Inhibition of Lymphangiogenesis by an Endogenous Soluble Vegf-c Receptor

Abstract

Purpose: : Angiogenesis comprises the intertwined growth and development of the blood (hemangiogenesis) and lymphatic (lymphangiogenesis) vasculatures. While VEGF-A primarily drives hemangiogenesis, VEGF-C is a key mediator of lymphangiogenesis. Endogenous inhibitors of VEGF-C have not been described. Here, we report the existence of an endogenous soluble receptor that traps VEGF-C and inhibits developmental and reparative lymphangiogenesis in the cornea and in the skin.

Methods: : PCR techniques were used to clone sVEGF-C receptor. A naked plasmid vector was constructed for over-expression and characterization of sVEGF-C receptor function. In situ hybridization, northern blotting, western blotting, immunohistochemistry and immunofluorescence were used to study sVEGF-C receptor in the cornea and skin. Transgenic mice conditionally deficient in sVEGF-C receptor in the cornea and skin were generated. Corneal suture injury and skin punch injury models were used to induce angiogenesis. Lymphangiogenesis modulation was also studied in the corn1 mice.

Results: : sVEGF-C receptor was cloned from a mouse cornea cDNA library. Its mRNA and protein were increased after corneal and skin injury. Conditionally sVEGF-C receptor ablation resulted in spontaneous corneal lymphangiogenesis and dermal lymphatic hyperplasia but did not alter the blood vasculature. Genetic deletion of sVEGF-C receptor in the adult mouse cornea and skin led to increased reparative lymphangiogenesis but not hemangiogenesis. The converse was observed when sVEGF-C receptor was over-expressed in the cornea of the sVEGF-C receptor deficient mice and corn1 mice.

Conclusions: : sVEGF-C receptor is a specific inhibitor of lymphangiogenesis. It provides a novel strategy to uncouple the growth of blood and lymphatic vessels during development and most importantly following injury. The identification of sVEGF-C receptor as an uncoupler of hemangiogenesis and lymphangiogenesis should prompt investigations on its role in quenching the abnormal proliferation of lymphatic vessels with minimal deleterious effects on the blood vasculature, which is critical in disorders such as lymphedema and lymphangiomas.

Keywords: cornea: basic science • cornea: epithelium • transplantation