A new study has uncovered the finer mechanisms behind damaged pericyte cells and the nanotube tunnels that provide communicative connections between them in glaucomatous eyes. This has raised hope toward developing potential therapeutics aimed specifically at addressing these microvascular deficits.
University of Montreal Hospital Research Centre’s Professor Adriana Di Polo led the study. Co-authored by lead postdoctoral research fellows Luis Alarcon-Martinez and Yukihiro Shiga, together they discovered how defective inter-pericyte tunneling nanotubes (IP-TNTs) lead to disruptions in neurovascular coupling as seen in glaucomatous eyes.1
Glaucoma is characterized by reduced blood flow and poor neurovascular connectivity. It has been long theorized that this lack of blood flow contributes to the degeneration of retinal ganglion cells (RGCs),2 the neurons that connect the retina to the brain, and as a result, enable the development of glaucoma.
However, the understanding of the finer workings of these microvascular deficits which contribute to vision loss at the molecular level has yet to be attained. Until now…
Gaining More Understanding
Pericyte cells regulate the flow of blood running through each capillary via a mechanism of contraction and relaxation wrapping around the capillary. This constriction and release of the capillaries is very much dependent on the level of calcium present in the pericytes.
Carrying signals of communication between these pericyte cells are the IP-TNTs, as the research team discovered in their recent study.3 The discovery of these nano-tubular processes has given researchers a better understanding of how blood is dispersed within retinal capillary networks while responding to neural activity.
Further, the researchers sought to understand the roles played by pericytes and IP-TNTs in the neurovascular coupling abnormalities found in glaucoma. The team used live microscopy imaging of mice retinas in a preclinical ocular hypertensive model (OHT) to recreate the conditions of open-angle glaucoma (OAG), the more common form of the disease. OAG is characterized by a gradual increase in intraocular pressure (IOP) and the accumulation of magnetic microbeads at the trabecular meshwork.
The results indicated several important key findings that shed light on the finer mechanisms behind the neurovascular dysfunction in glaucoma.
First, it demonstrated that higher IOP within pericytes negatively affected the pathology of microvascular damage in glaucoma, as they found capillary diameter reductions, decreased blood flow and defective neurovascular coupling.
Second, their findings suggest that in glaucoma, IP-TNTs’ structural and functional integrity, as well as their ability to serve as a conduit of signals between connected pericytes, were disrupted.
The Role of Calcium Equilibrium
Knowing that calcium plays a role in regulating the contraction and release mechanism of the pericyte cells,4 the researchers tested this and further found that an excess of calcium in the IP-TNT causes disruptions to normal microvascular flow. In essence, lowering calcium levels can restore IP-TNT balance, reinstating capillary functioning, blood flow and neurovascular coupling.
The results also demonstrated that restoring the equilibrium of calcium in pericytes led to the repair of cell functions, particularly its neural response to light, and this subsequently improved the survival of RGCs.
The findings challenge the conventional views of glaucoma pathology: That neuronal loss is more prominent than what happens at the vascular level. This deeper insight into vascular pathology at the early stages of glaucoma has caused the researchers to ponder if pericyte or capillary defects could cause neuronal dysfunction. The answer seemed to be a “yes.”
Another discovery from this study was that until recently, smooth muscle cells on arterioles were thought to be the only regulator of cerebral blood flow. Most research on vascular dysregulation in glaucoma patients has focused on abnormalities at the level of arterioles. 5, 6
The researchers suggested that the continuous damage to the neurovascular system caused at the pericyte level will impair the function of the RGCs in the long run.
These findings also point to the idea that the reduction in pericyte-induced blood flow, which obstructs oxygen and food supply to energetically demanding RGCs,7 causes dysfunction at the neuronal level — thus, making these neurons more vulnerable to the stresses related to IOP.
Overall, the significance of the discovery is in the continued survival of the RGCs when surplus calcium, which causes damage to the pericyte, is readjusted to a state of homeostasis.
The researchers earmarked pericytes as a target for potential therapeutics for glaucoma, perhaps offering a glimmer of hope at the end of the nanotube’s “tunnel” for the 80 million glaucoma patients worldwide.8 Furthermore, other neurodegenerative diseases involving vascular aspects could be similarly targeted as well.
- Alarcon-Martinez L, Shiga Y, Villafranca-Baughman D, et al. Pericyte dysfunction and loss of interpericyte tunneling nanotubes promote neurovascular deficits in glaucoma. Proc Natl Acad Sci U S A. 2022;119(7):e2110329119.
- Flammer J, Haefliger IO, Orgül S, Resink T. Vascular dysregulation: a principal risk factor for glaucomatous damage?. J Glaucoma. 1999;8(3):212-219.
- Alarcon-Martinez L, Villafranca-Baughman D, Quintero H, et al. Interpericyte tunnelling nanotubes regulate neurovascular coupling. Nature. 2020;585:91-95.
- Burdyga T, Borysova L. Ca2+ signalling in pericytes. Adv Exp Med Biol. 2018;1109:95–109.
- Wareham LK, Calkins DJ. The neurovascular unit in glaucomatous neurodegeneration. Front Cell Dev Biol. 2020;8:452.
- Newman A, Andrew N, Casson R. Review of the association between retinal microvascular characteristics and eye disease. Clin Exp Ophthalmol. 2018;46:531–552.
- Ito YA, Di Polo A. Mitochondrial dynamics, transport, and quality control: A bottleneck for retinal ganglion cell viability in optic neuropathies. Mitochondrion. 2017;36:186–192.
- Tham Y-C, Li X, Wong TY, et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: A systematic review and meta-analysis. Ophthalmology. 2014;121:2081–2090.