Endothelial Cell Flow-Mediated Quiescence Is Temporally Regulated and Utilizes the Cell Cycle Inhibitor p27. Arterioscler Thromb Vasc Biol 2024 Jun;44(6):1265-1282
Date
04/11/2024Pubmed ID
38602102Pubmed Central ID
PMC11238946DOI
10.1161/ATVBAHA.124.320671Scopus ID
2-s2.0-85193995802 (requires institutional sign-in at Scopus site) 1 CitationAbstract
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 (single-cell RNA sequencing) 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.
Author List
Tanke NT, Liu Z, Gore MT, Bougaran P, Linares MB, Marvin A, Sharma A, Oatley M, Yu T, Quigley K, Vest S, Cook JG, Bautch VLAuthor
Ziqing Liu PhD Assistant Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCell Cycle
Cell Proliferation
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p27
Endothelial Cells
Human Umbilical Vein Endothelial Cells
Humans
Inhibitor of Differentiation Proteins
Mechanotransduction, Cellular
Mice
Neoplasm Proteins
Regional Blood Flow
Time Factors
Zebrafish
Zebrafish Proteins
