Abstract
The cornea is a transparent and avascular tissue that plays a central role in light refraction and provides a physical barrier to the external environment. Corneal avascularity is a unique histological feature that distinguishes it from the other parts of the body. Functionally, corneal immune privilege critically relies on corneal avascularity. Corneal lymphangiogenesis is now recognized as a general pathological feature in many pathologies, including dry eye disease (DED), corneal allograft rejection, ocular allergy, bacterial and viral keratitis, and transient corneal edema. Currently, sizable data from clinical and basic research have accumulated on the pathogenesis and functional role of ocular lymphangiogenesis. However, because of the invisibility of lymphatic vessels, ocular lymphangiogenesis has not been studied as much as hemangiogenesis. We reviewed the basic mechanisms of lymphangiogenesis and summarized recent advances in the pathogenesis of ocular lymphangiogenesis, focusing on corneal allograft rejection and DED. In addition, we discuss future directions for lymphangiogenesis research.
Highlights
Cytokines and Molecular Markers for LymphangiogenesisBoth the peripheral and central cornea have a specific structure for maintaining transparency with limited blood and lymphatic vessels
There has been a remarkable improvement in our understanding of lymphangiogenesis and advances in the regulation of corneal lymphatics, complete regulation of corneal lymphangiogenesis is still not possible, even in an in vivo model
Lymphatic vessels (LVs) are distributed throughout the body, but the molecular mechanism of lymphangiogenesis is different in each tissue and organ and varies under different pathological conditions
Summary
Both the peripheral and central cornea have a specific structure for maintaining transparency with limited blood and lymphatic vessels. As in hemangiogenesis, the VEGF family is the key regulator of LV development in embryogenesis and lymphangiogenesis in adults, through activation of VEGF receptor-3 (VEGFR-3). VEGFs are essential cytokines for the development and maintenance, of both vascular and lymphatic endothelial cells (VECs and LECs). It is well known that the gradient of VEGFs that form by their interaction with proteoglycan [7] and co-receptors such as neuropilin 1 and 2 (NRP1–2) [8,9] induce endothelial cell (EC) activation, determine the polarity of the vascular sprout, and establishment of the mature vessel [7]. ANG, angiopoietin; LEC, lymphatic endothelial cell; LG, lymphangiogenesis; AG, angiogenesis. ANG1 exerts vascular stability by recruiting tyrosine protein kinase-like 7 (PTK7)+ mononuclear cells, which may have a pericyte-like function [23]. TGF-β-induced protein (TGFBIp), which is abundant in the cornea, enhances lymphangiogenesis; the underlying mechanisms remain unknown [46]
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