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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:487.)
© 2007 American Heart Association, Inc.

Vascular Biology

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

Fredrik Lanner; Marcus Sohl; Filip Farnebo

From the Departments of Cell and Molecular Biology (F.L., M.S., F.F.) and Molecular Medicine and Surgery-Section of Plastic and Reconstructive Surgery (F.F.), Karolinska Institutet, Stockholm, Sweden.

Correspondence to Fredrik Lanner, Department of Cell and Molecular Biology, Karolinska Institutet, Box 285, SE-17177 Stockholm, Sweden. E-mail fredrik.lanner{at}ki.se

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.

In this study we developed an ES cell in vitro differentiation system to address early specification of the developing vasculature into functional arteries and veins. We found arterial specification to be VEGF and Notch dependent, while inhibition of Notch signaling or low VEGF levels were permissive for venous differentiation.

Key Words: angiogenesis • embryonic stem cells • arteries and veins • VEGF • Notch

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