Diabetic retinopathy, the leading cause of blindness in adults, is recognized as a microvascular complication of the disease, with retinal microvessels characterized by microaneurysms, leukocyte-endothelial cell adhesion, hemorrhages, increased permeability, capillary occlusion, neovascularization, etc. We propose that an underlying contributor to the retinal pathology is the loss of the endothelial surface layer (glycocalyx). The glycocalyx is a dense layer of molecules including proteoglycans (e.g., syndecan-1) and glycosaminoglycans (GAGs, e.g., heparan sulfate). The glycocalyx facilitates the interactions between plasma molecules and their endothelial receptors, inhibits thrombosis, shields against leukocyte-endothelial cell adhesion, transduces shear force, and acts as a permeability barrier. Inasmuch as heparan sulfate can be cleaved by heparanase, and syndecan-1 has multiple sites on its extracellular domain susceptible to cleavage by matrix metalloproteinases (MMPs), we hypothesize a role for these enzymes in the loss of the glycocalyx in diabetes. With a combined attack on both syndecan-1 and heparan sulfate, the functions of the glycocalyx could be substantially lost, which has been shown in many models to enhance leukocyte-endothelial cell adhesion. Such adhesion is thought to promote the occlusion of capillaries in the diabetic retina, leading to the subsequent development of ?acellular? capillaries that are no longer perfused, creating ischemic zones. Ultimately, the resulting hypoxia promotes uncontrolled angiogenesis that interferes with clear vision. When a leukocyte adheres to the endothelial surface, it can eventually be coerced back into the bloodstream by shear forces, or alternatively, cross the endothelium (emigrate) into the surrounding tissue in a mechanism mediated by platelet endothelial cell adhesion molecule-1 (PECAM-1). However, loss of PECAM-1 prevents leukocyte emigration, and adherent leukocytes can be trapped within capillaries causing continued occlusion and eventual capillary death. We and others have noted a loss of PECAM-1 from the diabetic retinal microcirculation, with this loss possibly caused by mechanisms such as MMP-mediated cleavage, cytokine- mediated decrease in production, and/or proteasomal degradation. The following specific aims address the overall hypothesis that diabetes induces the loss of key endothelial surface molecules that results in leukocyte adhesion, capillary occlusion, and eventual development of acellular capillaries: (1) Investigate the hypothesis that the loss of heparan sulfate from the diabetic retinal microcirculation is mediated directly by heparanase and indirectly by MMP-facilitated cleavage of syndecan-1, (2) Determine the mechanism(s) responsible for the loss of PECAM-1 from the diabetic retinal microcirculation, by testing for decreased expression, increased proteasomal degradation, and cleavage from the endothelial cell surface, and (3) Investigate the hypothesis that capillary occlusion by leukocytes and the development of acellular capillaries can be attenuated by protection of the endothelial surface layer.

Public Health Relevance

Individuals with diabetes are likely to develop vision problems during their lifetime, with diabetic retinopathy the leading cause of blindness in adults. Changes in the retinal microcirculation are responsible for much of the altered vision. In the proposed studies, we will investigate ways to protect the inner lining of the retinal blood vessels, as we believe that this lining (specifically, the coating called the ?glycocalyx?) is critical to the health of the blood vessels and retinal tissue.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY025632-05
Application #
9975163
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Shen, Grace L
Project Start
2016-08-01
Project End
2021-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Louisiana State University Hsc Shreveport
Department
Physiology
Type
Schools of Medicine
DUNS #
095439774
City
Shreveport
State
LA
Country
United States
Zip Code
71103
Leskova, Wendy; Pickett, Haley; Eshaq, Randa S et al. (2018) Effect of diabetes and hyaluronidase on the retinal endothelial glycocalyx in mice. Exp Eye Res 179:125-131
Eshaq, Randa S; Aldalati, Alaa M Z; Alexander, J Steven et al. (2017) Diabetic retinopathy: Breaking the barrier. Pathophysiology 24:229-241