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Moderate GSK-3β inhibition improves neovascular architecture, reduces vascular leakage, and reduces retinal hypoxia in a model of ischemic retinopathy

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Abstract

In ischemic retinopathies, unrelieved hypoxia induces the formation of architecturally abnormal, leaky blood vessels that damage retina and ultimately can cause blindness. Because these newly formed blood vessels are functionally defective, they fail to alleviate underlying hypoxia, resulting in more pathological neovascularization and more damage to retina. With an established model of ischemic retinopathy, we investigated inhibition of glycogen synthase kinase-3β (GSK-3β) as a means for improving the architecture and functionality of pathological blood vessels in retina. In vitro, hypoxia increased GSK-3β activity in retinal endothelial cells, reduced β-catenin, and correspondingly impaired integrity of cell/cell junctions. Conversely, GSK-3β inhibitors restored β-catenin, improved cell/cell junctions, and enhanced the formation of capillary cords in three-dimensional collagen matrix. In vivo, GSK-3β inhibitors, at appropriately moderate doses, strongly reduced abnormal vascular tufts, reduced abnormal vascular leakage, and improved vascular coverage and perfusion during the proliferative phase of ischemia-driven retinal neovascularization. Most importantly, these improvements in neovasculature were accompanied by marked reduction in retinal hypoxia, relative to controls. Thus, GSK-3β inhibitors offer a promising strategy for alleviating retinal hypoxia by correcting key vascular defects typically associated with ischemia-driven neovascularization.

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Acknowledgments

We thank the V. Kann Rasmussen Foundation for financial support. This work also was supported by NIH grants CA129339 and NS064498 (DRS), NIH grants EY017017 and EY017017-S (LEHS), The Roche Foundation for Anemia Research (LEHS), and a Research to Prevent Blindness Senior Investigator Award (LEHS).

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Authors and Affiliations

  1. Department of Pathology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Avenue, Boston, MA, 02215, USA

    Mien V. Hoang & Donald R. Senger

  2. Department of Ophthalmology, Children’s Hospital Boston and Harvard Medical School, Boston, MA, 02115, USA

    Lois E. H. Smith

Authors
  1. Mien V. Hoang
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  2. Lois E. H. Smith
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  3. Donald R. Senger
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Correspondence to Donald R. Senger.

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Hoang, M.V., Smith, L.E.H. & Senger, D.R. Moderate GSK-3β inhibition improves neovascular architecture, reduces vascular leakage, and reduces retinal hypoxia in a model of ischemic retinopathy. Angiogenesis 13, 269–277 (2010). https://doi.org/10.1007/s10456-010-9184-y

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