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Lymphatic dysfunction and ZFP36 deficiency contribute to myxomatous valve degeneration in Marfan syndrome mice
Can Tan1, Ziyou Ren2, Shreya Kurup1
1Feinberg Cardiovascular and Renal Research Institute, Department of Medicine.
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.
Insights
Marfan syndrome (MFS) causes lymphatic vessel (LV) dysfunction in heart valves, leading to myxomatous degeneration. Restoring LV function ameliorates this condition, suggesting a new therapeutic target for MFS.
Area of Science:
- Cardiovascular Biology
- Lymphatic Research
- Genetic Syndromes
Background:
- Marfan syndrome (MFS), caused by Fibrillin-1 (FBN1) mutations, leads to enhanced TGFβ signaling and myxomatous mitral valve degeneration (MDMV).
- The role of lymphatic vessel (LV) dysfunction in MFS-related MDMV pathogenesis remains unclear.
Purpose of the Study:
- To investigate the contribution of lymphatic vessel dysfunction to MDMV in a mouse model of Marfan syndrome.
- To explore potential therapeutic strategies targeting lymphatic vessels for MFS-related MDMV.
Main Methods:
- Analysis of lymphatic vessel development and function in wild-type and Fbn1 mutant mice.
- Treatment with VEGF-C156S (a VEGFR3 agonist) and FTY720 (Fingolimod, a ZFP36 activator).
- Assessment of valvular endothelial cell (VEC) and immune cell characteristics, including Zfp36 expression and macrophage distribution.
Main Results:
- Lymphangiogenesis is inhibited in the mitral valves (MVs) of Fbn1 mutant mice, leading to disrupted lymphatic junctions, impaired drainage, and increased macrophage infiltration.
- VEGF-C156S treatment improved LV density and ameliorated MDMV in mutant mice.
- FTY720 treatment rescued MDMV phenotypes by reducing inflammation and restoring lymphatic function, linked to restored Zfp36 expression.
Conclusions:
- Fibrillin-1 mutations impair lymphatic vessel development and drainage in heart valves, contributing to MFS-related MDMV.
- Targeting lymphatic vessel function and inflammation presents a promising therapeutic avenue for Marfan syndrome patients with MDMV.
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