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) plays a role in flow-induced EC inflammation, but its signaling pathway requires further elucidation.

Purpose of the Study:

• To investigate the role of focal adhesion kinase (FAK) in flow-mediated signaling and its link to VEGFR2 in endothelial cells.
• To elucidate the molecular mechanisms connecting FAK and VEGFR2 in the context of disturbed flow-induced inflammation.

Main Methods:

• Utilized cell culture models and Apoe-/- mice fed a western diet.
• Investigated the activation of FAK, VEGFR2, and NF-κB under varying flow conditions.
• Examined the interaction between FAK, Casitas B-lineage lymphoma (CBL), and VEGFR2.

Main Results:

• VEGFR2 priming with VEGF is essential for flow-induced activation of FAK and NF-κB.
• FAK activation leads to tyrosine phosphorylation of CBL, which interacts with VEGFR2 under flow.
• Apoe-/- mice showed increased FAK activity in atheroprone disturbed flow regions, correlating with elevated surface VEGFR2 on ECs.

Conclusions:

• FAK activation is a key component of the VEGFR2 signaling pathway in flow-mediated endothelial inflammation.
• Targeting FAK activity in endothelial cells could be a therapeutic strategy to mitigate vascular inflammation in atherosclerosis.