Degeneration of Interpericyte Tunneling Nanotubes Can Occur in the Absence of Pericyte Loss in Diabetic Retina Disease

Purpose: Interpericyte tunneling nanotubes (IP-TNTs) synchronize pericyte-pericyte communication and regulate microvascular perfusion, processes disrupted in early diabetic retina disease (DRD). We conducted a comprehensive histological examination of IP-TNTs in the normal and diabetic retina using the streptozotocin (STZ)-induced rat model. Methods: High-resolution confocal microscopy was used to assess IP-TNT density, morphology, and their interactions with pericytes and retinal glia. Quantitative analysis was performed on vessel density, capillary diameter, pericyte distribution, and IP-TNT characteristics across three retinal vascular layers: superior vascular plexus (SVP), intermediate capillary plexus, and deep capillary plexus (DCP). Results: IP-TNTs were present across all retinal vascular plexuses, with the highest density in the SVP and DCP. Diabetic retinas exhibited a significant reduction in IP-TNT density, length, and morphological diversity, particularly in the DCP. The loss of IP-TNTs occurred independently of capillary loss and was associated with preserved vessel density and increased pericyte numbers. Notably, there was a shift in IP-TNT phenotype, with a significant increase in Type 1 (soma-to-soma) IP-TNTs in the DCP of diabetic rats. IP-TNTs were closely associated with retinal glial cells, including astrocytes and Müller cells, suggesting a role in neurovascular-glial interactions. Conclusion: Our findings indicate that IP-TNTs are critical components of the retinal microvascular network, and their early degeneration in diabetes may contribute to impaired microvascular autoregulation and pericyte dysfunction. The selective loss of IP-TNTs in the DCP highlights their potential as early biomarkers of diabetic microvascular injury. Modulating IP-TNT stability may represent a promising strategy for early intervention in diabetic retinopathy.