Wnt5A/Ryk signaling critically affects barrier function in human vascular endothelial cells

Area of Science:

• Vascular Biology
• Cell Signaling
• Immunology

Background:

• Septic shock lacks effective treatments, with elevated Wnt5A observed in patients.
• Wnt5A, released by macrophages, has poorly understood vascular effects.
• Understanding Wnt5A's endothelial actions is crucial for developing therapies.

Purpose of the Study:

• Investigate Wnt5A's effects on human coronary artery endothelial cells (HCAEC).
• Identify novel Wnt5A-regulated targets and signaling pathways.
• Determine Wnt5A's role in endothelial barrier function and wound healing.

Main Methods:

• Genome-wide differential gene expression analysis in HCAEC.
• Analysis of Wnt5A-induced changes in actin cytoskeleton and adherens junctions.
• Functional assays for endothelial permeability, wound healing, and Ryk receptor involvement.
• Pharmacological inhibition of ROCK signaling.

Main Results:

• Wnt5A primarily targets genes involved in actin cytoskeleton remodeling.
• Wnt5A activates Rho-associated protein kinase (ROCK)/LIM kinase-2 (LIMK2)/cofilin-1 (CFL1) signaling, promoting stress fiber formation.
• Wnt5A disrupts adherens junctions (β-catenin, VE-cadherin), increasing endothelial permeability.
• Ryk receptor is essential for Wnt5A-induced hyperpermeability and impaired wound healing.

Conclusions:

• Wnt5A enhances endothelial permeability via Ryk receptor and downstream ROCK/LIMK2/CFL1 signaling.
• Wnt5A impairs endothelial wound healing, which can be rescued by ROCK inhibition.
• Wnt5A/Ryk signaling presents a potential therapeutic target for managing capillary leakage in septic shock.