Hypoglycemia Reduces Vascular Endothelial Growth Factor A Production by Pancreatic Beta Cells as a Regulator of Beta Cell Mass
Hypoglycemia Reduces Vascular Endothelial Growth Factor A Production by Pancreatic Beta Cells as a Regulator of Beta Cell Mass
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DOI：
10.1074/jbc.m112.422949
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发表时间：
2013-03-22
影响因子：
4.8
通讯作者：
Gittes, George K.
中科院分区：
文献类型：
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作者：
Xiao, Xiangwei;Guo, Ping;Gittes, George K.
β细胞中血管内皮生长因子-A的表达对胰腺发育、胰岛特异性血管的形成和胰岛素的分泌至关重要。然而，有两个关键问题仍然存在。首先，β细胞释放的血管内皮生长因子-A是否与β细胞产生的血管内皮生长因子-A偶联？第二，代谢信号如何影响β细胞对血管内皮生长因子-A的反应？在这里，我们表明，无论是培养的胰岛细胞还是纯化的胰岛细胞，在低糖条件下，早期的血管内皮生长因子-A的分泌显著减少，但不是基因转录。在体内，用胰岛素颗粒诱导小鼠持续低血糖，导致β细胞质量显著减少。持续注射外源性血管内皮生长因子-A对正常血糖小鼠的β细胞质量没有影响，可以显著挽救这种β细胞质量的损失。此外，低血糖期间内皮细胞凋亡率的增加先于β细胞凋亡率的增加。外源性血管内皮生长因子-A可抑制血管内皮细胞和胰岛β细胞的凋亡，提示血管内皮生长因子-A的减少可能与胰岛血管系统和胰岛β细胞的丧失有关。此外，在这些试验组中，没有一组的β细胞增殖和胰岛血管密度发生变化，这表明这两个细胞间隔之间存在严格调控的平衡。胰岛平均大小在低血糖时减小，这也可被外源性血管内皮生长因子-A阻止。综上所述，我们的数据表明，β细胞中的血管内皮生长因子-A的释放不依赖于血管内皮生长因子-A的合成。根据生理需要，可以通过调节β细胞释放血管内皮生长因子-A来调节β细胞的质量。
VEGF-A expression in beta cells is critical for pancreatic development, formation of islet-specific vasculature, and Insulin secretion. However, two key questions remain. First, is VEGF-A release from beta cells coupled to VEGF-A production in beta cells? Second, how is the VEGF-A response by beta cells affected by metabolic signals? Here, we show that VEGF-A secretion, but not gene transcription, in either cultured islets or purified pancreatic beta cells, was significantly reduced early on during low glucose conditions. In vivo, a sustained hypoglycemia in mice was induced with Insulin pellets, resulting in a significant reduction in beta cell mass. This loss of beta cell mass could be significantly rescued with continuous delivery of exogenous VEGF-A, which had no effect on beta cell mass in normoglycemic mice. In addition, an increase in apoptotic endothelial cells during hypoglycemia preceded an increase in apoptotic beta cells. Both endothelial and beta cell apoptosis were prevented by exogenous VEGF-A, suggesting a possible causative relationship between reduced VEGF-A and the loss of islet vasculature and beta cells. Furthermore, in none of these experimental groups did beta cell proliferation and islet vessel density change, suggesting a tightly regulated balance between these two cellular compartments. The average islet size decreased in hypoglycemia, which was also prevented by exogenous VEGF-A. Taken together, our data suggest that VEGF-A release in beta cells is independent of VEGF-A synthesis. Beta cell mass can be regulated through modulated release of VEGF-A from beta cells based on physiological need.