Lymphatic therapies open the valve in Marfan syndrome
Yanna Tian, Kathleen M. Caron
Yanna Tian, Kathleen M. Caron
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Commentary

Lymphatic therapies open the valve in Marfan syndrome

Abstract

Myxomatous degeneration of the mitral valve (MDMV) is a common cardiovascular manifestation of Marfan syndrome (MFS), yet the role of lymphatic vessels in the disease progression remains unknown. In this Commentary, we discuss the study by Tan, Kume, and colleagues, which identifies defective lymphangiogenesis as a previously unrecognized driver of MDMV. Their work demonstrates that impaired lymphatic development and drainage promote valve inflammation through reduced ZFP36-mediated antiinflammatory signaling, whereas restoration of lymphatic function or pharmacological activation of ZFP36 with the FDA-approved drug FTY720 ameliorates disease progression. These findings establish lymphatic vessels as critical regulators of mitral valve homeostasis and support exploration of lymphatic-targeted therapeutic opportunities for MFS-associated valvular disease.

Authors

Yanna Tian, Kathleen M. Caron

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Figure 1

Implicating defective lymphatic vessel development in MFS-associated valvular disease.

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Implicating defective lymphatic vessel development in MFS-associated val...
Tan et al. (17) compared the development of VEGFR3+ lymphatic vessels (LVs) in the mitral valve (MV) of WT and FbnC1039G/+ mice, a model of MFS. (A) In WT mice, LVs emerged from the ventricle and septum and progressed from the anterior triangle (appearance at P0) to the anterior leaflet (aL) (invasion by P7), with posterior leaflet (pL) branching by P14. Normal lymphatic endothelial cells (LECs) displayed discontinuous VE-cadherin junctions in capillaries and continuous zipper junctions in collecting vessels, structures that are essential for maintaining LV function and MV morphology. (B) FbnC1039G/+ MVs exhibited disrupted VE-cadherin junctions, which corresponded with reduced LV density, impaired lymphatic drainage, and immune cell accumulation, leading to MDMV. VEGF-C156S restored VEGFC/VEGFR3 signaling, promoted lymphangiogenic extension, and corrected LV and MDMV defects. Mutant MVs also showed reduced ZFP36, and FDA-approved FTY720 enhanced ZFP36 activity via PP2A, stabilizing VE-cadherin junctions, improving lymphatic function, and mitigating MDMV. VEC, valvular endothelial cell.