Study examines how neurons build a 3D vascular structure to keep the retina healthy

While scientists have known for a long time that a lattice of blood vessels nourishes cells in the retina that allow us to see, just how this delicate structure is formed has remained a mystery.

A team of researchers at the University of California – San Francisco has discovered a new type of neuron that guides its formation. Their work was outlined in Cell, and could ultimately result in the development of new therapies for diseases related to impaired blood flow in the eyes and brain.¹

The study was supported by grants from the National Eye Institute and the Glaucoma Research Foundation.

Xin Duan, PhD, an associate professor of ophthalmology and senior author of the study, pointed out in the UCSF news release that it marked the first time anyone had seen retinal neurons using direct contact with blood vessels as a way of guiding them to form these precise 3D lattices.²

“This brings us closer to the possibility of repairing them when they’re damaged or rerouting them when they weren’t built right in the first place,” Duan said in the UCSF news release.

Protein senses the presence of nearby cells

According to the news release, the researchers worked with newborn mice, whose eyes still need several weeks to completely develop. Kenichi Toma, PhD, labeled the retinal neurons closest to the blood vessels with a protein that glows green when exposed to ultraviolet light so he could observe the lattice as it was forming.

The researchers then identified perivascular neurons, a subset of neurons which contact and then surround growing blood vessels, directing them to form the lattice. These perivascular neurons produce a protein called PIEZO2 that enables them to sense when they are touching another cell.¹

Perivascular neurons in mice that were unable to produce PIEZO2 could not maintain contact with blood vessels, and they grew in a tangled, disorganized way that disrupted blood flow.

Without a supply of oxygen, the surrounding nerve cells degraded, and the mutant mice were more vulnerable to stroke-like injuries.

Moreover, Duan discovered that these neurons lead the formation of a similar network of blood vessels in the cerebellum, a part of the brain that is involved in coordination, language, and sense perception.

“The fact that we see this same pattern repeated in the brain means that damage to this lattice might have a role in multiple neurodegenerative diseases,” Toma said in the news release.

The research team also worked with developmental biologist Arnold Kriegstein, MD, PhD, to confirm that perivascular retinal neurons also exist in humans.¹

How the lattice forms

To date, much of the work focusing on the link between the vascular and nervous systems has been limited by technology that only allows scientists to take two-dimensional pictures.

Duan and Toma reaped the benefits of a new technique, using multiphoton microscopy that was developed by Tyson Kim, MD, PhD, an assistant professor of ophthalmology, make 3D images of retinal blood networks without disturbing the eye.

Kim and Toma worked together to create revolving movies that captured the lattice from every angle and showed how it broke down in the absence of PIEZO2.

“We had been wanting to collaborate for some time, and this was the perfect opportunity,” Kim said in the UCSF news release. “It was really a confluence of what we’re each passionate about.”

Protecting neurons

The researchers noted in the news release their work ultimately could lead to new ways of treating neurodegenerative diseases by ensuring that neurons, which demand a lot of energy, maintain a healthy blood supply.²

“There are lots of people trying to understand the ways we can grow neurons,” Duan concluded in the UCSF news release. “But how in the world do we grow the intricate networks of blood vessels required to support them? That’s the question we’re trying to answer.”

References:

1. Xin Duan, Kenichi Toma, Mengya Zhao, Shaobo Zhang, Tyson N. Kim, Xin Ye. Perivascular neurons instruct 3D vascular lattice formation via neurovascular contact. Cell. Published May 10, 2024. Accessed May 30, 2024. DOI: https://doi.org.10.1016/j.cell.2024.04.010

2. How neurons build a 3-D vascular structure to keep the retina healthy. EurekAlert! Accessed May 30, 2024. https://www.eurekalert.org/news-releases/1045874