The Role of the Hypoxia Response in Shaping Retinal Vascular * Development in the Absence of Norrin/Frizzled4 Signaling

Abstract

In the absence of Norrin or Frizzled4, the vascular phenotype is determined by the primary defect in Norrin/Frizzled4 signaling (i.e., canonical Wnt signaling) and compensatory responses resulting from hypoxia. This work may be useful in guiding therapeutic strategies for the treatment of familial exudative vitreoretinopathy (FEVR).

Developmental regression of hyaloid vasculature is triggered by neurons

“…Interestingly, mice lacking Norrin show abundant up-regulation of VEGF in neurons, and blocking VEGF corrected the vascular defects in those mice (Xu et al, 2004;Wang et al, 2012;Rattner et al, 2014). Our present data fully support this scenario: persistent hyaloid vessels are ascribed to increased VEGF protein levels, occurring through either their overproduction or defective sequestration of VEGF by neurons.…”

“…Because increased VEGF production from retinal neurons is suggested to cause persistence of hyaloid vessels in Frizzled-4-deficient mice (Rattner et al, 2014), we measured the VEGF protein level in Vegfr2 Δneuro mice. Importantly, we found markedly increased VEGF protein levels in the vitreous cavity of Vegfr2 Δneuro mice (Fig.…”

Pharmacologic Activation of Wnt Signaling by Lithium Normalizes Retinal Vasculature in a Murine Model of Familial Exudative Vitreoretinopathy

“…In the absence of Wnt signaling in Lrp5 À/À retina, a compensatory VEGF elevation was observed, reflecting secondary hypoxia response in the lack of intralaminar vasculature, consistent with previous report of hypoxia-induced VEGF production in mice deficient of Norrin/Frizzled4 signaling. 62 Lithium treatment alleviated the VEGF induction in Lrp5 À/À retina, likely through partially improved deeper vascular layers, thereby resulting in suppressed pathologic glomeruloids at the vitreal surface of the retina.…”

Norrin restores blood-retinal barrier properties after vascular endothelial growth factor–induced permeability

“…Recent publications also suggest a role of norrin in hypoxia response. Norrin ablation decreases expression of the proangiogenic transcription factors such as Sox7, Sox17 and Sox18 (35), or VEGF-dependent expression of HIF (66), resulting in early specific loss of retinal ganglion cells (RGC) (67). Interestingly, in oxygen-induced retinopathy model, Wnt3a, Wnt7a and Wnt10a but not norrin are elevated (33), and norrin injection promotes revascularization of the hypoxic area in a mechanism dependent on IGF-1 expression (67-70), resulting in RGC survival (71).…”