Endothelial Cell Flow-Mediated Quiescence Is Temporally Regulated and Utilizes the Cell Cycle Inhibitor p27

Area of Science:

• Vascular Biology
• Cell Cycle Regulation
• Mechanotransduction

Background:

• Endothelial cells control blood vessel remodeling and quiescence through mechanotransduction.
• The mechanisms establishing and maintaining flow-mediated endothelial cell quiescence remain unclear.

Purpose of the Study:

• To investigate the establishment and maintenance of endothelial cell quiescence under different laminar flow conditions.
• To elucidate the role of the cell cycle inhibitor p27 and its regulatory factors in flow-mediated quiescence.

Main Methods:

• Primary human endothelial cells exposed to laminar flow and gene expression manipulations.
• Analysis of quiescence depth via cell cycle reentry time and gene expression.
• In vivo studies using mouse and zebrafish models, including p27-deficient mutants.

Main Results:

• Arterial flow induced a distinct transcriptome and temporal changes in quiescence depth (deep to shallow).
• Venous flow led to early deep quiescence without homeostatic changes.
• The cell cycle inhibitor p27 (CDKN1B) was essential for quiescence; its loss caused cell cycle upregulation and sprouting.
• HES1 and ID3 regulated p27 levels and quiescence depth changes in response to arterial flow.

Conclusions:

• Endothelial cell quiescence exhibits unique temporal regulation dependent on flow stimulus.
• Flow-mediated quiescence depth is temporally regulated by p27, influenced by HES1 and ID3.
• Understanding these mechanisms is critical for addressing vascular dysfunction and disease.