Abstract
Vascular abnormalities in the eye are the leading cause of many forms of inherited and acquired human blindness. Loss-of-function mutations in the Wnt-binding co-receptor LRP5 leads to aberrant ocular vascularization and loss of vision in genetic disorders such as osteoporosis-pseudoglioma syndrome. The canonical Wnt-β-catenin pathway is known to regulate retinal vascular development. However, it is unclear what precise role LPR5 plays in this process. Here, we show that loss of LRP5 function in mice causes retinal hypovascularization during development as well as retinal neovascularization in adulthood with disorganized and leaky vessels. Using a highly specific Flk1-CreBreier line for vascular endothelial cells, together with several genetic models, we demonstrate that loss of endothelium-derived LRP5 recapitulates the retinal vascular defects in Lrp5-/- mice. In addition, restoring LRP5 function only in endothelial cells in Lrp5-/- mice rescues their retinal vascular abnormalities. Furthermore, we show that retinal vascularization is regulated by LRP5 in a dosage dependent manner and does not depend on LRP6. Our study provides the first direct evidence that endothelium-derived LRP5 is both necessary and sufficient to mediate its critical role in the development and maintenance of retinal vasculature.
Highlights
Vision impairment and blindness are devastating conditions afflicting over 4% of the world population [1]
In adult Lrp5-/- mice, retinal angiography with FITC-dextran perfusion showed that the intraretinal vessel layers in the inner plexiform layer (IPL) and outer plexiform layer (OPL) were mostly absent, with occasional incomplete vascular development in the IPL, and vessels penetrating from the nerve fiber layer (NFL) terminated in clusters without branching (Fig 1B and S1 Movie and S2 Movie)
Total retinal VEGF levels in Lrp5-/- mice were only slightly increased, about 1.3-fold, at P5 and P8 compared to controls, but were 6.6-fold higher in adults. This suggests that elevated retinal VEGF is likely a secondary response to the retinal hypovascularization defect in Lrp5-/mice during postnatal development and a contributor to endothelial fenestrations (EF) defects when it reaches a high level in adulthood
Summary
Vision impairment and blindness are devastating conditions afflicting over 4% of the world population [1]. Vascular abnormalities are the major cause of many forms of inherited and acquired human blindness, such as Osteoporosis-Pseudoglioma Syndrome (OPPG), Norrie Disease (ND), Familial Exudative Vitreoretinopathy (FEVR) and diabetic retinopathy (DR) [2,3]. Both aberrant vascular development and pathological neovascularization can critically impair the high metabolic activities in the retina. The retinal vasculature consists of three vessel beds located in the nerve fiber layer (NFL), inner plexiform layer (IPL) and outer plexiform layer (OPL). PLOS ONE | DOI:10.1371/journal.pone.0152833 March 31, 2016
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