan and TGF-β mRNAs were expressed in the proliferating smooth muscle cells (SMCs) around the scent wire. These expressions gradually reduced as the intimal SMC proliferation ceased On the other hand, decorin and IL-1β mRNAs were rarely detected throughout the experimental period.In cholesterol-loaded rabbit aortas, stent implantation injured the fibrofatty lesion, and induced more advanced neointima formation than that induced in normal aorta. TGF-β and biglycan mRNAs were expressed diffusely in the newly formed intima and their expressions were detectable throughout the experimental period. Decorin protein and mRNA were expressed in close proximity to accumulated macrophages expressing IL-1β mRNA around the stent wire at 2 months after the stent implantation.In summary, the stent implantation in aorta with the pre-existing fibrofatty lesion enhanced neointima formation containing by further accumulation of biglycan and decorin as compared to normal aorta. Colocalization of ecorin and macrophages expressing IL-1β mRNA in the process of neointima formation provides a suggestive evidence that decorin synthesis and deposition are accelerated by IL-1β secreted from macrophages accumulating in the injured areas in the late stage after vascular injury.