OR WAIT null SECS
Insights into the pathophysiology of diabetic macular edema are providing a basis for therapeutic interventions.
This article was reviewed by Reiner O. Schlingemann, MD, PhD.
The circumstances that drive the development of DME include hypoxia from vascular damage. In addition, inflammation—which may be secondary to hypoxia, tissue damage, or protein extravasation—is important.
“Factors affecting the inner blood-retinal barrier, such as active hyperpermeability and possibly passive defects in the vascular wall involving lesions that are known as TelCaps, may also be important,” said Reiner O. Schlingemann, MD, PhD, professor of ophthalmology, Academic Medical Center, University of Amsterdam, The Netherlands.
The molecular factors involved in DME pathogenesis consist of both inflammatory mediators and compounds that are induced by hypoxia. The latter group includes VEGF-A, placental growth factor, angiopoietin-2, and vascular endothelial-protein tyrosine phosphatase (VE-PTP).
“All of these factors are now being studied as clinical targets for the treatment of DME,” Schlingemann said.
Knowledge of fluid and protein entry points is also important for understanding the pathophysiology of DME. Loss of the integrity of the inner blood-retinal barrier is an important factor in edema formation. Although it remains controversial, it has also been suggested that there is loss of the outer blood-retinal barrier secondary to dysfunction of the retinal pigment epithelium.
Furthermore, dysfunction of Mueller cells that regulate fluid homeostasis in the retina is thought to play a role in fluid accumulation, particularly within the Mueller cells themselves, Schlingemann said.
Discussing the breakdown of the inner blood-retinal barrier in DME, Schlingemann said that active transport of proteins through the transcellular pathway over the endothelial cells may be an important new target for therapeutic development. He explained that protein transport over the vascular wall is the main driver of differences in osmotic pressure that are important for edema formation. Transcellular transport of protein may also be an important driver of secondary inflammation.
In addition, knowledge that VEGF, angiopoietin-2, and inflammatory mediators cause breakdown of the blood-retinal barrier supports interventions aimed at these factors.
“It is important to know that in addition to their anti-inflammatory effects, corticosteroids have a direct effect in restoring the blood-retinal barrier,” Schlingemann said.
Angiopoietin-2 inhibition is already being explored as a target for treating DME. Schlingemann explained that under normal circumstances, the Tie-2 receptor that is located on endothelial cells is stimulated by angiopoietin-1, leading to activation of Tie-2 and stabilization of the vessel that decreases its permeability. In the settings of hypoxia and hyperglycemia, however, angiopoietin-2 is upregulated, and if anggiopoietin-2 binds to the Tie-2 receptor, the vessels become destabilized and prone to leakage.
In addition to angiopoietin-2 inhibition, inhibition of VE-PTP provides another strategy for DME treatment aimed at blood-retinal barrier restoration. This approach also targets the Tie-2-angiopoietin system and is based on knowledge that VE-PTP promotes vascular leakage by decreasing Tie-2 activation.
Evidence that proteins may also leak into the retina in a passive way through microvascular abnormalities known as TelCaps may explain anti-VEGF therapy resistance in some patients and provide a new target for therapeutic development. Schlingemann explained that these vascular microaneurysms, which are stained by indocyanine green (ICG), are usually associated with leakage of hard exudates. They respond well to laser treatment, but much less to anti-VEGF therapy.
The anatomical features of the TelCaps, which are thought to be described by the absence of endothelial cells and pericytes, fit well with their staining properties and support the idea that they have a role in edema formation.
“The staining with ICG may correspond to staining of the basal lamina of these large microaneurysms, and the passive leakage of proteins, such as lipoproteins, would be facilitated by the absence of endothelial cells and pericytes,” Schlingemann said. “This may cause VEGF-independent leakage through both the defective vascular wall and by secondary inflammation induced by the extravasated lipoproteins.”