Functional Arterial and Venous Fate Is Determined by Graded VEGF Signaling and Notch Status During Embryonic Stem Cell Differentiation

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Abstract
Objective— The aim of this work was to develop a mouse embryonic stem (ES) cell system addressing the early specification of the developing vasculature into functional arteries and veins. Methods and Results— ES cells were differentiated 4 days on collagen-type IV coated dishes to obtain Flk1 + endothelial precursors. Sub-culture of these precursors for additional 4 days robustly generated, in a VEGF dose-dependent manner, mature endothelial cells. Arterial marker genes were specifically expressed in cultures differentiated with high VEGF concentration whereas the venous marker gene COUP-TFII was upregulated in endothelial cells induced through low and intermediate VEGF concentrations. This VEGF-dependent arterialization could be blocked by inhibition of Notch resulting in an arterial to venous fate switch. Functional and morphological studies, ie, measurement of sprout length, pericyte recruitment, and interleukin-I-induced leukocyte adhesion, further confirmed their arterial and venous identity. Conclusions— We conclude that endothelial cells with distinct molecular, morphological, and functional characteristics of arteries and veins can be derived through in vitro differentiation of ES cells in a VEGF dose-dependent and Notch-regulated manner.

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