Interpericyte Tunneling Nanotubes Are Nonuniformly Distributed in the Human Macula

Purpose: Pericyte-to-pericyte communication via interpericyte tunneling nanotubes (IP-TNTs) is an important mechanism by which spatial and temporal precision in neurovascular coupling is achieved. This study quantifies the distribution and morphologic characteristics of IP-TNTs in the normal human macula. Methods: Ultra high-resolution, three-dimensional microscopic imaging of 11 perfusion-labeled normal human donor eyes was performed. Immunofluorescent markers for collagen IV, glial fibrillary acidic protein, nuclei, α-smooth muscle actin and phalloidin were used to distinguish IP-TNTs from perfused/nonperfused capillaries and glia processes. IP-TNT length, diameter and density in each capillary plexus was quantified and compared. Results: IP-TNTs were present in all capillary plexuses. IP-TNTs bridged capillary segments within and between capillary plexuses but did not connect capillaries to arterioles or venules. Mean length of IP-TNTs was 72.6 ± 39.5µm (range 14.0 to 202 µm) and mean diameter was 1.0 ± 0.42µm. IP-TNT length was non-normally distributed with a right-skewed distribution and 43% were 'short' (<55µm). Diameters were greater in the "long" (1.13 ± 0.44 µm) than "short" (0.82 ± 0.33 µm; P < 0.001) IP-TNTs. Density of IP-TNTs was greater in the superficial vascular plexus (3.80 ± 0.69 per 500 µm2) compared to the intermediate (1.85 ± 0.80 per 500 µm2; P < 0. 0001) and deep capillary plexus (1.58 ± 0.84 per 500 µm2; P < 0.0001). No significant difference in IP-TNT density was found between the four macula quadrants (P = 0.98). Conclusions: The distribution of IP-TNTs in the human macula is non-uniform and is associated with the compartmentalized nature of retinal energy consumption and microvascular perfusion. The nonuniform properties of IP-TNTs may predispose distinct vascular beds to injury in conditions such as diabetes.