Profibrotic VEGFR3-Dependent Lymphatic Vessel Growth in Autoimmune Valvular Carditis

Area of Science:

• Cardiovascular Biology
• Immunology
• Vascular Biology

Background:

• Rheumatic heart disease (RHD) is a leading cause of valvular heart disease globally.
• Endothelial cells (ECs) play a critical role in RHD pathogenesis, but their specific functions require further elucidation.

Purpose of the Study:

• To investigate the role and dynamics of endothelial cells in autoimmune valvular carditis.
• To characterize novel endothelial cell populations and their contribution to disease progression.

Main Methods:

• Utilized EC lineage tracing in the K/B.g7 mouse model of autoimmune valvular carditis.
• Employed single-cell RNA sequencing to profile mitral valve ECs.
• Validated findings using immunostaining, histology, and echocardiography.
• Assessed the impact of VEGFR3 inhibition and analyzed human RHD valves.

Main Results:

• Identified new capillary lymphatic vessels originating from valve surface ECs during disease.
• Discovered novel lymphatic valve ECs with a distinct profibrotic transcriptional profile.
• VEGFR3 inhibition prevented the expansion of the mitral valve lymphatic network.
• Increased valve lymphatic density correlated with worsened cardiac function and was observed in human RHD valves.

Conclusions:

• Revealed a novel mechanism of inflammation-associated, VEGFR3-dependent lymphangiogenesis in autoimmune valvular carditis.
• Demonstrated similarities between this murine model and human rheumatic heart disease.
• Highlighted the potential role of lymphatic vessels in RHD progression.