Pericytes, Nanotunnels, and Calcium Regulation in Neurovascular Mechanisms of Glaucoma

Article: Glaucoma: seeing the light at the end of the (nano)tunnel
Source: University of Montréal (Canada)
Published: February 7, 2022

Left: A network of retinal capillaries (green) and pericytes (red); arrowheads indicate interpericyte tunneling nanotubes. Middle: Close up of proximal pericyte and IP-TNT connecting to a distal pericyte process on a neighboring capillary. Right: Distruption of IP-TNT in ocular hypertension; arrowheads indicate disruption points.

Neurovascular deficits are a cause of some types of glaucoma, such as low- or normal-tension glaucoma. However, the underlying mechanism is poorly understood. Scientists in Canada are examining the role of retinal pericytes, cells that wrap around retinal capillaries to regulate the microcirculatory blood flow and to coordinate neurovascular coupling (the relationship between local neural activity and changes in subsequent cerebral blood flow) through interpericyte tunneling nanotubes (IP-TNTs), tiny structures that pericytes use to communicate with one another. In a mouse model of ocular hypertension (via microbead injection), the researchers observed that pericytes constrict capillaries in a calcium-dependent manner, decreasing blood supply and compromising neuronal function by causing retinal ganglion cell (RGC) death in the presence of glaucomatous stress. A key finding is that IP-TNTs are structurally and functionally damaged by ocular hypertension, resulting in disrupted light-evoked neurovascular responses. Finally, the study demonstrated how regulation of calcium influx could provide a therapeutic effect to rescue glautomatous retinas. Calcium entry into pericytes regulates their ability to constrict capillaries; however, in glaucomatous damage, there is excessive calcium influx, resulting in excessive capillary constriction and reduced blood flow. The authors report, "Pericyte-specific inhibition of excessive Ca²⁺ influx rescued hemodynamic responses, protected IP-TNTs and neurovascular coupling, and enhanced retinal neuronal function as well as survival in glaucomatous retinas." They conclude that the findings in this study provide a proof-of-concept for identifying pericytes and IP-TNTs as potential therapeutic targets in glaucoma and other neurovascular diseases.



Video 1 (left): A pericyte (red, arrow) constricting a retinal capillary (green), causing a red blood cell to stall (arrowhead) and interrupt blood flow in a mouse retina with glaucomatous damage.
Video 2 (right): Calcium response in a retinal ganglion cell is robust and decayed rapidly in normal capillary blood flow (first half of video). During pericyte-induced vessel constriction in glaucoma, calcium decay is delayed (second half of video) and signal amplitude reduced in the RGC.

My rating of this study: ⭐⭐⭐

Alarcon-Martinez L, Shiga Y, Villafranca-Baughman D, et al. "Pericyte dysfunction and loss of interpericyte tunneling nanotubes promote neurovascular deficits in glaucoma." PNAS.  119(7):e2110329119. 15 February 2022. https://doi.org/10.1073/pnas.2110329119