Regressed lymphatic vessels develop during corneal repair

Abstract

The fate of newly synthesized lymphatic vessels induced by inflammation is poorly understood. To address this question, we designed experiments to determine the morphologic, phenotypic, and functional differences in regressing lymphatic vessels in the context of corneal recovery after an inflammatory response. A suture removal modification was used to induce corneal recovery after suture induced inflammation. We identified an increase in markers of corneal inflammation in sutured cornea that resolved in 14 days after suture removal. Sprouting newly synthesized lymphatic vessels trafficking MHC-II-positive leukocytes were visualized in sutured cornea. Following suture removal and recovery, the visualized lymphatic vessels were thin and fragmented, had bulbous termini, discontinuous expression of CD31 and VE-cadherin, and excluded MHC-II-positive leukocytes. VEGF-A, VEGF-C, and TGF-b mRNA levels were increased during corneal recovery, suggesting a complex interaction between lymphangiogenic factors and the mechanisms that regulate corneal recovery. The balance of lymphatic vessel growth and regression is likely to have a central role in the pathogenesis of corneal inflammatory diseases.

The Hepatic Lymphatic Vascular System: Structure, Function, Markers, and Lymphangiogenesis

“…The extent and duration of lymphangiogenesis are determined by balances between lymphangiogenic factors and antilymphangiogenic factors. 89, 90 …”

Expression of the lymphatic marker podoplanin (D2-40) in human fetal eyes

“…Its expression was also demonstrated in lymphatic vessels of the dura mater surrounding the optic nerve and in a nonvascular pattern in the arachnoid mater . Under inflammatory conditions, podoplanin has been described in the anterior orbital adipose tissue and in the cornea during wound healing and neovascularization (Fogt et al, 2004;Kelley et al, 2011;Regina et al, 2007).…”

Nerve Growth Factor Regulates Neurolymphatic Remodeling during Corneal Inflammation and Resolution

“…We and others have previously shown that sutures induce lymphangiogenesis from the corneal limbus and that suture removal stimulates wound recovery and lymphatic vessel regression [21]. Suture placement may transect or induce neuropraxia in a subset of corneal nerves.…”

“…During homeostasis, the corneal vasculature is limited to a peri-corneal limbal arcade. Angiogenesis and lymphangiogenesis from the limbus can be stimulated experimentally using suture-induced inflammation [21], [22]. In this work corneal sutures were used to induce initial inflammation; suture removal stimulated wound recovery; and replacement of corneal sutures induced recurrent inflammation.…”