0042: The Pathogenic Role of Lymphatic Vessels in Autoimmune Valvular Carditis

Amritha Yellamilli¹, Victoria Osinski², Maria Firulyova³, Jennifer Auger⁴, Lee Meier², Jessica Faragher⁵, Aubyn Marath⁶, Konstantin Zaitsev³ and Bryce Binstadt⁵, ¹Stanford University School of Medicine, Palo Alto, ²University of Minnesota School of Medicine, Minneapolis, MN, ³ITMO University, Saint Petersburg, Russia, ⁴University of Minnesota Medical School, Minneapolis, MN, ⁵University of Minnesota, Minneapolis, MN, ⁶CardioStart, Portland

Background/Purpose: Valvular carditis is a serious complication of systemic autoimmune diseases. Although endothelial cells are thought to play an important role in autoimmune valvular carditis, little is known about their specific roles in this disease process.

Methods: We performed in vivo lineage tracing of endothelial cells in the K/B.g7 mouse model of systemic autoimmune arthritis and valvular carditis. Using immunofluorescent staining and imaging, we characterized and quantified endothelial cells during the progression of autoimmune valvular carditis in K/B.g7 mice. We then used single-cell RNA sequencing to further characterize lymphatic endothelial cells isolated from inflamed K/B.g7 valves using unsupervised cluster analysis and differential gene expression. Finally, we performed immunofluorescent staining and imaging of mitral valves from patients with rheumatic heart disease.

Results: We identified lymphatic endothelial cell networks within inflamed mitral valves of K/B.g7 mice. We showed that these networks expand and acquire a pro-fibrotic phenotype during the progression of autoimmune valvular carditis. Blocking lymphangiogenesis using a small molecular inhibitor of VEGFR-3 reduced inflammation and fibrosis of mitral valves in K/B.g7 mice but did not affect the development of arthritis. Importantly, we identified VEGFR-3-expressing lymphatic vessels in mitral valves of patients with rheumatic heart disease.

Conclusion: Our study shows that lymphangiogenesis is a maladaptive, pro-fibrotic process that can be therapeutically targeted in patients with autoimmune valvular carditis.

Disclosures: A. Yellamilli, None; V. Osinski, None; M. Firulyova, None; J. Auger, None; L. Meier, None; J. Faragher, None; A. Marath, None; K. Zaitsev, None; B. Binstadt, Pfizer, Pfizer.