Premium
The microenvironment of proliferative diabetic retinopathy supports lymphatic neovascularization
Author(s) -
Gucciardo Erika,
Loukovaara Sirpa,
Korhonen Ani,
Repo Pauliina,
Martins Beatriz,
Vihinen Helena,
Jokitalo Eija,
Lehti Kaisa
Publication year - 2018
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5070
Subject(s) - pathology , lymphatic endothelium , ex vivo , lymphatic system , neovascularization , diabetic retinopathy , angiogenesis , endothelial stem cell , biology , endothelium , vascular endothelial growth factor , inflammation , vasculogenesis , medicine , in vivo , cancer research , immunology , diabetes mellitus , in vitro , endocrinology , biochemistry , microbiology and biotechnology , vegf receptors
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 analysed ex vivo and related to clinical data. As characterized by three‐dimensional 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 coexisted with inflammatory cell infiltration and unique vascular islet formation. Ex vivo ‐cultured explants retained multicellularity, islet patterning and capillary or fibrotic outgrowth in response to vitreoretinal factors. Strikingly, PDR neovascular tissues, whose matched vitreous samples enhanced lymphatic endothelial cell sprouting, contained lymphatic‐like capillaries in vivo and developed Prox1 + capillaries and sprouts with lymphatic endothelial ultrastructures ex vivo . Among multiple vitreal components, vascular endothelial growth factor C was one factor found at lymphatic endothelium‐activating concentrations. These results indicate that the ischaemia‐induced and inflammation‐induced human PDR microenvironment supports pathological neolymphovascularization, providing a new concept regarding PDR mechanisms and targeting options. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.