Vascular endothelial growth factor increases functional β-cell mass by improvement of angiogenesis of isolated human and murine pancreatic islets
Vascular endothelial growth factor increases functional β-cell mass by improvement of angiogenesis of isolated human and murine pancreatic islets
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DOI：
10.1097/01.tp.0000163506.40189.65
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发表时间：
2005-06-15
期刊：
影响因子：
6.2
通讯作者：
Linn, T
中科院分区：
文献类型：
--
作者：
Lai, Y;Schneider, D;Linn, T
背景胰岛移植中血流受损，但通过促进血管形成来改善结果的证据相互矛盾。我们以前报道，胰岛内皮细胞（EC）具有显着的血管生成能力。为了进一步解决这个问题，我们研究了缺氧条件下培养的人类胰岛。此外，我们使用了一种转基因小鼠模型，在大鼠胰岛素启动子（RIP）的控制下，β细胞中产生人血管内皮生长因子（VEGF），以刺激胰岛EC增殖。继缺氧刺激，胰岛响应特定的表达模式的VEGF和成纤维细胞生长因子，但是，这是不足以防止胰岛EC的衰减。RIP-VEGF转基因胰岛的VEGF释放受葡萄糖控制，并导致芽的形成。当移植到糖尿病小鼠的肾包膜时，与对照组相比，RIP-VEGF胰岛显著增加了微血管密度和功能性血流量。胰岛移植的优化血管生成导致β细胞增殖引起的胰岛素的更大可用性和糖尿病治愈小鼠的显著更高百分比（90%对20%）。
Background. Blood flow is impaired in islet transplants, but there is conflicting evidence on improving the outcome by promoting vascularization. We previously reported that islet endothelial cells (EC) possess significant angiogenic capacity.Methods. To further address this issue, we studied human islets in culture under hypoxic conditions. Moreover, we used a transgene mouse model with human vascular endothelial growth factor (VEGF) production in beta-cells under the control of the rat insulin promoter (RIP) to stimulate islet EC proliferation.Results. Subsequent to a hypoxic stimulus, islets responded with specific expression patterns of VEGF and fibroblast growth factor; however, this was not sufficient to prevent the decay of islet EC. VEGF release of RIP-VEGF transgenic islets was controlled by glucose and resulted in the formation of sprouts. When transplanted to the kidney capsule of diabetic mice, RIP-VEGF islets significantly enhanced microvascular density and functional blood flow to the graft compared with controls.Conclusions. Optimized angiogenesis of islet transplants resulted in greater availability of insulin caused by beta-cell proliferation and a significantly higher percentage (90% versus 20%) of mice cured from diabetes.