Pathogenic lymphangiogenesis promotes autoimmune valvular carditis

Abstract Rheumatic heart disease (RHD) is a major cause of valvular heart disease in developing nations. Endothelial cells (ECs) are considered crucial contributors to RHD, but greater insight into contributing mechanisms is needed. Cdh5-driven EC lineage tracing in the K/B.g7 mouse model of autoimmune valvular carditis revealed new capillary lymphatic vessels that develop from valve surface endothelial cells during the progression of disease. Human rheumatic valves contained similar lymphatics. Unsupervised clustering of mitral valve single-cell RNA sequencing data revealed lymphatic valve ECs (VECs) that express a transcriptional profile distinct from other VEC populations and upregulate genes controlling extracellular matrix composition and fibrosis during disease progression. Finally, inhibiting VEGFR3 prevented expansion of this mitral valve lymphatic network and decreased valve thickening and collagen density. These studies reveal a novel form of postnatal pathogenic lymphangiogenesis that promotes autoimmune valvular carditis.