Loss of the retinal glycocalyx in diabetes - 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.
