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Effect of Combined Antisense Oligonucleotides Against High-Glucose–and Diabetes-Induced Overexpression of Extracellular Matrix Components and Increased Vascular Permeability

¹ Departments of Medicine and Ophthalmology, Boston University School of Medicine, Boston, Massachusetts
² Department of Ophthalmology, Center for Sensory Organ Diseases, Sannoh Medical Center, Chiba, Japan
³ Department of Ophthalmology, National Yang-Ming University, Taipei, Taiwan
⁴ Eye Research Laboratory, Shin-Yahashiradai Hospital, Chiba, Japan

Address correspondence and reprint requests to Sayon Roy, Department of Medicine, Boston University School of Medicine, 715 Albany St., Boston, MA 02118. E-mail: sayon{at}bu.edu

Abbreviations: AS-oligo, antisense oligonucleotide; BRB, blood-retinal barrier; ECM, extracellular matrix; FITC, fluorescein isothiocyanate; Ran-oligo; random oligonucleotide; RMEC, rat microvascular endothelial cell; STZ, streptozotocin; VEGF, vascular endothelial growth factor

The effect of combined antisense oligonucleotides (AS-oligos) against overexpression of extracellular matrix (ECM) components, fibronectin, laminin, and collagen IV and on cell monolayer permeability was examined in rat microvascular endothelial cells (RMECs) grown in high glucose medium and on retinal vascular permeability in diabetic rats. RMECs grown in high glucose for 10 days and transfected with combined AS-oligos showed a significantly reduced fibronectin, laminin, and collagen IV protein level. In parallel studies, high-glucose–induced excess monolayer permeability was also reduced in RMECs transfected with the combined AS-oligos. Similarly, diabetic rats intravitreally injected with the combined AS-oligos and examined after 2 months of diabetes showed significant reduction in retinal fibronectin, laminin, and collagen IV expression. In addition, vascular permeability, as determined from extravasation of fluorescein isothiocyanate–BSA in the surrounding areas of the retinal capillaries, was partially reduced in the combined AS-oligos–treated diabetic retinas. Our results indicate that the combined AS-oligos strategy is effective in simultaneously reducing fibronectin, collagen IV, and laminin overexpression and reducing vascular leakage in the retinal capillaries of diabetic rat retinas. The findings suggest that abnormal synthesis of ECM components may contribute to vascular leakage in the diabetic retina.

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