YAP Controls Endothelial Activation and Vascular Inflammation Through TRAF6

Area of Science:

• Endothelial biology
• Molecular mechanisms of inflammation
• Sepsis pathophysiology

Background:

• Microvascular inflammation and endothelial dysfunction are key in sepsis and organ failure.
• The mechanisms regulating endothelial cell activation are not fully understood.

Purpose of the Study:

• To investigate the role of Yes-associated protein (YAP) in controlling endothelial activation and vascular inflammation.

Main Methods:

• Generated endothelial-specific YAP knockout mice.
• Challenged mice with lipopolysaccharide and polymicrobial sepsis.
• Analyzed inflammatory markers, cell adhesion, and organ injury.
• Investigated YAP's interaction with TRAF6 and NF-κB signaling.

Main Results:

• YAP deletion in endothelial cells increased basal E-selectin and ICAM-1 expression and neutrophil adhesion.
• YAP deficiency exacerbated LPS-induced inflammation, neutrophil/monocyte adhesion, and lung injury.
• Endothelial YAP deletion worsened sepsis outcomes and cardiovascular dysfunction.
• YAP inhibits NF-κB activation by promoting TRAF6 ubiquitination and degradation.

Conclusions:

• YAP suppresses endothelial activation and vascular inflammation by preventing TRAF6-mediated NF-κB activation.
• YAP is essential for limiting sepsis-induced inflammation and organ failure.