PUBLICATION
VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells
- Authors
- Jerafi-Vider, A., Bassi, I., Moshe, N., Tevet, Y., Hen, G., Splittstoesser, D., Shin, M., Lawson, N.D., Yaniv, K.
- ID
- ZDB-PUB-210622-2
- Date
- 2021
- Source
- Cell Reports 35: 109255 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Neovascularization, Physiologic*/drug effects
- Cell Differentiation
- MAP Kinase Signaling System
- Roscovitine/pharmacology
- Veins/cytology*
- Endothelial Cells/cytology*
- Endothelial Cells/drug effects
- Endothelial Cells/metabolism
- Animals, Genetically Modified
- Vascular Endothelial Growth Factor Receptor-3/metabolism
- Cell Cycle Checkpoints*/drug effects
- G1 Phase
- Zebrafish Proteins/metabolism*
- Vascular Endothelial Growth Factor C/metabolism*
- Zebrafish
- Lymphatic Vessels/cytology*
- PubMed
- 34133928 Full text @ Cell Rep.
Citation
Jerafi-Vider, A., Bassi, I., Moshe, N., Tevet, Y., Hen, G., Splittstoesser, D., Shin, M., Lawson, N.D., Yaniv, K. (2021) VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells. Cell Reports. 35:109255.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping