CCM3 Loss-Induced Lymphatic Defect Is Mediated by the Augmented VEGFR3-ERK1/2 Signaling.

Area of Science:

• Vascular biology
• Genetics
• Lymphatic system research

Background:

• Cerebral cavernous malformations (CCMs) are typically found in the brain, but CCM genes are expressed ubiquitously.
• The role of CCM genes in non-brain vascular beds, like lymphatics, is understudied.

Purpose of the Study:

• To investigate the function of CCM genes, specifically CCM3 (Pdcd10), in lymphatic endothelial cells.
• To elucidate the molecular mechanisms underlying CCM3's role in lymphatic development and function.

Main Methods:

• Generated mice with inducible deletion of Ccm3 in endothelial cells (ECKO) or lymphatic ECs (LECKO).
• Assessed lymphatic structure and function using microscopy and dye/dextran transport assays.
• Analyzed signaling pathways including VEGFR3, ERK1/2, and NF-κB using molecular biology techniques.

Main Results:

• Ccm3 deletion in lymphatic ECs led to dilated lymphatic vessels and abnormal valves.
• Lymphatic dysfunction was observed in Pdcd10(LECKO) mice.
• Increased VEGFR3-ERK1/2 signaling and lymphatic hyperplasia were found, driven by NF-κB-dependent VEGFR3 transcription.
• CCM3 deletion releases KPNA2, promoting NF-κB P65 nuclear translocation and VEGFR3 expression.

Conclusions:

• CCM3 deficiency augments VEGFR3-ERK1/2 signaling in lymphatic ECs, causing hyperplasia and malformation.
• Inhibition of VEGFR3 or ERK1/2 signaling restored lymphatic structure and function.
• These findings highlight the clinical relevance of lymphatic dysfunction in CCM patients.