- Vascular Endothelial Growth Factor Receptor-3 (VEGFR-3, also known as Flt-4) is a receptor tyrosine kinase that plays a central role in lymphangiogenesis, the process of forming new lymphatic vessels.
- Unlike VEGFR-1 and VEGFR-2, which primarily regulate angiogenesis in blood vessels, VEGFR-3 is most strongly expressed in the endothelial cells of the lymphatic system. Its principal ligands are VEGF-C and VEGF-D, which, upon binding, stimulate lymphatic endothelial cell proliferation, migration, and survival.
- Although VEGFR-3 is predominantly associated with lymphatic vessels in adults, during embryonic development it is also expressed in blood vessel endothelium and is required for the early formation of the vascular system.
- Structurally, VEGFR-3 is similar to other VEGF receptors, with an extracellular domain containing immunoglobulin-like loops for ligand binding, a single transmembrane region, and an intracellular tyrosine kinase domain. Ligand binding induces dimerization and autophosphorylation, triggering downstream signaling pathways such as the PI3K/AKT pathway (promoting cell survival), the MAPK/ERK pathway (driving cell proliferation), and other cascades involved in cytoskeletal rearrangement and migration. These signals enable lymphatic endothelial cells to sprout, remodel, and form the complex lymphatic network required for tissue fluid balance and immune cell trafficking.
- Physiologically, VEGFR-3 is critical for maintaining lymphatic vessel integrity and function. The lymphatic system serves key roles in fluid homeostasis, absorption of dietary fats, and immune surveillance. Disruption of VEGFR-3 signaling can lead to impaired lymphatic development and function, resulting in lymphedema (swelling due to lymph accumulation). In fact, mutations in the VEGFR-3 gene (FLT4) are linked to congenital hereditary lymphedema, highlighting its essential role in human health.
- In pathological contexts, VEGFR-3 is implicated in cancer biology and chronic inflammation. Tumors can exploit VEGFR-3 signaling by secreting VEGF-C and VEGF-D to stimulate lymphangiogenesis within and around the tumor. This newly formed lymphatic network provides routes for cancer cells to spread to lymph nodes and beyond, making VEGFR-3 signaling a key mechanism in lymphatic metastasis. Additionally, in chronic inflammatory conditions, VEGFR-3–mediated lymphangiogenesis can contribute to tissue remodeling and persistent immune activation.
- Clinically, VEGFR-3 has become an important therapeutic target. Strategies to block VEGFR-3 signaling—using monoclonal antibodies, soluble receptor decoys, or small-molecule inhibitors—are being investigated to prevent tumor lymphangiogenesis and metastatic spread. Conversely, stimulating VEGFR-3 activity holds promise in regenerative medicine, where enhancing lymphatic growth could help treat secondary lymphedema after surgery or radiation.
