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

TL;DR

This study shows how FAK activity worsens atherosclerosis by interacting with VEGFR2 and CBL under disturbed blood flow conditions.

Contribution

The paper identifies a novel signaling pathway involving FAK, VEGFR2, and CBL in flow-mediated inflammation.

Findings

FAK activation is critical for VEGFR2-mediated NF-κB signaling under disturbed flow.

FAK inhibition reduces VEGFR2-FAK-CBL complex formation and VEGFR2 membrane expression.

Increased FAK activity in atheroprone regions correlates with elevated VEGFR2 on endothelial cells.

Abstract

Atherosclerosis develops at predictable sites in the vasculature where branch points and curvatures create non-laminar disturbed flow. This disturbed flow causes vascular inflammation by increased endothelial cell (EC) barrier permeability and the expression of inflammatory genes such as vascular cell adhesion molecule 1 (VCAM-1). Vascular endothelial growth factor receptor 2 (VEGFR2) regulates flow-induced EC inflammation; however, there are still some gaps in understanding the precise signaling mechanism or pathway. Focal adhesion kinase (FAK) is a protein tyrosine kinase whose expression has been implicated in flow-mediated signaling in ECs. However, the link between FAK and VEGFR2 in flow-mediated inflammation signaling has remained unelucidated. Here we found that priming of VEGFR2 with VEGF was critical for flow-mediated activation of FAK and NF-kB. Mechanistically, FAK activation triggers tyrosine phosphorylation of Casitas B-lineage lymphoma (CBL; an E3 ubiquitin ligase) that interacts with VEGFR2 under flow conditions. However, FAK inhibition reduced VEGFR2-FAK-CBL complex formation, partly due to reduced expression of VEGFR2 on the cell membrane. Further, Apoe−/− mice fed a Western diet (WD) exhibited increased FAK activity within the atheroprone disturbed flow region of the inner aortic arch compared to the outer arch. Disturbed flow-induced FAK activation is associated with elevated VEGFR2 on the surface of ECs of the inner aortic arch, but not in the outer arch. Taken together, these data suggest that suppression of augmented FAK activity under disturbed flow may prove beneficial in reducing pro-inflammatory signaling of the endothelial layer.

Figures