Flow-Dependent Endothelial YAP Regulation Contributes to Vessel Maintenance

Area of Science:

• Vascular biology
• Mechanotransduction
• Cell signaling

Background:

• Endothelial cells (ECs) are critical for blood vessel function and respond to mechanical forces like blood flow.
• The Hippo-Yap pathway regulates cell proliferation and organ size, but its role in ECs under flow is less understood.
• Actin cytoskeleton reorganization is a known response to mechanical stimuli in ECs.

Purpose of the Study:

• To investigate the role of YAP (Yes-associated protein) in endothelial cells in response to blood flow in vivo.
• To elucidate the molecular mechanisms underlying blood-flow-mediated YAP regulation in ECs.
• To determine the importance of endothelial YAP for vascular stability.

Main Methods:

• Utilized living zebrafish to monitor Yap1 (zebrafish YAP) transcriptional activity and localization in response to blood flow.
• Employed cultured human ECs subjected to laminar shear stress to study YAP nuclear import and transcriptional activity.
• Investigated the involvement of filamentous actin and angiomotin in flow-induced YAP translocation.
• Generated and analyzed Yap1 mutant zebrafish to assess vascular stability.

Main Results:

• Blood flow in zebrafish induced nuclear entry and transcriptional activation of Yap1 in ECs.
• Laminar shear stress in human ECs promoted YAP nuclear import and transcriptional activity independently of the Hippo pathway.
• Flow-induced YAP nuclear translocation was mediated by the regulation of filamentous actin and angiomotin.
• Yap1 mutant zebrafish exhibited compromised vascular stability.

Conclusions:

• Endothelial YAP is regulated by blood flow, promoting transcription and maintaining vascular integrity.
• The mechanism involves cytoskeletal changes and angiomotin, operating independently of canonical Hippo signaling.
• Endothelial Yap1 plays an essential role in ensuring blood vessel stability under physiological flow conditions.