THE MOLECULAR MECHANISMS OF ENDOTHELIAL DIFFERENTATION

血管发生是在发育中的胚胎中形成初级血管网络。该过程中最早的步骤之一是多能干细胞分化为内皮细胞。分子机制，特别是调节这一过程的特定转录因子仍然不完全清楚。沿着内皮谱系的分化沿着与内皮标志物的顺序表达相关，所述内皮标志物包括酪氨酸激酶FIk-1、Fit-1，随后是Tie 1和Tie 2。我们和其他人的研究表明 ETS和加塔转录因子家族的成员是血管发育过程中这些基因的关键调节因子。内皮细胞分化不仅在胚胎发育过程中很重要。在成人中，在冠状动脉缺血等病理条件下，内皮祖细胞（EPC）从骨髓动员到体循环中，并促进特定靶位点的血管生成血管的发育。我们的初步研究表明，富含EPCs的胚胎干细胞可以促进心肌梗死后的血管生成，导致毛细血管密度增加，与梗死面积减少和血流动力学改善相关。该建议的总体假设是，内皮分化是一个复杂的发育过程，其由特定细胞表面标志物和转录因子的严格调控的顺序表达所支配，并且在病理条件下被重演以促进血管生成。更好地了解分子机制，特别是参与内皮细胞分化的转录因子，可能会为促进缺血性心脏病和外周血管疾病的血管生成提供新的策略。

Vasculogenesis is the formation of a primary vascular network in the developing embryo. One of the earliest steps in this process is the differentiation of endothelial cells from pluripotent stem cells. The molecular mechanisms and in particular the specific transcription factors that regulate this process remain incompletely understood. Differentiation along the endothelial lineage is associated with the sequential expression of endothelial markers including the tyrosine kinases FIk-1, Fit-1, followed by Tie1, and Tie2. Our studies as well as those of others suggest that members of the ETS and GATA transcription factor families are critical regulators of these genes during vascular development. Endothelial differentiation is not only important during embryonic development. In the adult, in pathological conditions such as coronary ischemia, endothelial progenitor cells (EPC)s are mobilized from the bone marrow into the systemic circulation and promote the development of angiogenic blood vessels at specific target sites. Our preliminary studies demonstrate that embryonic stem cells enriched with EPCs can promote angiogenesis after myocardial infarction, resulting in increases in capillary density associated with a reduction in infarct size and hemodynamic improvements. The overall hypothesis for this proposal is that endothelial differentiation is a complex developmental process that is govemed by the tightly regulated sequential expression of specific cell surface markers and transcription factors and is recapitulated under pathological conditions to promote angiogenesis. A better understanding of the molecular mechanisms and in particular, the transcription factors involved in endothelial differentiation may provide insights into novel strategies toward promoting angiogenesis in ischemic hear disease and peripheral vascular disease.