| Description |
The lymphatic system is responsible for controlling systemic fluid buildup. Lymphangiogenesis is a dynamic process involving sprouting, and maintaining new lymphatic vasculature. Vascular endothelial growth factor C (VEGF-C) is as a key growth factor that induces lymphangiogenesis by binding VEGF receptors 2 and 3 (VEGFR-2 and VEGFR-3). Interestingly, the cornea expresses VEGF-C, but is alymphatic. We found that the soluble isoform of VEGFR-3, which lacks tyrosine kinase domains, is responsible for the alymphatic nature of the cornea by sequestering endogenous VEGF-C. Although soluble VEGFR-3 or soluble VEGFR-2 can be useful for inhibition of VEGF-C derived lymphangiogenesis, VEGFR-2 also binds VEGF-A. Inhibition of VEGF-A suppresses blood vessel formation, damaging tissue and creating additional side effects. The development of a new anti-lymphangiogenic drug, that only blocks VEGF-C, has many implications: preventing tumor metastasis and reducing rejection rates of tissue and organ transplants. To develop an anti-lymphangiogenic drug that specifically binds VEGF-C the binding domains were inserted into a vector that produces a recombinant protein (VEGF-C trap) that sequesters VEGF-C, suppressing lymphangiogenesis. Mice in a cornea transplantation model were treated, using plasmidbased gene therapy, with VEGF-C trap. After 8 weeks, 60% of the treated cornea survived (no rejection) compared to 10% in the empty vector control group. A 60% transplant survival rate is very high, compared to other single treatment methods. Blood and lymph vessel area calculations showed a decrease in lymph vasculature, but not in blood vessel area. This suggests only VEGF-C activity was affected. |
