Endothelial cell cycle state determines propensity for arterial-venous fate

Nicholas W. Chavkin, Gael Genet, Mathilde Poulet, Erin D. Jeffery, Corina Marziano, Nafiisha Genet, Hema Vasavada, Elizabeth A. Nelson, Bipul R. Acharya, Anupreet Kour, Jordon Aragon, Stephanie P. McDonnell, Mahalia Huba, Gloria M. Sheynkman, Kenneth Walsh and Karen K. Hirschi ()
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Nicholas W. Chavkin: University of Virginia School of Medicine
Gael Genet: University of Virginia School of Medicine
Mathilde Poulet: Yale Cardiovascular Research Center Yale University School of Medicine
Erin D. Jeffery: University of Virginia School of Medicine
Corina Marziano: University of Virginia School of Medicine
Nafiisha Genet: University of Virginia School of Medicine
Hema Vasavada: Yale Cardiovascular Research Center Yale University School of Medicine
Elizabeth A. Nelson: University of Virginia School of Medicine
Bipul R. Acharya: University of Virginia School of Medicine
Anupreet Kour: University of Virginia School of Medicine
Jordon Aragon: University of Virginia School of Medicine
Stephanie P. McDonnell: University of Virginia School of Medicine
Mahalia Huba: University of Virginia School of Medicine
Gloria M. Sheynkman: University of Virginia School of Medicine
Kenneth Walsh: University of Virginia School of Medicine
Karen K. Hirschi: University of Virginia School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract During blood vessel development, endothelial cells become specified toward arterial or venous fates to generate a circulatory network that provides nutrients and oxygen to, and removes metabolic waste from, all tissues. Arterial-venous specification occurs in conjunction with suppression of endothelial cell cycle progression; however, the mechanistic role of cell cycle state is unknown. Herein, using Cdh5-CreERT2;R26FUCCI2aR reporter mice, we find that venous endothelial cells are enriched for the FUCCI-Negative state (early G1) and BMP signaling, while arterial endothelial cells are enriched for the FUCCI-Red state (late G1) and TGF-β signaling. Furthermore, early G1 state is essential for BMP4-induced venous gene expression, whereas late G1 state is essential for TGF-β1-induced arterial gene expression. Pharmacologically induced cell cycle arrest prevents arterial-venous specification defects in mice with endothelial hyperproliferation. Collectively, our results show that distinct endothelial cell cycle states provide distinct windows of opportunity for the molecular induction of arterial vs. venous fate.

Date: 2022
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DOI: 10.1038/s41467-022-33324-7

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