Impaired collateral vessel development associated with reduced expression of vascular endothelial growth factor in ApoE-/- mice
Impaired collateral vessel development associated with reduced expression of vascular endothelial growth factor in ApoE-/- mice
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DOI：
10.1161/01.cir.99.24.3188
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发表时间：
1999-06-22
期刊：
影响因子：
37.8
通讯作者：
Isner, JM
中科院分区：
文献类型：
--
作者：
Couffinhal, T;Silver, M;Isner, JM
研究了单侧后肢ischemia.Methods和Results-Hindlimb血流和毛细血管密度在apoE（-/-）小鼠与C57对照组相比明显降低的载脂蛋白（apo）E-/-小鼠中脂质代谢紊乱对侧支血管发育的影响。这与apoE（-/-）小鼠缺血肢体中血管内皮生长因子（VEGF）表达减少有关。细胞特异性免疫染色将VEGF蛋白表达定位于C57小鼠缺血肢体的骨骼肌细胞和浸润性T细胞;相反，apoE-/-小鼠缺血肢体的T细胞浸润严重减少。T细胞对VEGF表达和侧支血管生长的关键贡献通过在手术诱导的后肢缺血的无胸腺裸鼠中发现加速肢体坏死而得到加强。腺病毒VEGF基因转移给apoE（-/-）小鼠导致后肢血流量和毛细血管密度的显著增加。结论-这些发现强调了高脂血症对原生侧支血管发育的不利影响，但并不排除对外源性细胞因子的反应增加侧支血管生长，此外，在apoE（-/-）和无胸腺裸鼠中获得的结果暗示了浸润性T细胞作为缺血组织的新血管形成中VEGF的来源的关键作用。
Background-The impact of disordered lipid metabolism on collateral vessel development was studied in apolipoprotein (apo)E-/- mice with unilateral hindlimb ischemia.Methods and Results-Hindlimb blood flow and capillary density were markedly reduced in apoE(-/-) mice versus C57 controls. This was associated with reduced expression of vascular endothelial growth factor (VEGF) in the ischemic limbs of apoE(-/-) mice. Cell-specific immunostaining localized VEGF protein expression to skeletal myocytes and infiltrating T cells in the ischemic limbs of C57 mice; in contrast, T-cell infiltrates in ischemic limbs of apoE-/- mice were severely reduced. The critical contribution of T cells to VEGF expression and collateral vessel growth was reinforced by the finding of accelerated limb necrosis in athymic nude mice with operatively induced hindlimb ischemia. Adenoviral VEGF gene transfer to apoE(-/-) mice resulted in marked augmentation of hindlimb blood now and capillary density.Conclusions-These findings thus underscore the extent to which hyperlipidemia adversely affects native collateral development but does not preclude augmented collateral vessel growth in response to exogenous cytokines, Moreover, results obtained in the apoE(-/-) and athymic nude mice imply a critical role for infiltrating T cells as a source of VEGF in neovascularization of ischemic tissues.