Microenvironment of proliferative diabetic retinopathy supports lymphatic neovascularization

Abstract

Proliferative diabetic retinopathy (PDR) is a major diabetic microvascular complication characterized by pathological angiogenesis. Several retinopathy animal models have been developed to study the disease mechanisms and putative targets. However, knowledge on the human proliferative disease remains incomplete, relying on steady-state results from thin histological neovascular tissue sections and vitreous samples. New translational models are thus required to comprehensively understand the disease pathophysiology and develop improved therapeutic interventions. We describe here a clinically relevant model, whereby the native multicellular PDR landscape and neo(fibro)vascular processes can be analyzed ex vivo and related to clinical data. As characterized by 3D whole-mount immunofluorescence and electron microscopy, heterogeneity in patient-derived PDR neovascular tissues included discontinuous capillaries coupled with aberrantly differentiated, lymphatic-like, and tortuous endothelia. Spatially-confined apoptosis and proliferation co-existed with inflammatory cell infiltration and unique vascular islet formation. Ex vivo-cultured explants sustained multicellularity, islet patterning and capillary or fibrotic outgrowth in response to vitreoretinal factors. Strikingly, PDR neovascular tissues, whose matched vitreous enhanced lymphatic endothelial cell sprouting, contained lymphatic-like capillaries in vivo and developed Prox1⁺ capillaries and sprouts with lymphatic endothelial ultrastructures ex vivo. Among elaborate vitreal components, VEGFC was one factor found at lymphatic endothelium activating concentrations. These results indicate that the ischemia- and inflammation-induced human PDR microenvironment supports pathological neolymphvascularization, bringing a new concept to the PDR mechanisms and targeting options.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2pajgOR