Lysophosphatidic acid-mediated NF-κB activation promotes FOXC2 expression essential for lymphatic valve development.

ABSTRACT: The lymphatic system maintains tissue fluid balance, and FOXC2 mutations cause lymphoedema-distichiasis syndrome, which is characterized by lymphatic valve defects. Although oscillatory shear stress regulates FOXC2 expression, other extracellular regulators remain unclear. In this study, we identified LPA4 and LPA6, two Gα12/Gα13-coupled receptors for the bioactive lipid lysophosphatidic acid (LPA), as key regulators of FOXC2 expression and lymphatic valve development. Lymphatic endothelial cell (LEC)-specific Lpa4;Lpa6-deficient mice exhibited impaired lymphatic valve formation and maintenance, which resembled phenotypes of LEC-specific Foxc2-deficient mice, including abnormal lymphatic vessel patterning. Mechanistically, lymphatic endothelial Lpa4/Lpa6 ablation reduced FOXC2 expression i

SUBMITTER: Yasuda D 

PROVIDER: S-EPMC12948439 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature