- Vascular Endothelial Growth Factor-C (VEGF-C) is a member of the VEGF family best known for its central role in lymphangiogenesis, the formation and maintenance of lymphatic vessels.
- Unlike VEGF-A, which primarily regulates angiogenesis, VEGF-C specifically acts through VEGFR-3 (Flt-4) on lymphatic endothelial cells, stimulating their proliferation, migration, and survival. At higher concentrations, VEGF-C can also bind to VEGFR-2 (KDR/Flk-1), thereby exerting some effects on blood vessel angiogenesis as well.
- VEGF-C is initially secreted as an inactive precursor that undergoes proteolytic processing to generate mature, active forms. These processed isoforms differ in receptor-binding affinity, with the fully processed VEGF-C having high affinity for both VEGFR-3 and VEGFR-2. This processing allows VEGF-C to be a versatile regulator, functioning mainly in lymphangiogenesis but also influencing angiogenesis in specific contexts. During embryonic development, VEGF-C is indispensable for the sprouting of lymphatic vessels from the venous endothelium, and genetic loss of VEGF-C or VEGFR-3 results in complete absence of lymphatic vasculature.
- Physiologically, VEGF-C is critical for lymphatic system function, which maintains tissue fluid homeostasis, absorbs dietary fats, and provides pathways for immune cell trafficking. By stimulating VEGFR-3 signaling, VEGF-C supports the growth, remodeling, and maintenance of lymphatic vessels. In adults, VEGF-C expression is upregulated in response to tissue injury, inflammation, and hypoxia, where it contributes to lymphangiogenesis and tissue repair.
- Pathologically, VEGF-C is strongly implicated in cancer metastasis. Many tumors overexpress VEGF-C, which drives the growth of peritumoral lymphatic vessels. These vessels facilitate the entry of tumor cells into the lymphatic system, promoting spread to regional lymph nodes and beyond. High VEGF-C expression is therefore often associated with poor prognosis in cancers such as breast, prostate, gastric, and lung cancer. Beyond oncology, dysregulated VEGF-C activity has been linked to inflammatory diseases and lymphedema. Mutations in VEGF-C or VEGFR-3 can cause congenital lymphedema, a condition characterized by defective lymphatic drainage and chronic swelling.
- Clinically, VEGF-C is both a therapeutic target and a therapeutic tool. On one hand, strategies to inhibit VEGF-C/VEGFR-3 signaling (e.g., monoclonal antibodies or receptor blockers) are being investigated to suppress tumor lymphangiogenesis and limit metastatic spread. On the other hand, enhancing VEGF-C activity holds promise for regenerative medicine and lymphedema therapy, where promoting lymphatic vessel growth could restore drainage after lymph node dissection or radiation therapy. Experimental therapies involving VEGF-C gene delivery or protein administration have shown potential in animal models of lymphedema.
