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

Area of Science:

• Molecular Biology
• Developmental Biology
• Physiology

Background:

• The lymphatic system is vital for fluid balance, and its proper function relies on lymphatic valves.
• Mutations in FOXC2 lead to lymphoedema-distichiasis syndrome, characterized by lymphatic valve defects.
• While shear stress influences FOXC2, other extracellular regulators of lymphatic development are not fully understood.

Purpose of the Study:

• To identify novel extracellular regulators of FOXC2 expression and lymphatic valve development.
• To elucidate the molecular mechanisms by which these regulators impact lymphatic endothelial cells.

Main Methods:

• Utilized lymphatic endothelial cell (LEC)-specific gene-deficient mouse models (Lpa4;Lpa6-deficient).
• Investigated FOXC2 expression in vitro and in vivo following receptor ablation.
• Examined the role of NF-κB and Rho kinase signaling pathways in LPA-induced FOXC2 expression.
• Assessed lymphatic valve formation and maintenance in genetically modified and pharmacologically treated mice.

Main Results:

• Lymphatic endothelial cell-specific deficiency of LPA4 and LPA6 impaired lymphatic valve formation and maintenance.
• Ablation of Lpa4 and Lpa6 in LECs reduced FOXC2 expression, mimicking Foxc2 deficiency.
• LPA-induced FOXC2 expression was dependent on the LPA4/LPA6-Gα12/Gα13-Rho kinase-NF-κB signaling axis.
• Pharmacological inhibition of NF-κB and Rho kinase disrupted lymphatic valve maintenance.

Conclusions:

• Lymphatic endothelial LPA4 and LPA6 receptors act synergistically to regulate FOXC2 expression via NF-κB activation.
• These receptors are critical for lymphatic valve formation and maintenance.
• The findings provide a molecular basis for lymphatic vessel development and suggest therapeutic strategies for lymphatic diseases.