Endothelial cell cycle state determines propensity for arterial-venous fate

Area of Science:

• Developmental Biology
• Cell Biology
• Vascular Biology

Background:

• Endothelial cells form a complex circulatory network essential for tissue homeostasis.
• Arterial-venous (A-V) specification is a critical process during blood vessel development.
• The role of endothelial cell cycle state in A-V specification remains mechanistically undefined.

Purpose of the Study:

• To investigate the mechanistic role of endothelial cell cycle states in arterial-venous specification.
• To determine the relationship between cell cycle phases and signaling pathways during A-V fate determination.

Main Methods:

• Utilized Cdh5-CreER^T2;R26FUCCI2aR reporter mice to track endothelial cell cycle states.
• Analyzed gene expression patterns associated with BMP and TGF-β signaling in relation to cell cycle phases.
• Employed pharmacological cell cycle arrest to assess the impact on A-V specification.

Main Results:

• Venous endothelial cells were enriched in the early G1 (FUCCI-Negative) state, associated with BMP signaling.
• Arterial endothelial cells were enriched in the late G1 (FUCCI-Red) state, associated with TGF-β signaling.
• Early G1 state is required for BMP4-induced venous gene expression, and late G1 state for TGF-β1-induced arterial gene expression.

Conclusions:

• Distinct endothelial cell cycle states create specific temporal windows for the molecular induction of arterial versus venous fates.
• Cell cycle regulation is a key determinant in the process of arterial-venous specification.
• Pharmacological cell cycle arrest can rescue A-V specification defects in conditions of endothelial hyperproliferation.