THE MOLECULAR MECHANISMS OF ENDOTHELIAL DIFFERENTATION

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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.