VEGF and Islet Vascularization

描述(申请人提供)：胰岛有广泛的血管，这对它们感知血糖和快速分泌胰岛素的能力很重要。虽然胰岛接收的血流量是周围胰腺腺泡组织的20倍，但导致胰岛血管形成的分子因素和机制尚不完全清楚。新的实验证据表明，胰岛表达多种血管生成因子，如血管内皮生长因子(VEGF)、血管生成素(Ang)和肾上腺素，并且胰岛与内皮细胞之间的相互作用在胰岛的发育和血管形成中都是重要的。胰岛移植是治疗1型糖尿病的一种新兴疗法，但我们科学知识中的主要障碍和差距阻碍了胰岛移植的广泛应用。例如，胰岛分离切断了必须通过血管生成/血管生成重新建立的血管连接；大量的胰岛(可能是大多数)在移植后的第一天死亡，而胰岛正在进行血管重建。血管内皮生长因子是一种重要的血管生成因子，在血管发育、缺血反应中的血管生成以及肿瘤相关的血管生成中起重要作用。尽管胰腺内分泌细胞和外分泌细胞具有共同的发育谱系，但胰岛细胞比周围的外分泌细胞具有更高的血管密度和更多的血管内皮生长因子的表达。为了验证胰岛血管化和血运重建需要胰岛细胞产生血管内皮生长因子-A的假设，我们将： 1)利用Cre-loxP系统暂时失活细胞特异性的血管内皮生长因子-A基因，阐明血管内皮生长因子-A在胰岛发育和功能中的作用。2)检测胰岛中血管内皮生长因子-A功能的增减对胰岛发育和功能的影响。3)确定血管内皮生长因子-A功能的获得或丧失是否会改变移植胰岛的血运重建、存活或功能。这些结果应该能更好地了解正常的胰岛血管形成，以及这如何影响正常的胰岛发育、结构和功能。来自移植研究的信息可能会提出新的治疗策略，以提高移植胰岛血运重建的速度和程度。

DESCRIPTION (provided by applicant): Pancreatic islets are extensively vascularized and this is important in their ability to sense the blood glucose and quickly secrete insulin. While islets receive up to 20 times more blood flow than surrounding pancreatic acinar tissue, the molecular factors and mechanisms responsible for islet vascularization are incompletely defined. New experimental evidence indicates that pancreatic islets express a number of angiogenic factors such as vascular endothelial growth factor (VEGF), angiopoietin (Ang), and ephrins, and that interactions between islet and endothelial cells are important in both islet development and vascularization. Pancreatic islet transplantation is an emerging therapy for type 1 diabetes, but major obstacles and gaps in our scientific knowledge preclude islet transplantation from being widely adapted. For example, islet isolation severs vascular connections that must be reestablished through angiogenesis/vasculogenesis; a large number of islets (perhaps the majority) die in the first days after transplantation while islet revascularization is occurring. VEGF is a crucial angiogenic factor in vascular development, angiogenesis in response to ischemia, and tumor-related angiogenesis. Even though pancreatic endocrine and exocrine cells share a common developmental lineage, islet cells have greater VEGF expression and vessel density than surrounding exocrine cells. To test the hypotheses that islet vascularization and revascularization requires production of VEGF-A by pancreatic islet cells, we will: 1) Elucidate the role of VEGF-A in pancreatic islet development and function using cell-specific, temporal inactivation of the VEGF-A gene using the Cre-loxP system. 2) Examine how gain or loss of VEGF-A function in pancreatic islets affects islet development and function. 3) Determine if gain or loss of VEGF-A function alters the revascularization, survival, or function of transplanted islets. These results should provide a better understanding of normal islet vascularization and how this affects normal islet development, architecture, and function. Information from the transplantation studies may suggest new therapeutic strategies to improve the rapidity and degree of revascularization of transplanted islets.