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Zhongxiao Wang, Yan Gong, Tara L Favazza, Lucy Evans, Katherine Tian, Peyton Morss, Thomas Fredrick, Nicholas Saba, James D Akula, Jing Chen; Small molecule activator of Wnt signaling protects retinal vasculature in a mouse model of FEVR disease. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3399.
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© ARVO (1962-2015); The Authors (2016-present)
Familial exudative vitreoretinopathy (FEVR) is a rare pediatric vascular eye disease characterized by incomplete retinal vessel development and persistent hyaloid vessels, associated with vision loss with no effective current treatments. Genetic mutations in FEVR occur in the Wnt signaling pathway including the receptors frizzled 4 (Fzd4), low-density lipoprotein receptor-related protein 5 (Lrp5) and the ligand Norrin. This study investigates if activating Wnt signaling downstream of the genetic receptor-level-defects may bypass the disease mutations and rescue abnormal retinal vasculature in Lrp5-/- mice modeling FEVR disease.
Retinal vasculature of Lrp5-/- and wild type (WT) control mice were analyzed with live fluorescent fundus imaging and vascular staining with isolectin in flat-mounted or cross-sectioned retinas at various days after birth. Visual function was analyzed with electroretinography at postnatal day (P) 30. Littermate Lrp5-/- mice were treated with a Wnt activator or vehicle control daily starting in the first week after birth, and eyes were assessed at P17 to analyze vascular morphology.
Lrp5-/- mice demonstrated persistent hyaloid vessels, delayed vascular growth and subsequent neovascularization in the superficial layer of retinal vessels. Lrp5-/- mice also lack deep layers of retinal capillary network, consistent with their significantly decreased visual function, including decreased photoreceptor sensitivity, and dampened inner retina visual function. Treatment with a Wnt activator ameliorated retinal vascular abnormalities in Lrp5-/- mice, with suppression of neovascularization in the superficial vessel layer and promotion of deep layer capillary development with enhanced endothelial tip cell and filopodia formation.
Lrp5-/- mice demonstrated defective retinal vasculature and decreased visual function. Treatment with a Wnt activator partially normalized the defective retinal vasculature in Lrp5-/- mice, suggesting a potential new approach for treating FEVR disorder through bypassing its genetic defects.
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