Lymphatics in Eye Fluid Homeostasis: Minor Contributors or Significant Actors?

SIMPLE SUMMARY: The eye contains fluid compartments whose tight regulation is essential for proper eye functioning. Lymphatic vessels are known to be important in several physiological functions including interstitial fluid homeostasis. Recent works has provided evidence of a potential role of lymphatic vessels in the drainage of ocular fluids. They may in particular contribute to the intraocular pressure regulation, whose increase is a major risk factor for the progression of glaucoma, an eye disease that can lead to blindness. They could also participate in the clearance of toxic waste products responsible for eye retinal neurodegenerative processes. In this review, we performed an update of ocular lymphatic vessel distribution, of their mechanisms of development and of their role in aqueous humor drainage and eye fluid regulation. We discussed these data and made some proposals to elucidate unresolved questions to improve knowledge concerning the lymphatic vessels roles in ocular fluid regulation, which could have repercussions in eye disease therapeutic strategies. ABSTRACT: Lymphatic vessels exert major effects on the maintenance of interstitial fluid homeostasis, immune cell trafficking, lipid absorption, tumor progression and metastasis. Recently, novel functional roles for the lymphatic vasculature have emerged, which can be associated with pathological situations. Among them, lymphatics have been proposed to participate in eye aqueous humor drainage, with potential consequences on intraocular pressure, a main risk factor for progression of glaucoma disease. In this review, after the description of eye fluid dynamics, we provide an update on the data concerning the distribution of ocular lymphatics. Particular attention is given to the results of investigations allowing the three dimensional visualization of the ocular surface vasculature, and to the molecular mechanisms that have been characterized to regulate ocular lymphatic vessel development. The studies concerning the potential role of lymphatics in aqueous humor outflow are reported and discussed. We also considered the novel studies mentioning the existence of an ocular glymphatic system which may have, in connection with lymphatics, important repercussions in retinal clearance and in diseases affecting the eye posterior segment. Some remaining unsolved questions and new directions to explore are proposed to improve the knowledge about both lymphatic and glymphatic system interactions with eye fluid homeostasis.