Abstract
Lymphangiogenesis is essential for fluid homeostasis in vascularized tissues. In the normally avascular cornea, however, pathological lymphangiogenesis mediates diseases like corneal transplant rejection, dry eye disease, and allergy. So far, a physiological role for lymphangiogenesis in a primarily avascular site such as the cornea has not been described. Using a mouse model of perforating corneal injury that causes acute and severe fluid accumulation in the cornea, we show that lymphatics transiently and selectively invade the cornea and regulate the resolution of corneal edema. Pharmacological blockade of lymphangiogenesis via VEGFR-3 inhibition results in increased corneal thickness due to delayed drainage of corneal edema and a trend towards prolonged corneal opacification. Notably, lymphatics are also detectable in the cornea of a patient with acute edema due to spontaneous Descemet´s (basement) membrane rupture in keratoconus, mimicking this animal model and highlighting the clinical relevance of lymphangiogenesis in corneal fluid homeostasis. Together, our findings provide evidence that lymphangiogenesis plays an unexpectedly beneficial role in the regulation of corneal edema and transparency. This might open new treatment options in blinding diseases associated with corneal edema and transparency loss. Furthermore, we demonstrate for the first time that physiological lymphangiogenesis also occurs in primarily avascular sites.
Highlights
Vessels seem to contribute to the induction and progression of corneal transplant rejection, dry eye and allergic disease and are mostly considered undesirable
We investigated whether a corneal injury that causes acute corneal edema is accompanied by the ingrowth of lymphatic vessels and whether corneal lymphangiogenesis contributes to the physiological healing response
We first analyzed whether a corneal injury that leads to a profound increase in corneal edema results in corneal lymphangiogenesis
Summary
Vessels seem to contribute to the induction and progression of corneal transplant rejection, dry eye and allergic disease and are mostly considered undesirable. Lymphangiogenesis is important to terminate inflammatory responses in the skin, as recent studies indicate that the blockade of cutaneous lymphatic vessels can result in chronic inflammation and edema, whereas the specific activation of lymphatic vessels can ameliorate these conditions[27,28,29]. It remains elusive, whether lymphatic vessels at the cornea might have physiological, possibly beneficial functions after tissue damage, e.g. facilitating adequate wound healing or regulation of corneal edema. We investigated whether a corneal injury that causes acute corneal edema is accompanied by the ingrowth of lymphatic vessels and whether corneal lymphangiogenesis contributes to the physiological healing response
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