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ResearchIn-Press PreviewCardiologyDevelopmentVascular biology Open Access | 10.1172/JCI195507

Lymphatic dysfunction and ZFP36 deficiency contribute to myxomatous valve degeneration in Marfan Syndrome mice

Can Tan,1 Ziyou Ren,2 Shreya Kurup,1 Xianpeng Liu,3 Zhi-Dong Ge,4 Shodai Suzuki,5 Pritika Jakka,1 Cheryl Tang,1 M. Luisa Iruela-Arispe,5 and Tsutomu Kume1

1Department of Medicine, Northwestern University, Chicago, United States of America

2Department of Dermatology, Northwestern University, Chicago, United States of America

3Division of Thoracic Surgery, Northwestern University, Chicago, United States of America

4Cardiovascular-Thoracic Surgery and the Heart Center, Northwestern University, Chicago, United States of America

5Department of Cell and Development Biology, Northwestern University, Chicago, United States of America

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1Department of Medicine, Northwestern University, Chicago, United States of America

2Department of Dermatology, Northwestern University, Chicago, United States of America

3Division of Thoracic Surgery, Northwestern University, Chicago, United States of America

4Cardiovascular-Thoracic Surgery and the Heart Center, Northwestern University, Chicago, United States of America

5Department of Cell and Development Biology, Northwestern University, Chicago, United States of America

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1Department of Medicine, Northwestern University, Chicago, United States of America

2Department of Dermatology, Northwestern University, Chicago, United States of America

3Division of Thoracic Surgery, Northwestern University, Chicago, United States of America

4Cardiovascular-Thoracic Surgery and the Heart Center, Northwestern University, Chicago, United States of America

5Department of Cell and Development Biology, Northwestern University, Chicago, United States of America

Find articles by Kurup, S. in: PubMed | Google Scholar

1Department of Medicine, Northwestern University, Chicago, United States of America

2Department of Dermatology, Northwestern University, Chicago, United States of America

3Division of Thoracic Surgery, Northwestern University, Chicago, United States of America

4Cardiovascular-Thoracic Surgery and the Heart Center, Northwestern University, Chicago, United States of America

5Department of Cell and Development Biology, Northwestern University, Chicago, United States of America

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1Department of Medicine, Northwestern University, Chicago, United States of America

2Department of Dermatology, Northwestern University, Chicago, United States of America

3Division of Thoracic Surgery, Northwestern University, Chicago, United States of America

4Cardiovascular-Thoracic Surgery and the Heart Center, Northwestern University, Chicago, United States of America

5Department of Cell and Development Biology, Northwestern University, Chicago, United States of America

Find articles by Ge, Z. in: PubMed | Google Scholar

1Department of Medicine, Northwestern University, Chicago, United States of America

2Department of Dermatology, Northwestern University, Chicago, United States of America

3Division of Thoracic Surgery, Northwestern University, Chicago, United States of America

4Cardiovascular-Thoracic Surgery and the Heart Center, Northwestern University, Chicago, United States of America

5Department of Cell and Development Biology, Northwestern University, Chicago, United States of America

Find articles by Suzuki, S. in: PubMed | Google Scholar

1Department of Medicine, Northwestern University, Chicago, United States of America

2Department of Dermatology, Northwestern University, Chicago, United States of America

3Division of Thoracic Surgery, Northwestern University, Chicago, United States of America

4Cardiovascular-Thoracic Surgery and the Heart Center, Northwestern University, Chicago, United States of America

5Department of Cell and Development Biology, Northwestern University, Chicago, United States of America

Find articles by Jakka, P. in: PubMed | Google Scholar

1Department of Medicine, Northwestern University, Chicago, United States of America

2Department of Dermatology, Northwestern University, Chicago, United States of America

3Division of Thoracic Surgery, Northwestern University, Chicago, United States of America

4Cardiovascular-Thoracic Surgery and the Heart Center, Northwestern University, Chicago, United States of America

5Department of Cell and Development Biology, Northwestern University, Chicago, United States of America

Find articles by Tang, C. in: PubMed | Google Scholar

1Department of Medicine, Northwestern University, Chicago, United States of America

2Department of Dermatology, Northwestern University, Chicago, United States of America

3Division of Thoracic Surgery, Northwestern University, Chicago, United States of America

4Cardiovascular-Thoracic Surgery and the Heart Center, Northwestern University, Chicago, United States of America

5Department of Cell and Development Biology, Northwestern University, Chicago, United States of America

Find articles by Iruela-Arispe, M. in: PubMed | Google Scholar |

1Department of Medicine, Northwestern University, Chicago, United States of America

2Department of Dermatology, Northwestern University, Chicago, United States of America

3Division of Thoracic Surgery, Northwestern University, Chicago, United States of America

4Cardiovascular-Thoracic Surgery and the Heart Center, Northwestern University, Chicago, United States of America

5Department of Cell and Development Biology, Northwestern University, Chicago, United States of America

Find articles by Kume, T. in: PubMed | Google Scholar

Published June 11, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI195507.
Copyright © 2026, Tan et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 11, 2026 - Version history
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Abstract

Enhanced TGFβ signaling caused by mutations in Fibrillin-1 (FBN1) in patients with Marfan syndrome (MFS) leads to myxomatous degeneration of the mitral valve (MDMV). MDMV can result in mitral valve prolapse, severe regurgitation, and sudden cardiac death. However, it remains unknown whether lymphatic vessel (LV) dysfunction contributes to MDMV development in MFS. Here, we show that lymphangiogenesis in murine mitral valves (MVs) begins postnatally. However, this process is inhibited in a mouse MFS model, Fbn1 mutant (Fbn1C1039G/+) mice, accompanied by disrupted lymphatic cell-cell junctions, impaired lymphatic drainage, and an abnormally widespread distribution of MHCII+ infiltrating macrophages. Treatment of Fbn1 mutant mice with VEGF-C156S, a selective VEGFR3 agonist, stimulates the ERK and Akt pathways, increases LV density in MVs, and ameliorates MDMV. Fbn1 mutant MVs display disorganized valvular endothelial cells (VECs) and decreased expression of the anti-inflammatory modulator Zfp36 (zinc finger protein 36) in VECs and immune cells. Treatment with FTY720 (Fingolimod), a ZFP36 activator and S1P antagonist, rescues MDMV phenotypes in Fbn1 mutant mice by reducing immune cell infiltration and restoring lymphatic cell junctions and drainage. These findings suggest that the Fbn1 mutation causes LV hypoplasia and defective lymphatic drainage in MVs, driven in part by pro-inflammatory VECs, leading to MFS-related MDMV.

Graphical Abstract
graphical abstract
Supplemental material

View Unedited blot and gel images

View Video 1. Lymphatic development in mitral valves

View Video 2. Lymphatic development in the posterior triangle

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Version history
  • Version 1 (June 11, 2026): In-Press Preview
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