Mechanism of matrix metalloproteinase axis-induced neointimal growth.

Tumor necrosis factor-α, platelet-derived growth factor, matrix metalloproteinases 9 and 2 have very important roles in neointimal hyperplasia, which develops after endovascular injury. However, the relationships among the four factors in inducing neointimal hyperplasia are unclear. Here, we used a mouse model of femoral arterial transluminal wire injury, and examined neointimal hyperplasia within the 28 days that followed the injury. We confirmed that the neointima kept growing during the 28 days, and found that expression of TNF-α and PDGF mRNAs in femoral arteries peaked within 24h after injury. However, MMP9 mRNA expression peaked 7 days, and MMP2 mRNA expression peaked 28 days after injury. Then, we administered exogenous TNF-α or PDGF to the peri-femoral artery following an injury, and found that exogenous TNF-α led to significantly more neointimal hyperplasia during the first 2 weeks, and PDGF led to increased neointimal hyperplasia during the second 2 weeks after injury. We also used the model of femoral artery injury in MMP9- or MMP2-deficient (MMP9-/- or MMP2-/-) mice. We found that neointimal hyperplasia was reduced in MMP9-/- mice during the first 2 weeks after injury, and neointimal hyperplasia was reduced in MMP2-/- mice during the second 2 weeks after injury. When TNF-α or PDGF was administered to the peri-femoral artery immediately after injury, TNF-α did not promote neointimal hyperplasia in MMP9-/- mice during the first 2 weeks after injury but did in MMP2-/- mice, and PDGF did not promote neointimal hyperplasia in MMP2-/- mice during the second 2 weeks after injury but did in MMP9-/- mice. We used an in vitro system to treat vascular smooth muscle cells (VSMCs) with TNF-α or PDGF; TNF-α induced MMP9, but not MMP2, expression at a fast reaction speed, while PDGF induced MMP2, but not MMP9, expression at a slow reaction speed. Meanwhile, TNF-α induced VSMC migration in a MMP9-dependent manner, and PDGF induced VSMC proliferation in a MMP2-dependent manner. Taken together, our studies elucidated the axis of TNF-α-MMP9-VSMC migration and PDGF-MMP2-VSMC proliferation, both of which contributed to the mechanism of neointimal hyperplasia formation.

Guo L ，Ning W ，Tan Z ，Gong Z ，Li X ... -  《-》

[Role of cytokine-matrix metalloproteinase axis on promoting vascular neointima hyperplasia in mice].

Liu Y ，Ning WH ，Shen XH ，Guo DL ，Guo L ... -  《-》

Targeted disruption of the prostaglandin E2 E-prostanoid 2 receptor exacerbates vascular neointimal formation in mice.

Zhu S ，Xue R ，Zhao P ，Fan FL ，Kong X ，Zheng S ，Han Q ，Zhu Y ，Wang N ，Yang J ，Guan Y ... -  《-》

Syndecan-4 deficiency limits neointimal formation after vascular injury by regulating vascular smooth muscle cell proliferation and vascular progenitor cell mobilization.

Ikesue M ，Matsui Y ，Ohta D ，Danzaki K ，Ito K ，Kanayama M ，Kurotaki D ，Morimoto J ，Kojima T ，Tsutsui H ，Uede T ... -  《-》

Zinc finger protein 191 deficiency attenuates vascular smooth muscle cell proliferation, migration, and intimal hyperplasia after endovascular arterial injury.

Restenosis engenders surgical vascular intervention failure. Zinc finger protein 191 (ZFP191) is a novel member of the SCAN domain family of Krüppel-like zinc finger transcription factors. Previous work reveals that ZFP191 is a pleiotropic factor that plays important roles in hematopoiesis, brain development, and tumor growth. Here, we sought to determine whether intimal hyperplasia was affected by the activity of ZFP191 and to investigate the molecular mechanisms that may underpin the process. Intimal hyperplasia was induced by guidewire injury in mouse femoral arteries. The arteries were harvested for morphometric assessment and determination of ZFP191 expression. Next, ZFP191 knockdown in cultured mouse aortic vascular smooth muscle cells (VSMCs) was achieved by lentiviral transduction of short-hairpin RNA. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay, [(3)H]thymidine incorporation assay, scratch assay, and transwell migration assay were used to evaluate the effects of ZFP191 knockdown on VSMC growth and migration. In addition, β-catenin, c-myc, cyclin D1, matrix metalloproteinase (MMP) 9, MMP2, and MMP7 were measured by Western blotting in the absence of ZFP191 in vitro and in vivo. Zymography was used to evaluate MMP activity in cell culture-conditioned media. Lastly, artery injury was performed in wild-type (WT) and heterozygous ZFP191 knockout (KO) mice, and morphometric analysis of the arteries was determined. Guidewire injury was associated with development of intimal hyperplasia, and ZFP191 expression was enhanced by 51% in the injured arteries. Cultured primary VSMCs transfected with lentiviral shZFP191 displayed reduced proliferation and migration compared with controls. Mechanically, ZFP191 knockdown potently decreased the level of β-catenin and its downstream targets c-myc and cyclin D1. ZFP191 knockdown downregulated the expression of MMP9, MMP2, and MMP7, and zymography confirmed that ZFP191 knockdown reduced the activity of MMPs. Consistent with the in vitro data, elevated expression of β-catenin, c-myc, cyclin D1, MMP9, MMP2, and MMP7 accompanied upregulation of ZFP191 after injury in the femoral arteries of mice, and these levels were downregulated in ZFP191 KO vessels. Finally, intimal hyperplasia was greatly blocked in heterozygous ZFP191 KO mice compared with WT mice (intima/media ratio, 0.124 vs 0.412; P < .05). ZFP191 played an essential role in aggressive proliferation and migration of VSMCs, which in turn facilitated intimal hyperplasia. Our findings offer the first genetic evidence of ZFP191 as a potential therapeutic target to prevent restenosis.

Lv L ，Zhang J ，Wang P ，Meng Q ，Liang W ，Zhang L ... -  《-》