Photoreceptor degeneration and retinal inflammation induced by very low-density lipoprotein receptor deficiency

Abstract

Our previous studies have shown that very low-density lipoprotein receptor (VLDLR) is a negative regulator of the Wnt pathway. The present study showed that VLDLR gene knockout (Vldlr −/− ) mice displayed impaired cone ERG responses at early ages. Immunostaining of mid-wavelength cones showed significantly decreased cone densities in the retina and shortened cone outer segments in Vldlr −/− mice. At older ages, Vldlr −/− mice displayed declined rod ERG responses, decreased layers of photoreceptor nuclei, reduced rhodopsin levels and decreased levels of 11-cis retinal, the chromophore of visual pigments. As shown by fluorescein angiography and permeability assay, Vldlr −/− mice had severe retinal vascular leakage. ZO-1, a tight junction protein, was down-regulated in Vldlr −/− mouse retinae, further supporting the impaired blood-retinal barrier. Double staining of pericytes and endothelial cells in retinal sections revealed that neovasculature in Vldlr −/− mice lacks pericyte coverage, suggesting impaired maturation of retinal vasculature in Vldlr −/− mice. Staining of adherent leukocytes in the retinal vasculature revealed significant leukostasis in Vldlr −/− mice. Moreover, Vldlr −/− mice displayed up-regulated expression of multiple pro-inflammatory factors and activated NF-κB and HIF-1α, key regulators of inflammation. These findings suggest that deficiency of VLDLR leads to retinal degeneration and inflammation.

Abnormal vascularization in mouse retina with dysregulated retinal cholesterol homeostasis

“…In contrast, in Cyp27a1 -/-mice, NV seems to occur in both the retina and choroid. The retinal phenotype of Vldlr -/-mice is also more severe than that of Cyp27a1 -/-animals, with a greater incidence of RCA and FA leakage as well as photoreceptor degeneration and reduced ERG amplitudes (82)(83)(84). In Cyp27a1 -/-mice, focal photoreceptor degeneration occurred only in areas of RCA formation, and the retina otherwise retained a normal appearance and function (Supplemental Figure 3).…”

“…Focal retinal proliferation and progression is observed in retinas lacking VLDLR, while focal retinal proliferation with preexisting or simultaneous choroidal proliferation is probably seen in mice lacking CYP27A1 (Figure 1, B-D). The availability of Vldlr -/-mice allows the angiogenic sequences to be carefully studied and experimental treatments evaluated (84)(85)(86)(87)(88). Despite these advances, our opportunities to study focal retinal proliferation with preexisting or simultaneous choroidal proliferation are currently limited.…”

Spontaneous CNV in a Novel Mutant Mouse Is Associated With Early VEGF-A–Driven Angiogenesis and Late-Stage Focal Edema, Neural Cell Loss, and Dysfunction

“…The thickness of the ONL was measured at four uniformly distributed locations along a radius from the center of the optic nerve head to ora serrata. 13 …”

Ischaemia-induced retinal neovascularisation and diabetic retinopathy in mice with conditional knockout of hypoxia-inducible factor-1 in retinal Müller cells

“…The assay was performed as described previously [21]. Briefly, mice were perfused through the left ventricle to remove circulating leucocytes in blood vessels.…”