How Neurons Build a 3-D Vascular Structure to Keep the Retina Healthy

Understanding how complex vascular networks form in the eye and brain could lead to new treatments for diseases such as diabetic retinopathy and stroke.

Scientists have known for years that a lattice of blood vessels nourishes the cells of the retina and allows us to see, but how this complex structure forms has been a mystery.

How Neurons Build a 3-D Vascular Structure to Keep the Retina Healthy

Now, researchers at the University of California, San Francisco have discovered a new type of neuron that controls the formation of this structure.

The discovery, described in the May 23, 2024 issue of Cell, could one day lead to new treatments for diseases related to impaired blood flow to the eye and brain.

"This is the first time we've observed how retinal neurons use direct contact with blood vessels to form such a precise 3D grid," said Dr. Xin Duan, associate professor of Ophthalmology and lead author of the study. "This brings us closer to being able to repair them if they're damaged or reroute them if they weren't built properly to begin with."

A protein that senses the presence of nearby cells

The researchers worked on newborn mice, whose eyes still needed a few weeks to fully develop. Dr. Kenichi Touma labeled the retinal neurons closest to the blood vessels with a protein that glows green under ultraviolet light, allowing them to watch as the grid formed.

The team then identified a subset of neurons called perivascular neurons, which contact and surround growing blood vessels, telling them to form a grid. These perivascular neurons produce a protein called PIEZO2 that allows them to sense when they are touching other cells.

The perivascular neurons in mice unable to produce PIEZO2 were unable to maintain contact with blood vessels and grew in a tangled, disorganized way, disrupting blood flow. The lack of oxygen caused surrounding nerve cells to degenerate, making the mice more susceptible to stroke-like damage.

Duan found that these neurons controlled the formation of a similar vascular network in the cerebellum, a part of the brain involved in coordination, language and sensory perception.

"The fact that we see this same pattern repeatedly in the brain means that damage to this grid may be involved in several neurodegenerative diseases," Thoma said.

The team worked with developmental biologist Arnold Kriegstein, M.D., Ph.D., to confirm that perivascular retinal neurons also exist in humans.

3D view shows how the grid forms

Most previous studies of the relationship between the vasculature and nervous systems have been limited by technology that only allowed scientists to obtain two-dimensional images.

But Duan and Toma benefited from a new technique using multiphoton microscopy developed by Tyson Kim, M.D., Ph.D., assistant professor of Ophthalmology, that allowed them to create 3D images of the retinal blood network without disturbing the eye.

Kim helped Toma capture the grid from every angle and create a rotating film that shows how the grid decays in the absence of PIEZO2.

"We've been wanting to work together for a while, and this was the perfect opportunity," Kim said. "It really was a combination of the things we're both passionate about."

A new way to protect neurons

The discovery could lead to new treatments for neurodegenerative diseases by ensuring that energy-intensive blood supply to neurons is maintained.

"A lot of people are trying to understand how we can grow neurons," Duan says. "But how on earth do we grow the complex vascular network needed to supply them with blood? That's the question we're trying to answer."

Authors: Other UCSF authors include Mengya Zhao, Shaobo Zhang, Fei Wang, Hannah K. Graham and Wenhao H. Shan, Nicole Y. Tsai, Guiyin Hong, Tyson N. Kim, and Arnold Kriegstein. Additional authors: Jun Zou and

Funding: This work was supported by grants from the National Eye Institute (F30EY033201, K08EY033030, and R01EY030138), NINDS (R35NS097305), and the Glaucoma Research Foundation.