FAK activity exacerbates disturbed flow-mediated atherosclerosis via VEGFR2-CBL-NF-κB signaling

Area of Science:

• Cardiovascular Biology
• Endothelial Cell Signaling
• Atherosclerosis Pathogenesis

Background:

• Atherosclerosis develops at sites of disturbed blood flow, leading to vascular inflammation.
• Disturbed flow increases endothelial cell (EC) permeability and inflammatory gene expression.
• Vascular endothelial growth factor receptor 2 (VEGFR2) is involved in flow-induced EC inflammation, but its precise signaling pathway remains unclear.

Purpose of the Study:

• To elucidate the signaling mechanism linking focal adhesion kinase (FAK) and VEGFR2 in flow-mediated endothelial inflammation.
• To investigate the role of FAK-VEGFR2 interaction in the context of atherosclerosis development.

Main Methods:

• Investigated flow-mediated activation of FAK and NF-kB in endothelial cells.
• Examined the interaction between FAK, VEGFR2, and Casitas B-lineage lymphoma (CBL) under flow conditions.
• Utilized Apoe-/- mice on a Western diet to assess FAK activity in atheroprone regions of the aorta.

Main Results:

• VEGF priming of VEGFR2 is critical for flow-mediated activation of FAK and NF-kB.
• FAK activation promotes tyrosine phosphorylation of CBL, which interacts with VEGFR2 under flow.
• FAK inhibition reduced VEGFR2-FAK-CBL complex formation and VEGFR2 cell membrane expression.
• Apoe-/- mice showed increased FAK activity in disturbed flow regions, correlating with elevated cell surface VEGFR2.

Conclusions:

• FAK activation is a key mediator of disturbed flow-induced endothelial inflammation.
• The FAK-VEGFR2-CBL axis plays a significant role in this inflammatory signaling pathway.
• Suppression of FAK activity may be a therapeutic target for reducing endothelial pro-inflammatory responses in atherosclerosis.