Diabetes Metab J.  2013 Aug;37(4):217-224. 10.4093/dmj.2013.37.4.217.

Identification of Novel Drug Targets for the Treatment of Diabetic Retinopathy

• Uemura A

• KMID: 2174261
• DOI: http://doi.org/10.4093/dmj.2013.37.4.217

Abstract

Vision loss in diabetic retinopathy (DR) is attributable to retinal vascular disorders that result in macular edema and neoangiogenesis. In addition to laser photocoagulation therapy, intraocular injections of antivascular endothelial growth factor drugs have contributed to the treatment of these disease conditions. Nonetheless, the clinical feasibility of intraocular drug administration has raised an increasing demand to develop alternative drugs that can fundamentally ameliorate the retinal vascular dysfunctions in DR. For this purpose, experimental animal models that reproduce human DR would be of clinical benefit. Despite the unavailability of DR models in rats or mice, pharmacological and genetic manipulations without hyperglycemia have successfully recapitulated retinal edema and neoangiogenesis in postnatal mouse retinas, thereby enabling the understanding of the pathophysiology underlying DR. This article highlights the utility of experimental mouse models of retinal vascular abnormalities and discusses cellular and molecular mechanisms responsible for the onset and progression of DR. These approaches will lead to the identification of novel drug targets for the restoration of vascular integrity and regeneration of functional capillaries in DR.

Keyword

Angiopoietins; Diabetic macular edema; Diabetic retinopathy; Neoangiogenesis; PlexinD1; RhoJ; Sema3E

MeSH Terms

Angiopoietins
Animals
Capillaries
Diabetic Retinopathy
Endothelial Growth Factors
Humans
Hyperglycemia
Injections, Intraocular
Light Coagulation
Macular Edema
Mice
Models, Animal
Papilledema
Rats
Regeneration
Retina
Retinaldehyde
Vision, Ocular
Angiopoietins
Endothelial Growth Factors
Retinaldehyde

Figure

• 

  Fig. 1 Impairment of retinal vascular integrity by pericyte dropout. (A) Transverse images of macular areas illustrated by optical coherence tomography. Note the fluid accumulation in diabetic macular edema (DME). Images courtesy of Akio Oishi, Kyoto University, Japan. (B) Interactions between endothelial cells (ECs) and pericytes (PCs) in newly formed blood vessels. EC-derived platelet-derived growth factor (PDGF)-B promotes proliferation and migration of PDGF receptor β (PDGFRβ)-expressing PCs, whereas PC-derived Ang1 stabilizes integrity of Tie2-expressing ECs. Ang2 acts as a natural antagonist for Ang1 in an autocrine fashion. (C) Restoration of retinal vascular integrity by Ang1 supplementation in the absence of PCs. H&E, hematoxylin and eosin staining; PECAM-1, platelet-endothelial cell adhesion molecule-1. Adapted from Uemura et al. J Clin Invest 2002;110:1619-28, with permission from American Society for Clinical Investigation [17].

• 

  Fig. 2 Signaling cues and matrix scaffolds requisite for intraretinal angiogenesis. (A) High magnification of sprouting blood vessels in the postnatal mouse retina. Note the endothelial filopodia projections along the pre-existing astrocyte network. (B) Signaling cues regulating projections and retractions of endothelial filopodia. (C) Hypoxia-inducible response in retinal astrocytes during development. (D) Intracellular signaling cascades that regulate endothelial filopodia formation. (E) Selective suppression of extraretinal angiogenesis by intraocular Sema3E injections in the oxygen-induced retinopathy model. Note the exacerbation of retinal ischemia after the blockade of vascular endothelial growth factor (VEGF) signaling. EC, endothelial cell; VEGFR2, vascular endothelial growth factor receptor 2; PAK, p21-activated kinase; N-WASP, neural Wiskott-Aldrich syndrome protein. Adapted from Fukushima et al. J Clin Invest 2011;121:1974-85, with permission from American Society for Clinical Investigation [40].

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