VEGFCD

VEGF-C and VEGF-D are members of the vascular endothelial growth factor (VEGF) family that primarily function as lymphangiogenic signals. In humans, the genes VEGFC and VEGFD encode the VEGF-C and VEGF-D proteins, respectively. They promote the growth and remodeling of the lymphatic vasculature by signaling through the VEGF receptor-3 (FLT4) on lymphatic endothelial cells, with mature forms capable of engaging VEGFR-2 (KDR/Flk-1) in certain contexts.

Both proteins are produced as precursor molecules containing a signal peptide, an N-terminal propeptide, a VEGF homology domain, and a C-terminal propeptide. Activation requires proteolytic processing that removes the propeptides, generating mature VEGF-C or VEGF-D that binds receptors with higher affinity. Proteases such as furin-like convertases and extracellular proteases, including ADAMTS3 for VEGF-C, contribute to maturation and lymphatic activity.

Receptors and signaling: the primary receptor is VEGFR-3 on lymphatic endothelium, driving lymphangiogenesis when engaged by mature VEGF-C or VEGF-D. VEGF-C and VEGF-D can also activate VEGFR-2 in some settings, influencing angiogenic responses. Co-receptors such as neuropilins may modulate these signals.

Physiological roles: VEGF-C/D signaling is essential for embryonic development of the lymphatic system and continues to regulate lymphatic maintenance and function in adults. They participate in wound healing and inflammatory responses, and in disease they can promote tumor lymphangiogenesis, facilitating metastasis to regional lymph nodes.

Clinical relevance: altered expression or activity of VEGF-C/D is linked to cancer progression and metastasis, lymphedema, and inflammatory disorders. Therapeutic approaches under investigation include inhibiting the VEGF-C/VEGFR-3 axis to limit metastasis and delivering activated VEGF-C to promote lymphatic regeneration in lymphedema.