Retinal and choroidal capillaries contribution to age-related macular degeneration (AMD) phenotypes in murine models of the disease

ABSTRACT

Mouse models of age-related macular degeneration (AMD) such as Ccl2^−/- and Ccl2^−/-/Cx3cr1^−/- have not yet been fully characterized ultrastructurally. Although we have previously shown extranuclear DNA (enDNA) leakage into the cytoplasm and damaged mitochondria in the retinal pigment epithelium (RPE) of these AMD mouse models, little is known about the state of their vascular capillaries of the retina and choroid. Our ultrastructural survey shows that the aberrations were not restricted to the RPE cells, but also extended to the vasculature of the retina and choroid. Their endothelial aberrations included cytoplasmic degeneration, pyknotic DNA, hypertrophic nuclei, and loss of fenestration in addition to duplication of basement membrane and loss of density in Bruch’s membrane. Moreover, the state of the vasculature in the mutant mice models suggests that the capillaries could also be active contributors to the pathological findings seen in AMD. The goal of this study is to gain insights into the early events of AMD that may lead to a better understanding of AMD’s pathogenesis, improve our preventative measures, and formulate designed therapeutic regimens that are tailored to target the initial pathological events.

Abbreviations: AMD: age-related macular degeneration; BM: Bruch’s membrane; DPC: degenerate pericyte; EN: endothelial nucleus; enDNA: extranuclear DNA; GCL: ganglion cell layer; HEN: hypertrophic endothelial nucleus; IPL: inner plexiform layer; NFL: nerve fiber layer; OPL: outer plexiform layer; RBC: red blood cell; RPE: retinal pigment epithelium; SNPs: Single nucleotide polymorphisms.

KEYWORDS:

• Transgenic mice
• blood vessel
• capillaries
• choriocapillaris
• endothelial cell
• endothelial fenestration
• Bruch’s membrane
• retinal pigment epithelium (RPE)
• retina

Acknowledgments

The mouse model, CCl2^−/-/Cx3Cr1^−/- double knockout, was generated at Dr. Chi Chao Chan’s laboratory at the National Eye Institute, NIH, Bethesda, MD.(14) We are thankful to Ms. Heba Mohammed for her editorial assistance.

Declaration of Interest

The authors declare they have no conflicting financial interests.

Additional information

Funding

The research was supported by the intramural program of the National Eye Institute.