Insights into the molecular pathogenesis and targeted treatment of lymphedema.

Abnormal function of the lymphatic vessels is associated with a variety of diseases, such as tumor metastasis and lymphedema. The development of strategies for local and controlled induction or inhibition of lymphangiogenesis would thus be of major importance for the treatment of such diseases. Two growth factors, vascular endothelial growth factor C (VEGF-C) and D (VEGF-D), have been found to be important in the proper formation and maintenance of the lymphatic network, through their receptor VEGFR-3. In patients with lymphedema, heterozygous inactivation of VEGFR-3 leads to primary lymphedema due to defective lymphatic drainage in the limbs. We have shown that VEGF-C gene transfer to the skin of mice with lymphedema induces regeneration of the cutaneous lymphatic vessel network. However, as is the case with VEGF, high levels of VEGF-C cause blood vessel growth and leakiness, resulting in tissue edema. Strategies to avoid these side-effects have also been developed. This new field of reseach has important implications for the development of new therapies for human lymphedema.