Pericyte and Vascular Smooth Muscle Death in Diabetic Retinopathy Involves Autophagy

Tom A Gardiner,Alan W Stitt

doi:10.3390/ijtm2010003

Tom A Gardiner, Alan W Stitt

Open Access

https://doi.org/10.3390/ijtm2010003

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Abstract

Diabetic retinopathy (DR) is the most common complication of diabetes and a major cause of vision loss worldwide. The premature death of the microvascular mural cells represents both a pathological hallmark of vasodegeneration in DR and a basis for therapeutic intervention to halt progression to the sight-threatening stages. Recent studies suggest that retinal microvascular mural cells, classed as pericytes in the capillaries and vascular smooth muscle cells in the larger vessels (VSMC), may undergo autophagy-dependent cell death during DR. The present investigation was undertaken to assess electron microscopic evidence for involvement of autophagy in mediation of cell death in the mural cells of the retinal vasculature, in eyes from human diabetic donors and diabetic dogs. All specimens examined showed widespread evidence of autophagosomes in processes of viable pericytes and VSMCs, and the membranous remnants of excessive autophagic activity in their “ghost cell” remnants within the vascular walls. Autophagy was termed “excessive” when it occupied the greater part of the cytoplasm in mural cell processes. This was notable in specimens from short-term diabetic donors with no evidence of basement-membrane thickening or mural cell loss, in which regions of mural cell cytoplasm filled with autophagic bodies appeared to be undergoing cytoplasmic cleavage. No equivalent evidence of autophagy was detected in the adjacent endothelial cells of the retinal vessels. We conclude that increased autophagy in the retinal pericytes and VSMCs is linked to the diabetic milieu, and over time may also act as a trigger for mural cell loss and progressive vasodegeneration.

Highlights

Published: 19 January 2022Diabetic retinopathy (DR) is the most common complication of diabetes [1], and as the incidence of the disease continues to rise, represents an increasing challenge to healthcare systems around the world [2]
What constitutes type-2 or “autophagic cell death” was first defined “as a type of cell death that occurs without chromatin condensation, accompanied by massive autophagic vacuolization of the cytoplasm. These vacuoles, by definition, are two-membraned and contain degenerating cytoplasmic organelles or cytosol” [44]. As this definition was based on morphology, with transmission electron microscopy as the desirable modality [44], we considered a review of electron micrographs that focused on retinal vascular pathology but with no particular focus on autophagy, to represent a valid approach that would add to our current knowledge
PM oxygen deprivation was reflected by the ultrastructure of the pericytes in donor retina, this was more profound with increased granularity of the nuclear chromatin (Figure 1E,F), and a swollen cytoplasm containing distended organelles with the vacant, electronlucent appearance typical of early PM necrosis (Figure 1A,B,E,F)

Summary

Introduction

Published: 19 January 2022Diabetic retinopathy (DR) is the most common complication of diabetes [1], and as the incidence of the disease continues to rise, represents an increasing challenge to healthcare systems around the world [2]. The selective loss of microvascular pericytes was established as a histopathological hallmark of vasodegeneration in diabetic retinopathy over 70 years ago [3] and the concomitant loss of vascular smooth muscle cells (VSMCs) has been recognised [4]. Such loss of vascular mural cells is described as selective because the associated endothelial cells continue to survive for much longer, and the parent vessels remain perfused [4]. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations

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