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The establishment of arterial and venous identity of endothelial cells is critical for the proper anatomic configuration and function of the vascular tree. Arterial and venous specification of endothelial cells is determined by genetic factors, although surrounding cells and hemodynamic forces may also contribute to vascular remodeling. This review provides an overview of the signaling pathways and related transcription factors implicated in differentiation of endothelial cells. We will discuss, in particular, the role of upstream and downstream effectors of Wnt, Sox, and Notch pathways. The understanding of the molecular mechanisms that orchestrate endothelial differentiation may have therapeutic relevance for diseases such as atherosclerosis, arteriovenous malformations, aneurysms, and others.

(C) 2014 American Heart Association, Inc.