# Role of FAK in vascular inflammation

> **NIH NIH R01** · UNIVERSITY OF SOUTH ALABAMA · 2020 · $426,490

## Abstract

Atherosclerosis is a chronic inflammatory disease that arises due to a combination of various stimuli, such as
cytokines and disturbed blood flow. These stimuli result in pro-inflammatory cell adhesion molecule expression,
an early event in atherogenesis, which recruit leukocytes to the activated endothelium, leading to a chronic
inflammatory state. Although the use of preventative pharmacological approaches for these conventional risks,
such as lipid lowering and antihypertensive drugs, have been beneficial, there is no treatment available to
reduce these early steps of atherogenesis. Focal adhesion kinase (FAK) is an integrin-associated protein
tyrosine kinase that plays a critical role in maintaining normal vascular physiology upon changes in both
cytokine and blood flow signaling. Our preliminary findings have revealed that FAK inhibition in endothelial cells
(EC) prevented tumor necrosis factor-α (TNF-α)-induced expression of various pro-inflammatory molecules,
suggesting a potential “ant-inflammatory role” for FAK inhibition. Interestingly, in ApoE-/- model, FAK inhibitor
was able to block vascular cell adhesion molecule-1 (VCAM-1) expression and reduced macrophage
recruitment, implicating FAK as a potential target for atherosclerosis. While NF-κB is normally inhibited by IκBα,
inflammatory stimuli lead to rapid IκBα degradation and NF-κB activation. IκBα is then upregulated by NF-κB
activity, thus inhibiting NF-κB. In atherosclerosis, however, sustained NF-κB activation occurs due to continued
inflammatory stimuli, which leads to oscillations of NF-κB activity as IκBα is continually made and degraded. We
discovered that FAK inhibition in ECs prevented sustained NF-κB activation due to increased stability of IκBα,
sequestering NF-κB in cytoplasm inactive. Further, we found that this long term IκBα stabilization by FAK
inhibition may be mediated by reduced FAK-mediated tyrosine phosphorylation of IκBα kinase (IKK). Taken
together, our data suggest that FAK activity drives TNF-α-induced pro-inflammatory gene expression through
sustained NF-κB oscillations. Surprisingly, FAK inhibitor blocks plaque formation in ApoE -/- model of disturbed
flow, indicating a potential role of FAK activity in flow signaling. Taken together, our central hypothesis is that
FAK inhibition may prevent atherosclerosis by blocking stimuli-induced pro-inflammatory molecule expression
via dampened NF-κB oscillations. In aim-1, we will determine the molecular mechanism of FAK action in
maintaining sustained NF-κB signaling upon TNF-α and disturbed blood flow in ECs. In aim-2, we will evaluate
if FAK-mediated NF-κB activity in ECs has therapeutic potential by using pharmacological and genetic FAK
atherosclerosis mouse models. This study will produce new insights into atherogenesis via FAK-mediated
NF-κB activity in ECs. Furthermore, FAK inhibitor's ability to block sustained NF-κB activity and plaque
formation might provide a new therapeutic option in the treatment vascul...

## Key facts

- **NIH application ID:** 9886279
- **Project number:** 5R01HL136432-04
- **Recipient organization:** UNIVERSITY OF SOUTH ALABAMA
- **Principal Investigator:** Steve Lim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $426,490
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9886279

## Citation

> US National Institutes of Health, RePORTER application 9886279, Role of FAK in vascular inflammation (5R01HL136432-04). Retrieved via AI Analytics 2026-08-03 from https://api.ai-analytics.org/grant/nih/9886279. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*