Lymphatic dysfunction and ZFP36 deficiency contribute to myxomatous valve degeneration in Marfan syndrome mice
Can Tan, Ziyou Ren, Shreya Kurup, Xianpeng Liu, Zhi-Dong Ge, Shodai Suzuki, Pritika Jakka, Cheryl Tang, M. Luisa Iruela-Arispe, Tsutomu Kume
Can Tan, Ziyou Ren, Shreya Kurup, Xianpeng Liu, Zhi-Dong Ge, Shodai Suzuki, Pritika Jakka, Cheryl Tang, M. Luisa Iruela-Arispe, Tsutomu Kume
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Research Article Cardiology Development Vascular biology

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

Abstract

Enhanced TGF-β 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 antiinflammatory 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 proinflammatory VECs, leading to MFS-related MDMV.

Authors

Can Tan, Ziyou Ren, Shreya Kurup, Xianpeng Liu, Zhi-Dong Ge, Shodai Suzuki, Pritika Jakka, Cheryl Tang, M. Luisa Iruela-Arispe, Tsutomu Kume

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Figure 6

FTY720 rescues MDMV phenotypes in Fbn1 mutant mice.

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FTY720 rescues MDMV phenotypes in Fbn1 mutant mice. (A) Timeline of FTY7...
(A) Timeline of FTY720 treatment. (B) Representative hearts collected at P60. Scale bars: 1 mm. (C) Representative images showing MVs by Movat pentachrome staining. Black and blue scale bars: 100 and 20 μm, respectively. (D) Quantification of length (upper panel) and width (lower panel) of the MV leaflets based on the data shown in C. Data are mean ± SEM, unpaired 2-tailed Student’s t test, each symbol represents 1 mouse. N = 4-8 per group, male/female = 3:3, 6:2, 4:3, and 2:2 in the WT-water, Fbn1-water, WT-FTY720, and Fbn1-FTY720 groups, respectively. *P < 0.05, **P < 0.01, ***P < 0.001. (E) Quantification of the average percentage of proteoglycan (upper panel) and collagen (lower panel) in both MV leaflets. Data are mean ± SEM, ordinary 1-way ANOVA test, each symbol represents 1 mouse. For percent proteoglycan, N = 4-7 per group, male/female = 3:3, 3:3, 4:3, and 2:2 in the 4 groups, respectively; for percent collagen, N = 4-7, male/female = 3:3, 2:2, 4:3, and 2:2 in these groups, respectively. *P < 0.05, ***P < 0.001, ****P < 0.0001. (F) Schematic graph and representative confocal images show CD45+ immune cells in MVs. Scale bar: 100 μm. LA, left atrium. (G) Quantification of the percentage of CD45+ cells in both MV leaflets. Data are mean ± SEM, ordinary 1-way ANOVA, each symbol represents 1 mouse. N = 4-8, male/female = 3:3, 5:2, 4:4, and 3:1 in the 4 groups, respectively. **P < 0.01, ***P < 0.001, ****P < 0.0001.