Formation and Function of Luminal Lymphatic Valves During Lymphangiogenesis

Lymphatic dysfunction is associated with a wide array of disorders from transplant rejection to cancer metastasis. There are currently few effective treatments for lymphatic diseases. The transparent and easily accessible cornea provides an ideal tissue for lymphatic research because the growth of new lymphatics can be readily induced in a normal, healthy alymphatic cornea. While most studies have focused on preventing lymphangiogenesis (LG) before it is initiated, a new research direction of our lab is to define critical factors involved in lymphatic maturation and regression. This is important because many patients who are in need of lymphatic treatment are already at the middle or late stage of LG. Results from our studies have shown for the first time that luminal valves are formed inside corneal lymphatics as LG proceeds, and this process is mediated by an up-regulation of integrin alpha-9. Moreover, we have defined the peak of valvulogenesis in relation to LG, and the functional relevance of the valves in directing lymph flow. We also show that it is possible to suppress valvulogenesis with anti-integrin alpha-9 treatment in a transplantation model. Lastly, we provide strong evidence that corneal distribution of lymphatic vessels and valves are predominantly localized in the nasal region. Taken together, our studies not only reveal new mechanisms underlying lymphatic maturation but also provide novel therapeutic targets for lymphatic-related diseases occurring inside or outside the eye.