FOXE3 mutations predispose to thoracic aortic aneurysms and dissections
Shao-Qing Kuang, … , Milan Jamrich, Dianna M. Milewicz
Shao-Qing Kuang, … , Milan Jamrich, Dianna M. Milewicz
Published February 8, 2016
Citation Information: J Clin Invest. 2016;126(3):948-961. https://doi.org/10.1172/JCI83778.
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Research Article Vascular biology

FOXE3 mutations predispose to thoracic aortic aneurysms and dissections

Abstract

The ascending thoracic aorta is designed to withstand biomechanical forces from pulsatile blood. Thoracic aortic aneurysms and acute aortic dissections (TAADs) occur as a result of genetically triggered defects in aortic structure and a dysfunctional response to these forces. Here, we describe mutations in the forkhead transcription factor FOXE3 that predispose mutation-bearing individuals to TAAD. We performed exome sequencing of a large family with multiple members with TAADs and identified a rare variant in FOXE3 with an altered amino acid in the DNA-binding domain (p.Asp153His) that segregated with disease in this family. Additional pathogenic FOXE3 variants were identified in unrelated TAAD families. In mice, Foxe3 deficiency reduced smooth muscle cell (SMC) density and impaired SMC differentiation in the ascending aorta. Foxe3 expression was induced in aortic SMCs after transverse aortic constriction, and Foxe3 deficiency increased SMC apoptosis and ascending aortic rupture with increased aortic pressure. These phenotypes were rescued by inhibiting p53 activity, either by administration of a p53 inhibitor (pifithrin-α), or by crossing Foxe3–/– mice with p53–/– mice. Our data demonstrate that FOXE3 mutations lead to a reduced number of aortic SMCs during development and increased SMC apoptosis in the ascending aorta in response to increased biomechanical forces, thus defining an additional molecular pathway that leads to familial thoracic aortic disease.

Authors

Shao-Qing Kuang, Olga Medina-Martinez, Dong-chuan Guo, Limin Gong, Ellen S. Regalado, Corey L. Reynolds, Catherine Boileau, Guillaume Jondeau, Siddharth K. Prakash, Callie S. Kwartler, Lawrence Yang Zhu, Andrew M. Peters, Xue-Yan Duan, National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) Investigators, National Heart, Lung, and Blood Institute (NHLBI) Grand Opportunity (GO) Exome Sequencing Project (ESP), Michael J. Bamshad, Jay Shendure, Debbie A. Nickerson, Regie L. Santos-Cortez, Xiurong Dong, Suzanne M. Leal, Mark W. Majesky, Eric C. Swindell, Milan Jamrich, Dianna M. Milewicz

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Figure 5

Foxe3–/– mice have altered aortic remodeling and rupture of the aorta after TAC.

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Foxe3–/– mice have altered aortic remodeling and rupture of the aorta a...
(A) qPCR analysis of Foxe3 expression in WT ascending aortae 2 weeks after TAC indicated that Foxe3 expression was induced with TAC. n = 5 per group. **P < 0.01, by Student’s t test. (B) Cross sections of ascending aortae from mice before and after TAC, immunostained with anti-FOXE3 Ab. Foxe3 staining was not detected in aortic medial layer tissue from WT mice at baseline or in tissue from Foxe3–/– mice, but there was nonspecific staining in the aortic adventitial layer from Foxe3–/– and WT mice. FOXE3 staining was detected in the medial layer of ascending aortae from WT mice after TAC; adventitial layer staining was also present but may have been nonspecific. (C) Echocardiograms show the maximum (Max) systolic velocities and heart rate (bpm) in ascending aortae after sham operation or TAC. (D) Whole mounts of aortae from mice after TAC; arrows show banding location. Half of the aortae from Foxe3–/– mice were similar to those from WT mice (upper 2 panels), but half of the Foxe3–/– mice had complications including aortic hematoma formation (left lower panel, red arrow) or death due to aortic rupture (right lower panel; green arrow). Original magnification, ×15. (E) Echocardiographic assessment of the ascending aortic lumen in WT and Foxe3–/– mice after sham operation or TAC. n = 6 per group. *P < 0.05, by 1-way ANOVA. (F) Cross sections of ascending aortae from WT and Foxe3–/– mice 2 weeks after TAC with H&E, TUNEL, and anti–p-H3 staining. Blue line shows the boundary between the media and adventitia. Bar graphs show the quantification of aortic wall thickness, total medial area, total adventitial area, and the percentage of TUNEL-positive and anti–p-H3–positive medial cells. n = 5 per group. *P < 0.05, by Student’s t test.