부산대학교 도서관

OBJECTIVE: The mechanism of postangioplasty restenosis remains poorly understood. Low molecular weight (LMW) heparin has been shown to inhibit the proliferation of vascular smooth muscle cells (VSMCs), which is the principal characteristic of restenosis. Studies have shown that LMW heparin could bind to CD44. We hypothesized that LMW heparin might modulate CD44 expression thereby decreasing vascular remodeling. METHODS: Vascular remodeling was induced in CD44 and CD44 mice and treated with LMW heparin. The arteries were harvested for histologic assessment and determination of CD44 expression. Bone marrow transplantation was introduced to further explore the role and functional sites of CD44. Effects of LMW heparin on growth capacity, CD44 expression were further studied using the cultured mouse VSMCs. RESULTS: Transluminal injury induced remarkable remodeling in mouse femoral artery (sham wall thickness percentage [WT%]: 3.4 ± 1.2% vs injury WT%: 31.8 ± 4.7%; P < .001). LMW heparin reduced the remodeling significantly (WT%: 17.8 ± 3.5%, P < .005). CD44 mice demonstrated considerably thicker arterial wall remodeling (WT%: 46.2 ± 7.6%, P = .0035), and CD44-chimeric mice exhibited equal contributions of the local and circulating CD44 signal to the neointima formation. LMW heparin markedly upregulated CD44 expression in the injured femoral arteries. In vitro, LMW heparin decreased mouse VSMC growth capacity and upregulated its CD44 expression simultaneously in a dose-dependent and time-dependent manner, which could be partially blocked by CD44 inhibitor. CONCLUSIONS: LMW heparin inhibits injury-induced femoral artery remodeling, at least partially, by upregulating CD44 expression. CLINICAL RELEVANCE: Angioplasty is widely used in clinical practice to treat various stenostic vascular disorders, but the postangioplasty reocclusion has been a big limit and the mechanism underlying the vascular remodeling remains poorly understood. LMW heparin has been a promising medicine to inhibit VSMC proliferation. However, the mechanism of LMW heparin inhibition against smooth muscle cell (SMC) proliferation and its clinical usefulness is still not clear. Our present data, which were based on in vivo and in vitro studies, suggested that LMW heparin induced higher CD44 expression in VSMCs, and through the CD44 pathway, LMW heparin significantly reduced SMC proliferation and injury-induced femoral artery remodeling. Our study clarified the roles of LMW heparin in vascular occlusive diseases. This study helps to elucidate the underlying cellular and molecular mechanism by which LMW heparin inhibits injury-induced remodeling and could promote creating new therapeutics to control the exaggerated neointimal hyperplasia.