Diabetic retinopathy (DR) is the leading cause of vision loss globally in the working, middle-aged adult population.¹ Nearly all patients with insulin-dependent diabetes develop vascular complications within 15 years of diagnosis, and approximately 34.6% of patients with diabetes exhibit some form of retinopathy.^1,2 Though the precise pathophysiologic mechanism of DR is not completely understood, it has long been associated with damage to the retinal vasculature and loss of pericytes specifically.^3,4

This patient with proliferative DR shows signs of severe vascular dysregulation.

High Demand 

The oxygen requirement for the retina is the highest of all tissues in the human body, exceeding even the brain. To accommodate this demand, the retina requires an extensive—and intact—vascular network to obtain the oxygen and nutrients necessary for adequate function. As such, the retina is supplied by two vascular systems: the central retinal artery nourishes the inner retinal layers, while the choroidal capillaries nourish the outer retinal layers.³ 

Damage from DR, observed at the microvascular level, is split into two categories: non-proliferative and proliferative. Early, or non-proliferative, DR manifests clinically as retinal microaneurysms or microhemorrhages. In later stages, proliferative DR appears as neovascular growth from existing retinal vessels.³ One of the earliest abnormalities in the diabetic retina, leading to these microvascular aneurysms and hemorrhages, is pericyte dropout.⁴

Surface Support  

Pericytes were first described in the 1870s by Eberth and Rouget and were initially named Rouget cells. They were later renamed “pericytes” because of their perivascular location relative to the endothelial cells. Pericytes are located on the surface of capillaries and function primarily to stabilize and support the blood vessels. They arise from neuroectodermal neural crest cells and have the highest density in the central nervous system.⁵ 

Identifying pericytes is often difficult because their cytoplasm may span several endothelial cells and exhibit different morphologies. As such, investigators have studied histological methods, revealing pericyte-specific markers that can aid with recognition. These include platelet-derived growth factor receptor β, NG2, CD13, desmin and vimentin.⁴ 

Pericytes in the retina are not readily observed on routine testing; they are approximately 7µm and extend distal processes that are even smaller, limiting the use of conventional imaging techniques. Experimental methods have included in vitro and post-mortem histological examinations. More recently, a study using adaptive optics scanning laser ophthalmoscopy showed success in visualizing the retinal cellular structure in vivo using mouse models.⁶ 

Pericytes in the adult retina work as regulators of gene expression to protect the retinal vessels from stress and injury.⁴ In healthy eyes, the endothelial cell-to-pericyte ratio is 1:1. In diabetic retinas, this ratio drops to 4:1. Prolonged hyperglycemia and genetic factors in diabetics lead to DR damage through several mechanisms, such as activation of protein kinase C, activation of the polyol pathway, non-enzymatic glycation, inflammation and oxidative stress. These events trigger pericyte death through apoptosis and dropout, leading to retinal microaneurysms, vessel tortuosity, hyperpermeability and capillary non-perfusion.^2,3 

Studies investigating pericytes in mice found that those with reduced numbers of pericytes experienced severe hemorrhage. Furthermore, mice with less than 52% of normal pericyte density developed signs of proliferative DR.⁵ Microaneurysm formation in DR is partially due to the over-proliferation of pericyte-deficient endothelial cells in response to vascular endothelial growth factor from hypoxia.²  

Research also suggests that pericyte loss from retinal capillary walls is responsible for the breakdown of the inner blood-retina barrier (BRB). While research shows that the tight junctions of the endothelial cells and the retinal pigmented epithelial cells make up the inner and outer BRB, many studies have concluded that reduced pericyte numbers also lead to increased permeability and BRB breakdown.⁵ 

Valuable and Vulnerable

Pericytes—small, specialized cells on the surface of capillaries—have a significant impact on vascular homeostasis. A better understanding of their prominent role in the pathogenesis of DR, and possibly other ocular diseases, can help spur the development of potential therapeutic targets to delay or treat this leading cause of vision loss.