- Vascular Endothelial Growth Factor-D (VEGF-D) is a member of the VEGF family closely related to VEGF-C, and it primarily regulates lymphangiogenesis (formation of lymphatic vessels) and, to a lesser extent, angiogenesis (formation of blood vessels).
- VEGF-D is a secreted glycoprotein that binds to VEGFR-3 (Flt-4) as its main receptor, stimulating the growth, migration, and survival of lymphatic endothelial cells. Similar to VEGF-C, VEGF-D can also interact with VEGFR-2 (KDR/Flk-1) after proteolytic processing, thereby contributing to angiogenesis under certain conditions.
- VEGF-D is produced as an inactive precursor that undergoes proteolytic cleavage to become biologically active. The degree of processing determines its receptor specificity: partially processed VEGF-D binds primarily to VEGFR-3, while fully processed VEGF-D acquires the ability to activate VEGFR-2. This dual receptor-binding ability allows VEGF-D to influence both lymphatic and blood vascular systems, though its physiological effects are more strongly associated with the lymphatic network.
- During development, VEGF-D is less critical than VEGF-C for lymphatic formation, but in adults it plays an important role in lymphatic remodeling and maintenance. VEGF-D expression is often upregulated in response to tissue stress, inflammation, or hypoxia, and it contributes to immune regulation by promoting lymphatic vessel expansion, which facilitates the transport of immune cells and antigens. In the lung, VEGF-D is particularly important, as it is highly expressed in pulmonary tissues and has been implicated in the development of pulmonary lymphatic and vascular networks.
- Pathologically, VEGF-D has a well-established role in cancer progression and metastasis. Many tumors secrete VEGF-D to promote peritumoral lymphangiogenesis, thereby creating new lymphatic routes for cancer cells to disseminate to regional lymph nodes and distant organs. High VEGF-D expression is associated with aggressive behavior and poor prognosis in cancers such as breast, colorectal, gastric, and lung cancer. VEGF-D also contributes to angiogenesis within tumors, especially when fully processed, which further enhances tumor growth and spread. Beyond oncology, VEGF-D has been linked to inflammatory disorders and vascular diseases, particularly in the lung, where it may contribute to conditions such as pulmonary hypertension or interstitial lung disease.
- From a therapeutic standpoint, VEGF-D is both a target and a potential therapeutic agent. In cancer, blocking VEGF-D/VEGFR-3 signaling is a promising strategy to inhibit tumor lymphangiogenesis and metastasis. In contrast, stimulating VEGF-D signaling could be useful in regenerative medicine or the treatment of lymphedema, where the growth of new lymphatic vessels is beneficial. Experimental therapies involving VEGF-D delivery have shown potential in promoting lymphatic regeneration after lymph node removal, a common complication of cancer surgery.
