Arteries and veins are anatomically, functionally and molecularly distinct. The current model of arterial–venous identity proposes that binding of vascular endothelial growth factor to its heterodimeric receptor—Flk1 and neuropilin 1 (NP-1; also called Nrp1)—activates the Notch signalling pathway in the endothelium, causing induction of ephrin B2 expression and suppression of ephrin receptor B4 expression to establish arterial identity1,2,3,4. Little is known about vein identity except that it involves ephrin receptor B4 expression, because Notch signalling is not activated in veins; an unresolved question is how vein identity is regulated. Here, we show that COUP-TFII (also known as Nr2f2), a member of the orphan nuclear receptor superfamily, is specifically expressed in venous but not arterial endothelium. Ablation of COUP-TFII in endothelial cells enables veins to acquire arterial characteristics, including the expression of arterial markers NP-1 and Notch signalling molecules, and the generation of haematopoietic cell clusters. Furthermore, ectopic expression of COUP-TFII in endothelial cells results in the fusion of veins and arteries in transgenic mouse embryos. Thus, COUP-TFII has a critical role in repressing Notch signalling to maintain vein identity, which suggests that vein identity is under genetic control and is not derived by a default pathway.
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We thank W. Qian and C. Yang for technical assistance; M. Yanagisawa for providing the Tie2-Cre transgenic mice; Y. Furuta for providing the Efnb2 construct for RNA in situ hybridization; and F. Petit for the COUP-TFII minigene construct. We also thank L.-Y. Yu-Lee and H. J. Bellen for discussions and critical reading of the manuscript. This work was supported by NIH grants to S.Y.T. and M.-J.T.
The authors declare that they have no competing financial interests.
Differential expression pattern of COUP-TFII using knockin lacZ reporter as a marker in the vasculature. (PDF 158 kb)
Model of cell autonomous versus non-cell autonomous functions. (PDF 50 kb)
Endothelial-specific knockout of COUP-TFII by Tie2-Cre. (PDF 125 kb)
The endothelial-specific COUP-TFII null mutants exhibited a variety of vascular defects. (PDF 138 kb)
The haematopoietic-specific markers in haematopoietic cell clusters of the mutant. (PDF 99 kb)
Legends to accompany the above Supplementary Figures. (DOC 25 kb)
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You, LR., Lin, FJ., Lee, C. et al. Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity. Nature 435, 98–104 (2005). https://doi.org/10.1038/nature03511
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