PUBLICATION
Endothelial Cell Flow-Mediated Quiescence Is Temporally Regulated and Utilizes the Cell Cycle Inhibitor p27
- Authors
- Tanke, N.T., Liu, Z., Gore, M.T., Bougaran, P., Linares, M.B., Marvin, A., Sharma, A., Oatley, M., Yu, T., Quigley, K., Vest, S., Cook, J.G., Bautch, V.L.
- ID
- ZDB-PUB-240411-15
- Date
- 2024
- Source
- Arteriosclerosis, Thrombosis, and Vascular Biology 44(6): 1265-1282 (Journal)
- Registered Authors
- Bautch, Victoria, Gore, Michaelanthony
- Keywords
- cell cycle, endothelial cells, laminar shear stress, quiescence depth, zebra fish
- MeSH Terms
-
- Animals
- Cell Cycle
- Cell Proliferation
- Cells, Cultured
- Cyclin-Dependent Kinase Inhibitor p27*/genetics
- Cyclin-Dependent Kinase Inhibitor p27*/metabolism
- Endothelial Cells*/metabolism
- Human Umbilical Vein Endothelial Cells/metabolism
- Humans
- Inhibitor of Differentiation Proteins/genetics
- Inhibitor of Differentiation Proteins/metabolism
- Mechanotransduction, Cellular
- Mice
- Neoplasm Proteins
- Regional Blood Flow
- Time Factors
- Zebrafish*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 38602102 Full text @ Arterio., Thromb., and Vas. Bio.
Citation
Tanke, N.T., Liu, Z., Gore, M.T., Bougaran, P., Linares, M.B., Marvin, A., Sharma, A., Oatley, M., Yu, T., Quigley, K., Vest, S., Cook, J.G., Bautch, V.L. (2024) Endothelial Cell Flow-Mediated Quiescence Is Temporally Regulated and Utilizes the Cell Cycle Inhibitor p27. Arteriosclerosis, Thrombosis, and Vascular Biology. 44(6):1265-1282.
Abstract
Background Endothelial cells regulate their cell cycle as blood vessels remodel and transition to quiescence downstream of blood flow-induced mechanotransduction. Laminar blood flow leads to quiescence, but how flow-mediated quiescence is established and maintained is poorly understood.
Methods Primary human endothelial cells were exposed to laminar flow regimens and gene expression manipulations, and quiescence depth was analyzed via time-to-cell cycle reentry after flow cessation. Mouse and zebrafish endothelial expression patterns were examined via scRNA-seq analysis, and mutant or morphant fish lacking p27 were analyzed for endothelial cell cycle regulation and in vivo cellular behaviors.
Results Arterial flow-exposed endothelial cells had a distinct transcriptome, and they first entered a deep quiescence, then transitioned to shallow quiescence under homeostatic maintenance conditions. In contrast, venous flow-exposed endothelial cells entered deep quiescence early that did not change with homeostasis. The cell cycle inhibitor p27 (CDKN1B) was required to establish endothelial flow-mediated quiescence, and expression levels positively correlated with quiescence depth. p27 loss in vivo led to endothelial cell cycle upregulation and ectopic sprouting, consistent with loss of quiescence. HES1 and ID3, transcriptional repressors of p27 upregulated by arterial flow, were required for quiescence depth changes and the reduced p27 levels associated with shallow quiescence.
Conclusions Endothelial cell flow-mediated quiescence has unique properties and temporal regulation of quiescence depth that depends on the flow stimulus. These findings are consistent with a model whereby flow-mediated endothelial cell quiescence depth is temporally regulated downstream of p27 transcriptional regulation by HES1 and ID3. The findings are important in understanding endothelial cell quiescence misregulation that leads to vascular dysfunction and disease.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping