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Related Experiment Video

Updated: May 30, 2025

Ultrasound Imaging of the Thoracic and Abdominal Aorta in Mice to Determine Aneurysm Dimensions

Ultrasound Imaging of the Thoracic and Abdominal Aorta in Mice to Determine Aneurysm Dimensions

Published on: March 8, 2019

XOR-Derived ROS in Tie2-Lineage Cells Including Endothelial Cells Promotes Aortic Aneurysm Progression in Marfan

Hiroki Yagi^1,2, Hiroshi Akazawa¹, Qing Liu¹

¹Department of Cardiovascular Medicine (H. Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan.

Arteriosclerosis, Thrombosis, and Vascular Biology

|January 30, 2025

Summary

In Marfan syndrome, mechanosensitive signaling activates endothelial xanthine oxidoreductase (XOR), increasing reactive oxygen species and driving aortic aneurysm progression. Febuxostat, an XOR inhibitor, shows potential therapeutic benefits for MFS.

Keywords:

Marfan syndrome aortic aneurysm drug repositioning reactive oxygen species stress, mechanical

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Last Updated: May 30, 2025

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Published on: March 8, 2019

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Published on: August 24, 2019

Area of Science:

Cardiovascular Biology
Genetics and Inherited Diseases
Molecular Medicine

Background:

Marfan syndrome (MFS) is an inherited connective tissue disorder caused by FBN1 gene mutations.
Thoracic aortic aneurysm and dissection are the primary causes of morbidity and mortality in MFS.
The precise mechanisms underlying aortic aneurysm progression in MFS are not fully understood.

Purpose of the Study:

To investigate the role of endothelial xanthine oxidoreductase (XOR)-derived reactive oxygen species (ROS) in the progression of aortic aneurysms in Marfan syndrome.
To explore the therapeutic potential of inhibiting XOR in MFS.

Main Methods:

Utilized MFS mouse models with an FBN1 missense mutation (p.(Cys1041Gly)) and endothelial cell-specific Xdh gene disruption.
Administered febuxostat, an XOR inhibitor, systemically to MFS mice.
Assessed aortic aneurysm progression, mechanosensitive signaling pathways (FAK-p38 MAPK-Egr-1), ROS generation, and macrophage infiltration.

Main Results:

Elevated ROS generation and increased XOR protein expression/activity were observed in the aortas of MFS patients and mice.
Inhibition of XOR, either genetically or pharmacologically with febuxostat, significantly reduced aortic aneurysm progression and macrophage infiltration.
Aberrant activation of FAK-p38 MAPK-Egr-1 mechanosensitive signaling was identified in MFS aortas, with mechanical stress upregulating XOR via Egr-1.

Conclusions:

Aberrant mechanosensitive signaling in vascular endothelial cells triggers XOR activation and ROS production, contributing to aortic aneurysm development in MFS.
Febuxostat, a repurposed uric acid-lowering drug, presents a potential therapeutic strategy for Marfan syndrome by targeting endothelial XOR-derived ROS.