Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy.

TLDR

Accelerated endothelial cell death and renewal may drive vascular remodeling and eventual capillary obliteration. The study compared in situ retinal microvascular cell death between diabetic and nondiabetic subjects to elucidate vasoobliteration mechanisms. Retinal sections from diabetic and control patients were analyzed by TUNEL staining to detect apoptotic DNA fragmentation. Diabetic retinal microvessels showed markedly increased TUNEL+ pericytes and endothelial cells, whereas neural tissue was unaffected; similar accelerated vascular cell death appeared in experimental diabetes and galactosemia before histological retinopathy, demonstrating that hyperhexosemia specifically triggers early vascular cell loss.

Abstract

To reconstruct the mechanisms for the vasoobliteration that transforms diabetic retinopathy into an ischemic retinopathy, we compared the occurrence of cell death in situ in retinal microvessels of diabetic and nondiabetic individuals. Trypsin digests and sections prepared from the retinas of seven patients (age 67 +/- 7 yr) with .9 +/- 4 yr of diabetes and eight age- and sex-matched nondiabetic controls were studied with the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) reaction which detects preferentially apoptotic DNA fragmentation. The count of total TUNEL+ nuclei was significantly greater in the microvessels of diabetic (13 +/- 12 per one-sixth of retina) than control subjects (1.3 +/- 1.4, P = 0.0016), as were the counts of TUNEL+ pericytes and endothelial cells (P < 0.006). The neural retinas from both diabetic and nondiabetic subjects were uniformly TUNEL-. Retinal microvessels of rats with short duration of experimental diabetes or galactosemia and absent or minimal morphological changes of retinopathy, showed TUNEL+ pericytes and endothelial cells, which were absent in control rats. These findings indicate that (a) diabetes and galactosemia lead to accelerated death in situ of both retinal pericytes and endothelial cells; (b) the event is specific for vascular cells; (c) it precedes histological evidence of retinopathy; and (d) it can be induced by isolated hyperhexosemia. A cycle of accelerated death and renewal of endothelial cells may contribute to vascular architectural changes and, upon exhaustion of replicative life span, to capillary obliteration.