Brissova Marcela, Shostak Alena, Shiota Masakazu, Wiebe Peter O, Poffenberger Greg, Kantz Jeannelle, Chen Zhongyi, Carr Chad, Jerome W Gray, Chen Jin, Baldwin H Scott, Nicholson Wendell, Bader David M, Jetton Thomas, Gannon Maureen, Powers Alvin C
Division of Diabetes, Endocrinology, and Metabolism, 715 PRB, Vanderbilt University, Nashville, TN 37232, USA.
Diabetes. 2006 Nov;55(11):2974-85. doi: 10.2337/db06-0690.
To investigate molecular mechanisms controlling islet vascularization and revascularization after transplantation, we examined pancreatic expression of three families of angiogenic factors and their receptors in differentiating endocrine cells and adult islets. Using intravital lectin labeling, we demonstrated that development of islet microvasculature and establishment of islet blood flow occur concomitantly with islet morphogenesis. Our genetic data indicate that vascular endothelial growth factor (VEGF)-A is a major regulator of islet vascularization and revascularization of transplanted islets. In spite of normal pancreatic insulin content and beta-cell mass, mice with beta-cell-reduced VEGF-A expression had impaired glucose-stimulated insulin secretion. By vascular or diffusion delivery of beta-cell secretagogues to islets, we showed that reduced insulin output is not a result of beta-cell dysfunction but rather caused by vascular alterations in islets. Taken together, our data indicate that the microvasculature plays an integral role in islet function. Factors modulating VEGF-A expression may influence islet vascularity and, consequently, the amount of insulin delivered into the systemic circulation.
为了研究移植后控制胰岛血管生成和再血管化的分子机制，我们检测了分化中的内分泌细胞和成年胰岛中三类血管生成因子及其受体在胰腺中的表达。利用活体凝集素标记，我们证明了胰岛微血管的发育和胰岛血流的建立与胰岛形态发生同时发生。我们的遗传学数据表明，血管内皮生长因子（VEGF）-A是胰岛血管生成和移植胰岛再血管化的主要调节因子。尽管胰腺胰岛素含量和β细胞量正常，但β细胞VEGF-A表达降低的小鼠葡萄糖刺激的胰岛素分泌受损。通过将β细胞促分泌剂经血管或扩散方式递送至胰岛，我们表明胰岛素分泌减少不是β细胞功能障碍的结果，而是由胰岛血管改变引起的。综上所述，我们的数据表明微血管在胰岛功能中起着不可或缺的作用。调节VEGF-A表达的因子可能影响胰岛血管状态，从而影响进入体循环的胰岛素量。
