Nerve Growth Factor Mediates Corneal Lymphangiogenesis

Abstract

Purpose: Lymphangiogenesis (LG), the growth of new lymphatic vessels, is a critical process involved in many pathological conditions, including cancer metastasis, tissue inflammation and graft rejection. This study was designed to investigate the critical role of nerve growth factor (NGF) in mediating corneal LG by using a repertoire of in vivo, in vitro and in real-time models and methods.

Methods: A variety of in vivo corneal LG and nerve injury models (pellet implantation, cautery, trephination, axotomy and transplantation), ex vivo immunofluoresent microscopic assays, intravital imaging technology, and in vitro lymphatic endothelial cell (LEC) culture systems were used to investigate NGF expressional changes during corneal LG, the role of NGF in inducing corneal LG in vivo and in real-time, and the role of NGF in mediating LEC functions in vitro.

Results: NGF was significantly increased during corneal LG and nerve damage and it mediated LG in both dose- and time-dependent manners. NGF also directly mediated LEC functions in vitro. Anti-NGF treatment suppressed NGF-induced LG in micropocket assay. However, it exacerbated LG after nerve injury. Accordingly, NGF administration inhibited LG during concurrent nerve injury.

Conclusions: Our study suggests that NGF has a dual function by maintaining nerve survival at a critical level, while inducing LG at higher concentrations. This study not only offers a direct link between NGF and LG, but also reveals a critical balance that is regulated by NGF between the lymphatic and nerve supplies within a tissue, which necessitates consideration in therapeutic approaches.