Pancreatic islets are highly vascularized mini-organs, and vascular endothelial growth factor (VEGF)-A is a critical factor in the development of islet vascularization. To investigate the role of VEGF-A and endothelial cells (ECs) in adult islets, we used complementary genetic approaches to temporally inactivate VEGF-A in developing mouse pancreatic and islet progenitor cells or in adult β-cells. Inactivation of VEGF-A early in development dramatically reduced pancreatic and islet vascularization, leading to reduced β-cell proliferation in both developing and adult islets and, ultimately, reduced β-cell mass and impaired glucose clearance. When VEGF-A was inactivated in adult β-cells, islet vascularization was reduced twofold. Surprisingly, even after 3 months of reduced islet vascularization, islet architecture and β-cell gene expression, mass, and function were preserved with only a minimal abnormality in glucose clearance. These data show that normal pancreatic VEGF-A expression is critical for the recruitment of ECs and the subsequent stimulation of endocrine cell proliferation during islet development. In contrast, although VEGF-A is required for maintaining the specialized vasculature observed in normal adult islets, adult β-cells can adapt and survive long-term reductions in islet vascularity. These results indicate that VEGF-A and islet vascularization have a lesser role in adult islet function and β-cell mass.

译文

:胰岛是高度血管化的小器官,而血管内皮生长因子(VEGF)-A是胰岛血管化发展的关键因素。为了研究VEGF-A和内皮细胞(EC)在成年胰岛中的作用,我们使用互补的遗传方法在发育中的小鼠胰腺和胰岛祖细胞或成年β细胞中暂时失活了VEGF-A。早期发育中的VEGF-A失活极大地减少了胰腺和胰岛的血管形成,从而导致发育中和成年胰岛的β细胞增殖减少,最终导致β细胞量减少和葡萄糖清除率降低。当成年β细胞中VEGF-A失活时,胰岛血管形成减少了两倍。令人惊讶的是,即使在减少了3个月的胰岛血管形成后,胰岛结构和β细胞基因表达,质量和功能仍得以保留,而葡萄糖清除率仅有极少的异常。这些数据表明,正常的胰腺VEGF-A表达对于胰岛细胞的募集以及胰岛发育过程中内分泌细胞增殖的后续刺激至关重要。相反,尽管维持正常成年胰岛中观察到的特定脉管系统需要VEGF-A,但成年β细胞可以适应并在胰岛血管的长期减少中存活下来。这些结果表明,VEGF-A和胰岛血管化在成年胰岛功能和β细胞量中的作用较小。

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