July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Role of Endothelial Cell Stiffening in Choriocapillaris Atrophy Associated with Dry AMD
Author Affiliations & Notes
  • Andrea Cabrera
    Bioengineering, University of California, Riverside, Riverside, California, United States
  • Jonathan Stoddard
    Oregon National Primate Research Center, Oregon Health Sciences University, Beaverton, Oregon, United States
  • Martha Neuringer
    Oregon National Primate Research Center, Oregon Health Sciences University, Beaverton, Oregon, United States
  • Trevor J McGill
    Oregon National Primate Research Center, Oregon Health Sciences University, Beaverton, Oregon, United States
  • Kaustabh Ghosh
    Bioengineering, University of California, Riverside, Riverside, California, United States
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 3474. doi:
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      Andrea Cabrera, Jonathan Stoddard, Martha Neuringer, Trevor J McGill, Kaustabh Ghosh; Role of Endothelial Cell Stiffening in Choriocapillaris Atrophy Associated with Dry AMD. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3474.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Age-related macular degeneration (AMD) is the leading cause of blindness in the aging population. Despite the prevalence of AMD, only 10-15% of those with advanced wet AMD benefit from current therapies. Thus, there is a need to develop early stage treatment. Recent studies have implicated choriocapillaris (CC) dropout in early AMD pathogenesis, potentially mediated by hypoxia-induced retinal pigment epithelium dysfunction. However, the precise mechanism underlying CC atrophy remains unknown. Complement activation, a risk factor for AMD, leads to membrane attack complex (MAC) deposition on the CC. Since MAC causes membrane pore formation, it likely results in choroidal endothelial cell (EC) lysis and CC atrophy. Interestingly, MAC also deposits on the CC of young normal eyes. Thus here we used a rhesus monkey model of dry AMD to explore the role of EC stiffening, a common phenomenon known to occur in aging vessels, in MAC-induced CC atrophy associated with dry AMD.

Methods : Stiffness of choroidal ECs isolated from eyes of young normal (6 yrs; YN), old normal (20 yrs; ON) and old rhesus monkeys with severe drusen (19 yrs; OD) was measured by atomic force microscopy (AFM). Susceptibility of these choroidal ECs to MAC-induced injury was assessed by treating cells with complement-competent serum, measuring C5b-9 deposition by flow cytometry, and quantification of cell-matrix adhesion strength and cell lysis. Since lysosomes promote repair of damaged cell membranes, immunofluorescence of lysosomal membrane protein LAMP1 was used to evaluate the extent of membrane repair following MAC injury.

Results : AFM measurements revealed that OD ECs are significantly stiffer than their YN counterparts, which correlated with their increased susceptibility to MAC injury. Further, when compared with YN ECs, OD cells undergo significantly greater detachment in response to complement attack. Surprisingly, the more susceptible OD ECs also exhibit a higher density of lysosomal vesicles, thus raising the possibility that increased stiffness of OD ECs impairs their ability to undergo lysosome-mediated membrane fusion repair.

Conclusions : Together, these findings implicate age-dependent EC stiffening as a key determinant of complement-mediated CC atrophy. Our ongoing work aimed at deciphering the underlying molecular mechanisms may lead to the identification of new therapeutic targets for dry AMD.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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