Interpericyte tunnelling nanotube loss in very early diabetic retinal disease.

AIMS/HYPOTHESIS: Interpericyte tunnelling nanotubes (IP-TNTs) regulate microvascular blood flow by coordinating pericyte-pericyte communication across distant capillaries in the retina. Perfusion abnormalities are observed in preclinical diabetic retinopathy, and the state of IP-TNTs in this condition is unknown.

METHODS

Using high-resolution confocal microscopy with isolated perfusion labelling of human donor retina, we investigated changes to IP-TNTs, pericytes and capillaries in the macular vasculature of individuals with preclinical diabetic retinopathy (n=7) and control individuals (n=12).

RESULTS

We observed diffuse loss of IP-TNTs in the superficial vascular plexus (SVP), the intermediate capillary plexus (ICP) and the deep capillary plexus (DCP) as well as in the four quadrants of the macula in preclinical diabetic retinopathy. The mean ± SD numbers of IP-TNTs per 500 × 500 µm area were 2.5 ± 0.79 (diabetic) and 3.93 ± 0.82 (control) (p<0.0001) in the SVP; 1.40 ± 0.83 (diabetic) and 1.98 ± 0.88 (control) (p=0.012) in the ICP; and 1.11 ± 0.87 (diabetic) and 1.75 ± 0.99 (control) (p=0.011) in the DCP. Within the ICP and DCP, IP-TNT losses were identified despite an absence of pericyte density changes. In the SVP, IP-TNT losses were present despite an absence of capillary density change.

CONCLUSIONS/INTERPRETATION: These observations suggest that IP-TNT loss is a very early feature of diabetic retinopathy that can selectively precede alterations to pericytes and retinal capillaries. Given that IP-TNTs are intimately associated with pericytes, there is the potential that IP-TNT loss contributes to perfusion abnormalities and may be one of the major pathogenic factors in diabetic retinopathy. Future studies should confirm this exploratory work; the development of therapeutic agents designed to maintain IP-TNT structure and function may be an important factor for the preservation of retinal health.