UMMS Affiliation

Department of Molecular, Cell, and Cancer Biology

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Cell Biology | Cellular and Molecular Physiology | Developmental Biology


The formation of new vessels requires a tight synchronization between proliferation, differentiation, and sprouting. However, how these processes are differentially activated, often by neighboring endothelial cells (ECs), remains unclear. Here, we identify cell cycle progression as a regulator of EC sprouting and differentiation. Using transgenic zebrafish illuminating cell cycle stages, we show that venous and lymphatic precursors sprout from the cardinal vein exclusively in G1 and reveal that cell-cycle arrest is induced in these ECs by overexpression of p53 and the cyclin-dependent kinase (CDK) inhibitors p27 and p21. We further demonstrate that, in vivo, forcing G1 cell-cycle arrest results in enhanced vascular sprouting. Mechanistically, we identify the mitogenic VEGFC/VEGFR3/ERK axis as a direct inducer of cell-cycle arrest in ECs and characterize the cascade of events that render "sprouting-competent" ECs. Overall, our results uncover a mechanism whereby mitogen-controlled cell-cycle arrest boosts sprouting, raising important questions about the use of cell cycle inhibitors in pathological angiogenesis and lymphangiogenesis.


endothelial cells, cell cycle

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Copyright 2021 The Authors. This is an open access article under the CC BY-NC-ND license (

DOI of Published Version



Jerafi-Vider A, Bassi I, Moshe N, Tevet Y, Hen G, Splittstoesser D, Shin M, Lawson ND, Yaniv K. VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells. Cell Rep. 2021 Jun 15;35(11):109255. doi: 10.1016/j.celrep.2021.109255. PMID: 34133928; PMCID: PMC8220256. Link to article on publisher's site

Journal/Book/Conference Title

Cell reports

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Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.