Norrin-induced activation of β-catenin-dependent signaling through the receptor frizzled4 in endothelial cells (ECs) is essential for establishing and maintaining blood-CNS barrier function. We sought to determine how this pathway is modulated under stress or disease conditions. Specifically, we investigated the role of p53 in endothelial blood-CNS barriers because increased abundance of the transcription factor p53 in ECs correlates with leaky CNS blood vessels in type 2 diabetes. Using transcriptomic, cell-based, and mouse genetic approaches, we identified interplay between p53 and its negative regulator MDM2 and norrin/frizzled4 signaling. Mice with an EC-specific ablation of Mdm2 showed decreased norrin/frizzled4 signaling, reduced EC proliferation and retinal angiogenesis, and disrupted blood-retina barrier function, all of which were largely restored by concurrent Trp53 deletion. Decreased norrin/frizzled4 signaling and inhibition of EC proliferation in response to p53 were associated with reduced expression of the condensin I complex component non-SMC condensin I complex subunit H (NCAPH). This study identifies a regulator of norrin/frizzled4 signaling and suggests that the clinical use of MDM2 inhibitors might impair the blood-CNS barrier. In addition, NCAPH may be a downstream effector of p53 in ECs and a candidate gene for familial exudative vitreoretinopathy (FEVR), which is caused by defects in norrin signaling.